WATANABE Tomohiro

Researcher Information

Research funding number

• 40444468

J-Global ID

• 201401067043016852

Research Interests

• 粘膜免疫学   消化器免疫学   消化器内科学   

Research Areas

• Life sciences / Gastroenterology
• Life sciences / Immunology
• Life sciences / Allergies and connective tissue disease
• Life sciences / Bacteriology
• Life sciences / Molecular biology

Academic & Professional Experience

• 2016/04 - Today  Kyoto UniversityGraduate School of Medicine非常勤講師
• 2016/04 - Today  Kindai UniversityFaculty of Medicine准教授
• 2011/04 - 2016/03  Kyoto UniversityGraduate School of Medicine
• 2007/04 - 2011/03  Kyoto UniversityGraduate School of Medicine
• 2006/10 - 2007/03  Kyoto UniversityHospital, Gastroenterology and Hepatology
• 2003/04 - 2006/09  米国国立衛生研究所粘膜免疫研究室 博士研究員
• 2002/04 - 2003/03  Kyoto UniversityGraduate School of Medicine
• 1995/06 - 1998/03  神戸市立中央市民病院消化器内科専攻医
• 1993/06 - 1995/05  神戸市立中央市民病院内科研修医

Education

• 1998 - 2002  京都大学大学院  医学研究科  内科系専攻
• 1987 - 1993  Kyoto University  Faculty of Medicine  Department of Medical Science

Published Papers

• Indigo naturalis as a promising novel treatment for type 2 autoimmune pancreatitis

  Ken Kamata; Masatoshi Kudo; Tomohiro Watanabe

  Pancreatology Elsevier BV 1424-3903 2024/03 [Refereed]
  
• Role of leucine-rich repeat kinase 2 in severe acute pancreatitis

  Yasuo Otsuka; Kosuke Minaga; Masatoshi Kudo; Tomohiro Watanabe

  Frontiers in Immunology Frontiers Media SA 15 2024/02 [Refereed]
   

  Introduction Intrapancreatic activation of trypsinogen caused by alcohol or high-fat intake and the subsequent autodigestion of the pancreas tissues by trypsin are indispensable events in the development of acute pancreatitis. In addition to this trypsin-centered paradigm, recent studies provide evidence that innate immune responses triggered by translocation of intestinal bacteria to the pancreas due to intestinal barrier dysfunction underlie the immunopathogenesis of acute pancreatitis. Although severe acute pancreatitis is often associated with pancreatic colonization by fungi, the molecular mechanisms linking fungus-induced immune responses to the development of severe acute pancreatitis are poorly understood. Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that mediates innate immune responses to fungi and bacteria. Mutations in Lrrk2 is a risk factor for Parkinson’s disease and Crohn’s disease, both of which are driven by innate immune responses to gut organisms. Discussion In this Minireview article, we discuss how activation of LRRK2 by the recognition of fungi induces severe acute pancreatitis.
• Maintenance steroid therapy is associated with decreased risk of malignancy and better prognosis of patients with autoimmune pancreatitis: A multicenter cohort study in Japan

  Tetsuya Takikawa; Kazuhiro Kikuta; Takanori Sano; Tsukasa Ikeura; Nao Fujimori; Takeji Umemura; Itaru Naitoh; Hiroshi Nakase; Hiroyuki Isayama; Atsushi Kanno; Ken Kamata; Yuzo Kodama; Dai Inoue; Akio Ido; Toshiharu Ueki; Hiroshi Seno; Hiroaki Yasuda; Eisuke Iwasaki; Takayoshi Nishino; Kensuke Kubota; Toshihiko Arizumi; Atsushi Tanaka; Kazushige Uchida; Ryotaro Matsumoto; Shin Hamada; Seiji Nakamura; Kazuichi Okazaki; Yoshifumi Takeyama; Atsushi Masamune; Shinji Nakayama; Akira Nakamura; Yoshiharu Masaki; Mako Ushio; Tomohiro Watanabe; Masahiro Tsujimae; Shiro Tanoue; Toru Maruo; Masahiro Shiokawa; Satoki Yamane; Atsuto Kayashima

  Pancreatology Elsevier BV 1424-3903 2024/01 [Refereed]
  
• Recurrent skin rash, epigastralgia, and arthralgia following SARS-CoV-2 mRNA immunization and breakthrough infection

  Kohei Katsube; Tomoyuki Nagai; Tomohiro Watanabe

  Gastroenterology Elsevier BV 0016-5085 2024/01 [Refereed]
  
• Crosstalk between NOD2 and TLR2 suppresses the development of TLR2-mediated experimental colitis

  Natsuki Okai; Yasuhiro Masuta; Yasuo Otsuka; Akane Hara; Sho Masaki; Ken Kamata; Kosuke Minaga; Hajime Honjo; Masatoshi Kudo; Tomohiro Watanabe

  Journal of Clinical Biochemistry and Nutrition The Society for Free Radical Research Japan 0912-0009 2023/12 [Refereed]
  
• Reciprocal regulation of protein arginine deiminase 2 and 4 expression in the colonic mucosa of ulcerative colitis

  Yasuo Otsuka; Yasuhiro Masuta; Kosuke Minaga; Natsuki Okai; Akane Hara; Ryutaro Takada; Sho Masaki; Ken Kamata; Hajime Honjo; Kouhei Yamashita; Masatoshi Kudo; Tomohiro Watanabe

  Journal of Clinical Biochemistry and Nutrition The Society for Free Radical Research Japan 0912-0009 2023/12 [Refereed]
  
• An Unusual Cause of Severe Wall Thickening and Stenosis of the Sigmoid Colon Accompanied by Polyposis

  Sho Masaki; Hajime Honjo; Tomohiro Watanabe

  Gastroenterology Elsevier BV 0016-5085 2023/12 [Refereed]
  
• Visualization of Gastrointestinal Bezoar Movement Causing and Releasing Small Bowel Obstruction on Computed Tomography in a Patient With Diabetes Mellitus

  Hironobu Sugimori; Sho Masaki; Hajime Honjo; Masatoshi Kudo; Tomohiro Watanabe

  Cureus Springer Science and Business Media LLC 2168-8184 2023/11 [Refereed]
  
• Leucine-rich repeat kinase 2 promotes the development of experimental severe acute pancreatitis

  Yasuo Otsuka; Akane Hara; Kosuke Minaga; Ikue Sekai; Masayuki Kurimoto; Yasuhiro Masuta; Ryutaro Takada; Tomoe Yoshikawa; Ken Kamata; Masatoshi Kudo; Tomohiro Watanabe

  Clinical and Experimental Immunology Oxford University Press (OUP) 0009-9104 2023/10 [Refereed]
   

  Abstract Translocation of gut bacteria into the pancreas promotes the development of severe acute pancreatitis (SAP). Recent clinical studies have also highlighted the association between fungal infections and SAP. The sensing of gut bacteria by pattern recognition receptors promotes the development of SAP via the production of proinflammatory cytokines; however, the mechanism by which gut fungi mediate SAP remains largely unknown. Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that regulates innate immunity against fungi via Dectin-1 activation. Here, we investigated the role of LRRK2 in SAP development and observed that administration of LRRK2 inhibitors attenuated SAP development. The degree of SAP was greater in Lrrk2 transgenic (Tg) mice than in control mice and was accompanied by an increased production of nuclear factor-kappaB-dependent proinflammatory cytokines. Ablation of the fungal mycobiome by anti-fungal drugs inhibited SAP development in Lrrk2 Tg mice, whereas the degree of SAP was comparable in Lrrk2 Tg mice with or without gut sterilization by a broad range of antibiotics. Pancreatic mononuclear cells from Lrrk2 Tg mice produced large amounts of IL-6 and TNF-α upon stimulation with Dectin-1 ligands, and inhibition of the Dectin-1 pathway by a spleen tyrosine kinase inhibitor protected Lrrk2 Tg mice from SAP. These data indicate that LRRK2 activation is involved in the development of SAP through proinflammatory cytokine responses upon fungal exposure.
• Low‐dose gemcitabine plus nab‐paclitaxel versus standard‐dose gemcitabine plus nab‐paclitaxel in elderly patients with metastatic pancreatic cancer: A randomized Phase II trial

  Ken Kamata; Hajime Imai; Hisakazu Matsumoto; Yukitaka Yamashita; Takao Kato; Katsuhisa Nishi; Shunsuke Omoto; Kosuke Minaga; Kentaro Yamao; Tomoko Hyodo; Sung‐Woon Im; Akane Hara; Tomoe Yoshikawa; Rei Ishikawa; Ayana Okamoto; Tomohiro Yamazaki; Atsushi Nakai; Kazuomi Ueshima; Yasutaka Chiba; Mamoru Takenaka; Tomohiro Watanabe; Masayuki Kitano; Masatoshi Kudo

  JGH Open Wiley 2397-9070 2023/09 [Refereed]
   

  Abstract Background and Aim A multicenter, open‐label randomized Phase II trial was conducted to determine whether low‐dose gemcitabine plus nab‐paclitaxel (GnP) could improve tolerability and show equivalent efficacy to the standard‐dose GnP for elderly patients with metastatic pancreatic cancer. Methods Consecutive patients aged ≥65 years with metastatic pancreatic cancer who presented at one of four Japanese referral centers between November 2016 and January 2021 were enrolled. The 60 patients were randomly assigned to low‐ or standard‐dose groups with a 1:1 ratio. Patients in the low‐dose GnP group received gemcitabine at a dose of 250 mg/m² and nab‐paclitaxel at 125 mg/m². Results Low‐dose GnP significantly decreased the rate of cases requiring dose reduction (16.7% vs 63.3%). The response rate (36.7% vs 33.3%) and progression‐free survival (7.3 vs 8 months) were comparable between the low‐ and standard‐dose groups as determined by independent review. The difference in the median overall survival between the two groups was not significant (7.9 vs 12 months). The proportion of patients with hematologic and non‐hematologic treatment‐related adverse events was comparable between the two groups. Conclusion Low‐dose GnP had an equivalent efficacy to conventional therapy; however, it did not reduce adverse events.
• 【膵臓がん研究の最前線】腸内細菌と膵がん

  三長 孝輔; 渡邉 智裕

  BIO Clinica (株)北隆館 38 (10) 829 - 833 0919-8237 2023/09 

  膵がんは最も致死率の高い消化器癌であり,早期診断のためのバイオマーカーや治療標的の同定が喫緊の課題である。近年,腸内細菌や真菌をはじめとする微生物叢の均衡の乱れ,いわゆる"dysbiosis"が,膵がんの発がんや進展に深く関与することが明らかとなってきており,腸内微生物が腫瘍進展に関わる分子メカニズムも少しずつ解明されてきている。さらに,腸内微生物は化学療法の治療効果や生命予後の予測にも利用できる可能性が示唆されており,治療標的として有望な可能性がある。今後の腸内微生物叢を標的とした膵がんの病態解明が期待される。(著者抄録)
• 最先端医履の今 高脂肪食による肥満は自己免疫性膵炎の危険因子である

  三長 孝輔; 瀬海 郁衣; 渡邉 智裕

  Medical Science Digest (株)ニュー・サイエンス社 49 (10) 556 - 557 1347-4340 2023/09 

  自己免疫性膵炎はIgG4関連疾患の膵表現型であり,中高年男性に好発するが,この謎は解明されていない。われわれは中高年男性が好む高脂肪食の摂取が自己免疫性膵炎の発症に及ぼす効果を疾患モデルマウスで検討した。高脂肪食の摂取により肥満化したマウスの膵臓では形質細胞様樹状細胞が活性化され,I型IFNの産生を促進することにより自己免疫性膵炎を悪化させることを見出した。この結果は生活習慣が疾患の予防と治療につながる可能性を示している。(著者抄録)
• Cytokine and Chemokine Profiles in Ulcerative Colitis Relapse after Coronavirus Disease 2019 Vaccination

  Yasuhiro Masuta; Kosuke Minaga; Yasuo Otsuka; Natsuki Okai; Akane Hara; Sho Masaki; Tomoyuki Nagai; Hajime Honjo; Masatoshi Kudo; Tomohiro Watanabe

  Journal of Clinical Biochemistry and Nutrition The Society for Free Radical Research Japan 0912-0009 2023/09 [Refereed]
  
• Circumferential Stenosis of the Second Part of the Duodenum Caused by Eosinophilic Gastroenteritis

  Hajime Honjo; Kosuke Minaga; Akane Hara; Ryutaro Takada; Yasuo Otsuka; Yasuhiro Masuta; Sho Masaki; Shigenaga Matsui; Masatoshi Kudo; Tomohiro Watanabe

  Internal Medicine Japanese Society of Internal Medicine 0918-2918 2023/09 [Refereed]
  
• Impact of Smad4 and p53 mutations on the prognosis of patients with pancreatic ductal adenocarcinoma undergoing chemotherapy.

  Ken Kamata; Mamoru Takenaka; Naoshi Nishida; Akane Hara; Yasuo Otsuka; Hidekazu Tanaka; Shunsuke Omoto; Kosuke Minaga; Kentaro Yamao; Yasutaka Chiba; Kazuko Sakai; Kazuto Nishio; Tomohiro Watanabe; Masatoshi Kudo

  International journal of clinical oncology 28 (11) 1511 - 1519 2023/08 

  BACKGROUND: This prospective cohort study evaluated the feasibility of using endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) samples for comprehensive mutational analysis of cancer-related genes using microtissues. METHODS: Fifty patients with suspected pancreatic cancer presenting consecutively at the Kindai University Hospital between January 2018 and January 2019 were enrolled. Cancerous tissues from EUS-FNB were obtained from each tumor and subjected to histological examination and mutational analysis. The primary endpoint was the collection rate of EUS-FNB specimens suitable for comprehensive cancer panels using deep sequencing. Clinical history and genetic variations between the disease control and progressive disease groups of patients on chemotherapy were evaluated as secondary endpoints. RESULTS: The collection rate of EUS-FNB specimens suitable for comprehensive cancer panels using deep sequencing was 93.6%. The cancer panel was sequenced for 25 patients with pancreatic cancer treated initially with systemic chemotherapy. Mutation in p53 and Smad4 were positively and negatively associated, respectively, with disease control at the initial evaluation. The median time to progression in 15 patients with p53 and without Smad4 mutations was 182.0 days; whereas, it was 92.5 days in other 10 patients; this difference was significant (p = 0.020). CONCLUSIONS: Tissue samples from EUS-FNB were suitable for mutational analysis. Pancreatic cancers with p53 and without Smad4 mutations responded better to chemotherapy and had a better prognosis than those others.
• 【常在微生物叢の異常から自己免疫疾患を読み解く】自己免疫性膵炎/IgG4関連疾患の発症に腸内細菌の乱れが関与する

  三長 孝輔; 渡邉 智裕

  Microbiome Science (株)先端医学社 2 (3) 159 - 165 2758-2094 2023/07 

  IgG4関連疾患は,全身性・局所性のIgG4産生反応の亢進と多臓器病変を特徴とする自己免疫疾患であり,自己免疫性膵炎はIgG4関連疾患の膵病変である.自己免疫性膵炎/IgG4関連疾患の病態は十分解明されていないが,われわれは自然免疫に着目し,形質細胞様樹状細胞(pDC)の活性化とpDCが産生するI型IFN・IL-33が病態形成に深く関与することを見出した.この自然免疫経路の活性化には腸内細菌叢の乱れが関与しており,動物モデルを用いた研究により,腸管バリア機能の破綻が腸内細菌叢の均衡を乱し,病原性細菌が腸管から膵臓へ移行することで自己免疫性膵炎を起こすことを明らかにした.本稿では,自己免疫性膵炎/IgG4関連疾患と腸内細菌のかかわりについて概説する.(著者抄録)
• Regulation of type I IFN responses by deubiquitinating enzyme A in inflammatory bowel diseases

  Yasuhiro Masuta; Yasuo Otsuka; Kosuke Minaga; Hajime Honjo; Masatoshi Kudo; Tomohiro Watanabe

  Journal of Clinical Biochemistry and Nutrition The Society for Free Radical Research Japan 0912-0009 2023/07 [Refereed]
  
• Oral administration of ovalbumin protects mice from concanavalin A-induced hepatitis through suppression of interferon-gamma responses

  Tomohiro Watanabe; Kosuke Minaga; Hajime Honjo; Masatoshi Kudo

  Biochemical and Biophysical Research Communications Elsevier BV 0006-291X 2023/06 [Refereed]
  
• Activation of the aryl hydrocarbon receptor inhibits the development of experimental autoimmune pancreatitis through IL-22-mediated signaling pathways

  Ken Kamata; Akane Hara; Kosuke Minaga; Tomoe Yoshikawa; Masayuki Kurimoto; Ikue Sekai; Natsuki Okai; Naoya Omaru; Yasuhiro Masuta; Yasuo Otsuka; Ryutaro Takada; Shiki Takamura; Masatoshi Kudo; Warren Strober; Tomohiro Watanabe

  Clinical and Experimental Immunology Oxford University Press (OUP) 0009-9104 2023/05 [Refereed]
   

  Abstract The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor expressed in hematopoietic and non-hematopoietic cells. Activation of the AhR by xenobiotics, microbial metabolites, and natural substances induces immunoregulatory responses. Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory disorder of the pancreas driven by autoimmunity. Although AhR activation generally suppresses pathogenic autoimmune responses, the roles played by the AhR in AIP have been poorly defined. In this study, we examined how AhR activation affected the development of experimental AIP caused by the activation of plasmacytoid dendritic cells producing IFN-α and IL-33. Experimental AIP was induced in MRL/MpJ mice by repeated injections of polyinosinic-polycytidylic acid. Activation of the AhR by indole-3-pyruvic acid and indigo naturalis, which were supplemented in the diet, inhibited the development of experimental AIP, and these effects were independent of the activation of plasmacytoid dendritic cells producing IFN-α and IL-33. Interaction of indole-3-pyruvic acid and indigo naturalis with AhRs robustly augmented the production of IL-22 by pancreatic islet α cells. The blockade of IL-22 signaling pathways completely canceled the beneficial effects of AhR ligands on experimental AIP. Serum IL-22 concentrations were elevated in patients with type 1 AIP after the induction of remission with prednisolone. These data suggest that AhR activation suppresses chronic fibroinflammatory reactions that characterize AIP via IL-22 produced by pancreatic islet α cells.
• Analyses of cytokine gene expression and fecal microbiota in a patient with Cronkhite‐Canada syndrome successfully treated with prednisolone

  Hajime Honjo; Yasuhiro Masuta; Yasuo Otsuka; Sho Masaki; Kosuke Minaga; Masatoshi Kudo; Tomohiro Watanabe

  DEN Open Wiley 4 (1) 2692-4609 2023/05 [Refereed]
  
• 【マイクロバイオームが切り拓く肝胆膵の新未来】膵疾患 マイクロバイオームと自己免疫性膵炎

  三長 孝輔; 吉川 智恵; 原 茜; 瀬海 郁衣; 栗本 真之; 大塚 康生; 益田 康弘; 鎌田 研; 工藤 正俊; 渡邉 智裕

  肝胆膵 (株)アークメディア 86 (3) 377 - 385 0389-4991 2023/03
• 【胆膵疾患と腸内細菌の現状と展望】膵臓 腸内細菌の慢性膵炎・自己免疫性膵炎発生における役割

  三長 孝輔; 原 茜; 瀬海 郁衣; 栗本 真之; 大塚 康生; 益田 康弘; 吉川 智恵; 鎌田 研; 工藤 正俊; 渡邉 智裕

  胆と膵 医学図書出版(株) 44 (3) 235 - 241 0388-9408 2023/03 

  膵臓に慢性炎症性変化をきたす疾患は慢性膵炎と自己免疫性膵炎に大別される。これらの慢性炎症性膵疾患の病態生理は十分に解明されておらず,病態生理の理解に基づいた根治療法は開発されていない。近年,膵臓の慢性炎症性疾患である慢性膵炎と自己免疫性膵炎の病態形成における腸内細菌の関与を示唆する報告が相次ぎ,注目を浴びている。われわれは主に自然免疫反応の観点から,これらの慢性炎症性膵疾患の病態生理の解明に取り組む過程で,それぞれの病態形成に炎症性サイトカインであるI型IFN・IL-33が重要な役割を果たしていることを見出した。さらに,これらのサイトカインの産生には腸内細菌が深く関与しており,病的な膵臓・腸管間免疫ネットワーク機構が膵臓の慢性炎症や線維化に関与していることを明らかにした。腸内細菌は,根治療法が存在しない慢性膵炎および自己免疫性膵炎の新たな治療標的として有望である可能性があり,今後の研究が期待される。(著者抄録)
• An Overlooked Cause of Multiple Liver Nodules Exhibiting the Bull’s-Eye Sign

  Yasuo Otsuka; Kosuke Minaga; Tomohiro Watanabe

  Gastroenterology Elsevier BV 0016-5085 2023/02 [Refereed]
  
• Reducing relapse through maintenance steroid treatment can decrease the cancer risk in patients with IgG4‐sclerosing cholangitis: Based on a Japanese nationwide study

  Kensuke Kubota; Terumi Kamisawa; Takahiro Nakazawa; Atsushi Tanaka; Itaru Naitoh; Yusuke Kurita; Hajime Takikawa; Michiaki Unno; Shigeyuki Kawa; Atsushi Masamune; Seiji Nakamura; Kazuichi Okazaki; Keisuke Furumatsu; Shigeaki Sawai; Takuma Goto; Toshikatsu Okumura; Daisuke Suzuki; Masayuki Otsuka; Ikuhiro Kobori; Masaya Tamano; Mitsuhito Koizumi; Yoichi Hiasa; Naoto Kawabe; Yoshiki Hirooka; Satoshi Yamamoto; Yukio Asano; Kazuo Inui; Akihiko Horiguchi; Hiroyuki Watanabe; Daishu Toya; Katsuko Hatayama; Toshiharu Ueki; Norikatsu Kinoshita; Mitsuru Sugimoto; Hiromasa Ohira; Tsuyoshi Mukai; Eiichi Tomita; Keisuke Iwata; Shogo Shimizu; Jun Suetsugu; Masahito Shimizu; Keiji Tsuji; Ryoko Ishida; Masanori Ito; Ryutaro Furukawa; Naoya Sakamoto; Masahiro Araki; Satoshi Tanno; Yasunari Sakamoto; Tetsuhide Ito; Satoshi Takai; Shinichi Ikeya; Takanori Yamada; Norihiko Kudara; Akinori Shimizu; Keiji Hanada; Yasunori Ichiki; Hideki Kitada; Michio Hifumi; Hiroyuki Kimura; Masayuki Kurosaki; Namiki Izumi; Hajime Sumi; Jun‐ichi Haruta; Katsumi Hayashi; Ryo Harada; Masafumi Inoue; Shinichiro Nakamura; Tetsuya Ito; Ko Tomishima; Hiroyuki Isayama; Kyoko Oura; Tsutomu Masaki; Naoto Shimokawahara; Shirou Tanoue; Kousei Maemura; Akio Ido; Ichiro Mizushima; Mitsuhiro Kawano; Katsunori Yoshida; Makoto Naganuma; Miki Murata; Akiyoshi Nishio; Yuji Fujita; Takuma Teratani; Shohei Matsubara; Hironao Tamai; Yuu Yoshida; Ryousaku Azemoto; Ken Kamata; Tomohiro Watanabe; Takahiro Kurosu; Wasaburou Koizumi; Jun Fujita; Hideyuki Seki; Yasuhiro Ueda; Takumi Fukumoto; Takuhiro Kousaki; Kazushige Uchida; Toshimasa Ochiai; Takeshi Kawasaki; Motohiko Tanaka; Etsuji Ishida; Kenji Notohara; Hideaki Mori; Toshiyuki Mori; Hideaki Kawabata; Masatoshi Miyata; Junichi Sakagami; Yoshito Itoh; Masahiro Shiokawa; Hiroshi Seno; Noriko Watanabe; Hiromi Kataoka; Toshinori Aoki; Mitsuhiro Fujishiro; Toru Niihara; Hiroto Nishimata; Akira Mitoro; Hitoshi Yoshiji; Motoyuki Yoshida; Masafumi Ikeda; Kengo Tomita; Ryota Hokari; Kenji Hayasaka; Yuji Amano; Kazuhiko Shioji; Kazunao Hayashi; Shuji Terai; Michiko Nakajima; Junya Yamahana; Ryusuke Matsumoto; Hideaki Kikuchi; Akira Kanamori; Seiki Kiriyama; Shinichi Iwatsu; Yuji Kato; Shigeru Horiguchi; Takahito Yagi; Hiroyuki Okada; Kazuyoshi Ohkawa; Motohiro Hirao; Naoki Hiramatsu; Noriko Oza; Haruo Imamura; Takeshi Baba; Shigeru Nakano; Tetsuya Shinobi; Shomei Ryozawa; Masayo Motoya; Hiroshi Nakase; Noboru Kinoshita; Kei Ito; Tatsuya Miyake; Naruaki Kohge; Hiroshi Tobita; Satoru Joshita; Takeji Umemura; Shinya Kawaguchi; Kazuya Ohno; Koichi Sonobe; Akihiko Satoh; Tooru Shimosegawa; Fumihiko Miura; Minami Yagi; Keiji Sano; Toshifumi Kin; Akio Katanuma; Kazuhiko Koike; Shin Miura; Youhei Kawashima; Tatehiro Kagawa; Seishin Azuma; Mamoru Watanabe; Mitsuyoshi Honjyo; Takao Itoi; Akira Honda; Katsumasa Kobayashi; Toru Asano; Suguru Mizuno; Kazuhiko Koike; Takayoshi Nishino; Hideaki Taniguchi; Kazuto Tajiri; Ichiro Yasuda; Yoshiya Tanaka; Shinji Oe; Masaru Harada; Masanao Kurata; Mituharu Fukasawa; Nobuyuki Enomoto; Yuki Kawaji; Masayuki Kitano; Yuko Nishise; Hidetoshi Hirakawa; Tetsuya Ishizawa; Yoshiyuki Ueno; Miyuki Kaino; Yuko Fujimoto; Isao Sakaida

  Journal of Gastroenterology and Hepatology Wiley 38 (4) 556 - 564 0815-9319 2023/01 [Refereed]
   

  OBJECTIVE: IgG4-related sclerosing cholangitis (IgG4-SC) is recognized as a benign steroid-responsive disease; however, little is known about the risk of development of cancer in patients with IgG4-SC and about how to counter this risk. DESIGN: We conducted a retrospective review of the data of 924 patients with IgG4-SC selected from a Japanese nationwide survey. The incidence, type of malignancy, and risk of malignancy in these patients were examined. Then, the standardized incidence ratio (SIR) of cancer in patients with IgG4-SC was calculated. RESULTS: Relapse was recognized in 19.7% (182/924) of patients, and cancer development was noted in 15% (139/924) of patients. Multivariate analysis identified only relapse as an independent risk factor for the development of cancer. In most of these patients with pancreato-biliary cancer, the cancer developed within 8 years after the diagnosis of IgG4-SC. The SIR for cancer after the diagnosis of IgG4-SC was 12.68 (95% confidence interval [CI] 6.89-8.79). The SIRs of cancers involving the biliary system and pancreas were 27.35 and 18.43, respectively. The cumulative survival rate was significantly better in the group that received maintenance steroid treatment (MST) than in the group that did not; thus, MST influenced the prognosis of these patients. CONCLUSION: Among the cancers, the risk of pancreatic and biliary cancers is the highest in these patients. Because of the elevated cancer risk, surveillance after the diagnosis and management to prevent relapse are important in patients with IgG4-SC to reduce the risk of development of cancer.
• IL-6応答亢進を伴う潰瘍性大腸炎関連脊椎関節炎の一例

  藤田 峻輔; 本庶 元; 高田 隆太郎; 原 茜; 益田 康弘; 半田 康平; 三長 孝輔; 渡邉 智裕; 工藤 正俊; 辻 成佳

  日本消化器病学会近畿支部例会プログラム・抄録集 日本消化器病学会-近畿支部 118回 88 - 88 2023/01
• Ulcerative Colitis-associated Spondyloarthritis Successfully Treated with Infliximab in the Absence of Enhanced TNF-α Responses

  Shunsuke Fujita; Hajime Honjo; Ryutaro Takada; Akane Hara; Yasuhiro Masuta; Yasuo Otsuka; Kohei Handa; Kosuke Minaga; Shigeyoshi Tsuji; Masatoshi Kudo; Tomohiro Watanabe

  Internal Medicine Japanese Society of Internal Medicine 0918-2918 2023/01 [Refereed]
   

  Although concurrent occurrence of spondyloarthritis (SpA) and ulcerative colitis (UC) is sometimes seen, the profiles of cytokines have been poorly understood in UC-associated SpA. We herein report a case of UC-associated SpA successfully treated with infliximab. Profiles of cytokines in the serum and colonic mucosa were characterized by an enhanced expression of IL-6 but not TNF-α. Successful induction of remission by infliximab was associated with the downregulation of IL-6 expression but no significant alteration in TNF-α expression. These findings suggest that some cases of UC-associated SpA might be driven by IL-6, and infliximab might be effective in cases lacking enhanced TNF-α responses.
• Hepatobiliary and Pancreatic: Multiple pancreatic masses with rich vascularity

  S Yoshida; K Minaga; T Watanabe; M Kudo

  Journal of Gastroenterology and Hepatology Wiley 0815-9319 2022/12 [Refereed]
  
• High-fat diet aggravates experimental autoimmune pancreatitis through the activation of type I interferon signaling pathways

  Ikue Sekai; Kosuke Minaga; Akane Hara; Yasuo Otsuka; Masayuki Kurimoto; Naoya Omaru; Natsuki Okai; Yasuhiro Masuta; Ryutaro Takada; Tomoe Yoshikawa; Ken Kamata; Masatoshi Kudo; Tomohiro Watanabe

  Biochemical and Biophysical Research Communications Elsevier BV 0006-291X 2022/11 [Refereed]
  
• Activation of NOD1 and NOD2 in the development of liver injury and cancer

  Naoya Omaru; Tomohiro Watanabe; Ken Kamata; Kosuke Minaga; Masatoshi Kudo

  Frontiers in Immunology Frontiers Media SA 13 1004439 - 1004439 2022/10 [Refereed]
   

  Hepatocytes and liver-resident antigen-presenting cells are exposed to microbe-associated molecular patterns (MAMPs) and microbial metabolites, which reach the liver from the gut via the portal vein. MAMPs induce innate immune responses via the activation of pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), nucleotide-binding oligomerization domain 1 (NOD1), and NOD2. Such proinflammatory cytokine responses mediated by PRRs likely contribute to the development of chronic liver diseases and hepatocellular carcinoma (HCC), as shown by the fact that activation of TLRs and subsequent production of IL-6 and TNF-α is required for the generation of chronic fibroinflammatory responses and hepatocarcinogenesis. Similar to TLRs, NOD1 and NOD2 recognize MAMPs derived from the intestinal bacteria. The association between the activation of NOD1/NOD2 and chronic liver diseases is poorly understood. Given that NOD1 and NOD2 can regulate proinflammatory cytokine responses mediated by TLRs both positively and negatively, it is likely that sensing of MAMPs by NOD1 and NOD2 affects the development of chronic liver diseases, including HCC. Indeed, recent studies have highlighted the importance of NOD1 and NOD2 activation in chronic liver disorders. Here, we summarize the roles of NOD1 and NOD2 in hepatocarcinogenesis and liver injury.
• 急激な経過を辿ったClostridium perfringens肝膿瘍・多臓器ガス壊疽の1例

  原 茜; 大塚 康生; 三長 孝輔; 渡邉 智裕; 工藤 正俊; 梶山 博

  日本消化器病学会近畿支部例会プログラム・抄録集 日本消化器病学会-近畿支部 117回 91 - 91 2022/10
• COVID-19ワクチン接種後のI型インターフェロン反応を特徴とする潰瘍性大腸炎再発の一例

  益田 康弘; 三長 孝輔; 渡邉 智裕; 工藤 正俊

  日本消化器病学会近畿支部例会プログラム・抄録集 日本消化器病学会-近畿支部 117回 102 - 102 2022/10
• 空腸瀘胞性リンパ腫から形質転換した腹部Double Expressor Lymphoma(DEL)の1例

  高田 隆太郎; 三長 孝輔; 渡邉 智裕; 工藤 正俊

  日本消化器病学会近畿支部例会プログラム・抄録集 日本消化器病学会-近畿支部 117回 103 - 103 2022/10
• 【IgG4関連疾患大全-自己免疫性膵炎とIgG4関連硬化性胆管炎を中心に-】IgG4関連疾患の概要 IgG4関連疾患の病因・病態 自然免疫の視点から

  原 茜; 三長 孝輔; 瀬海 郁衣; 栗本 真之; 大塚 康生; 益田 康弘; 吉川 智恵; 鎌田 研; 渡邉 智裕; 工藤 正俊

  胆と膵 医学図書出版(株) 43 (臨増特大) 1049 - 1053 0388-9408 2022/10 

  IgG4関連疾患は,全身の罹患臓器へのIgG4陽性形質細胞の浸潤を特徴として,異時性・同時性に多臓器に慢性炎症と線維化をきたす疾患である。自己免疫性膵炎はその膵臓特異的表現型であることが判明しているが,病態生理はあまり解明されていない。われわれは自己免疫性膵炎の発症には形質細胞様樹状細胞の活性化やIFN-αなどの炎症性サイトカインが関与することを見出している。またこの自然免疫経路を活性化させるトリガーとして,好中球細胞外トラップや腸内細菌叢がかかわることも見出した。IgG4関連疾患は多彩な症状を呈する疾患であるが,その治療法は限られており,診断や治療に難渋する症例も多い。自然免疫反応の観点からのメカニズム解明により新たな治療法・予防法の発見が期待される。(著者抄録)
• Pitting Edema in a Patient with Acute Hepatitis B Virus Infection

  Yasuhiro Masuta; Kosuke Minaga; Tomohiro Watanabe

  Gastroenterology Elsevier BV 0016-5085 2022/10 [Refereed]
  
• Activation of nucleotide-binding oligomerization domain 2 by muramyl dipeptide negatively regulates Toll-like receptor 9-mediated colonic inflammation through the induction of deubiquitinating enzyme A expression

  Yasuhiro Masuta; Kosuke Minaga; Masayuki Kurimoto; Ikue Sekai; Akane Hara; Naoya Omaru; Natsuki Okai; Yasuo Otsuka; Ryutaro Takada; Tomoe Yoshikawa; Sho Masaki; Ken Kamata; Hajime Honjo; Yasuyuki Arai; Kouhei Yamashita; Masatoshi Kudo; Tomohiro Watanabe

  International Immunology Oxford University Press (OUP) 2022/09 [Refereed]
   

  Abstract Mutations in nucleotide-binding oligomerization domain 2 (NOD2) are associated with Crohn’s disease (CD). Although NOD2 activation contributes to the maintenance of intestinal homeostasis through the negative regulation of pro-inflammatory cytokine responses mediated by Toll-like receptors (TLRs), the effects of NOD2 activation on interferon (IFN)-α responses induced by TLR9 have been poorly defined. To explore the cross-talk between NOD2 and TLR9, human monocytes or dendritic cells (DCs) were stimulated with NOD2 and/or TLR9 ligands to measure IFN-α production. The severity of dextran sodium sulfate (DSS)-induced colitis was compared in mice treated with NOD2 and/or TLR9 ligands. Expression of IFN-α and IFN-stimulated genes (ISGs) was examined in the colonic mucosa of patients with inflammatory bowel disease (IBD). NOD2 activation reduced TLR9-induced IFN-α production by monocytes and DCs in a deubiquitinating enzyme A (DUBA)-dependent manner. Activation of DUBA induced by the co-stimulation of TLR9 and NOD2 inhibited Lys63-linked polyubiquitination of TRAF3 and suppressed TLR9-mediated IFN-α production. NOD2 activation in hematopoietic cells protected mice from TLR9-induced exacerbation of DSS-induced colitis by down-regulating IFN-α responses and up-regulating DUBA expression. Colonic mucosa of patients with active and remitted IBD phases was characterized by the enhanced and reduced expression of ISGs, respectively. Expression levels of IFN-α and IL-6 positively correlated in the active colonic mucosa of patients with ulcerative colitis and CD, whereas DUBA expression inversely correlated with that of IFN-α in patients with CD. Collectively, these data suggest that DUBA-dependent negative effect of NOD2 on TLR9-mediated IFN-α responses contributes to the maintenance of intestinal homeostasis.
• Circumferential Gastric Wall Thickening with Lymphadenopathy

  Hisakazu Matsumoto; Kosuke Minaga; Tomohiro Watanabe

  Gastroenterology Elsevier BV 0016-5085 2022/09 [Refereed]
  
• 芳香族炭化水素受容体 (AhR)

  鎌田 研; 渡邉 智裕; 工藤 正俊

  消化器病学サイエンス 6 (3) 52  2022/09 [Invited]
  
• Disruption of the intestinal barrier exacerbates experimental autoimmune pancreatitis by promoting the translocation of Staphylococcus sciuri into the pancreas

  Tomoe Yoshikawa; Kosuke Minaga; Akane Hara; Ikue Sekai; Masayuki Kurimoto; Yasuhiro Masuta; Yasuo Otsuka; Ryutaro Takada; Ken Kamata; Ah-Mee Park; Shiki Takamura; Masatoshi Kudo; Tomohiro Watanabe

  International Immunology Oxford University Press (OUP) 2022/09 [Refereed]
   

  Abstract Autoimmune pancreatitis (AIP) and IgG4-related disease (IgG4-RD) are new disease entities characterized by enhanced IgG4 antibody responses and involvement of multiple organs, including the pancreas and salivary glands. Although the immunopathogenesis of AIP and IgG4-RD is poorly understood, we previously reported that intestinal dysbiosis mediates experimental AIP through the activation of IFN-α- and IL-33-producing plasmacytoid dendritic cells (pDCs). Because intestinal dysbiosis is linked to intestinal barrier dysfunction, we explored whether the latter affects the development of AIP and autoimmune sialadenitis in MRL/MpJ mice treated with repeated injections of polyinosinic–polycytidylic acid [poly (I:C)]. Epithelial barrier disruption was induced by the administration of dextran sodium sulfate (DSS) in the drinking water. Mice co-treated with poly (I:C) and DSS, but not those treated with either agent alone, developed severe AIP, but not autoimmune sialadenitis, which was accompanied by the increased accumulation of IFN-α- and IL-33-producing pDCs. Sequencing of 16S ribosomal RNA revealed that Staphylococcus sciuri translocation from the gut to the pancreas was preferentially observed in mice with severe AIP co-treated with DSS and poly (I:C). The degree of experimental AIP, but not of autoimmune sialadenitis, was greater in germ-free mice mono-colonized with S. sciuri and treated with poly (I:C) than in germ-free mice treated with poly (I:C) alone, which was accompanied by the increased accumulation of IFN-α- and IL-33-producing pDCs. Taken together, these data suggest that intestinal barrier dysfunction exacerbates AIP through the activation of pDCs and translocation of S. sciuri into the pancreas.
• Pancreatic colonization of fungi in the development of severe acute pancreatitis

  Yasuo Otsuka; Ken Kamata; Kosuke Minaga; Tomohiro Watanabe; Masatoshi Kudo

  Frontiers in Cellular and Infection Microbiology Frontiers Media SA 12 940532 - 940532 2022/07 [Refereed]
   

  Acute pancreatitis is a common emergent disorder, a significant population of which develops the life-threatening condition, called severe acute pancreatitis (SAP). It is generally accepted that bacterial infection is associated with the development and persistence of SAP. In addition to bacterial infection, recent clinical studies disclosed a high incidence of fungal infection in patients with SAP. Moreover, SAP patients with fungal infection exhibit a higher mortality rate than those without infection. Although these clinical studies support pathogenic roles played by fungal infection in SAP, beneficial effects of prophylactic anti-fungal therapy on SAP have not been proved. Here we summarize recent clinical findings as to the relationship between fungal infection and the development of SAP. In addition, we discuss molecular mechanisms accounting for the development of SAP in the presence of fungal infection.
• Alterations of autophagic and innate immune responses by the Crohn’s disease-associated ATG16L1 mutation

  Natsuki Okai; Tomohiro Watanabe; Kosuke Minaga; Ken Kamata; Hajime Honjo; Masatoshi Kudo

  World Journal of Gastroenterology Baishideng Publishing Group Inc. 28 (26) 3063 - 3070 1007-9327 2022/07 [Refereed]
   

  Crohn's disease (CD) is driven by the loss of tolerance to intestinal microbiota and excessive production of pro-inflammatory cytokines. These pro-inflammatory cytokines are produced by macrophages and dendritic cells (DCs) upon sensing the intestinal microbiota by the pattern recognition receptors (PRRs). Impaired activation of PRR-mediated signaling pathways is associated with chronic gastrointestinal inflammation, as shown by the fact that loss-of-function mutations in the nucleotide-binding oligomerization domain 2 gene increase the risk of CD development. Autophagy is an intracellular degradation process, during which cytoplasmic nutrients and intracellular pathogens are digested. Given that impaired reaction to intestinal microbiota alters signaling pathways mediated by PRRs, it is likely that dysfunction of the autophagic machinery is involved in the development of CD. Indeed, the loss-of-function mutation T300A in the autophagy related 16 like 1 (ATG16L1) protein, a critical regulator of autophagy, increases susceptibility to CD. Recent studies have provided evidence that ATG16L1 is involved not only in autophagy, but also in PRR-mediated signaling pathways. ATG16L1 negatively regulates pro-inflammatory cytokine responses of macrophages and DCs after these cells sense the intestinal microbiota by PRRs. Here, we discuss the molecular mechanisms underlying the development of CD in the T300A ATG16L1 mutation by focusing on PRR-mediated signaling pathways.
• Pancreatic neuroendocrine carcinoma with unique morphological features mimicking intraductal papillary mucinous carcinoma: A case report

  Hidekazu Tanaka; Kosuke Minaga; Yasuo Otsuka; Yasuhiro Masuta; Ken Kamata; Kentaro Yamao; Mamoru Takenaka; Tomoko Hyodo; Masatomo Kimura; Tomohiro Watanabe; Masatoshi Kudo

  Frontiers in Medicine Frontiers Media SA 9 951834 - 951834 2022/07 

  Background Pancreatic neuroendocrine carcinoma (PanNEC) is a rare disease entity with rapid progression and poor prognosis. Here, we report a PanNEC case with unique morphological features mimicking intraductal papillary mucinous carcinoma. Case presentation A 69-year-old Japanese man was referred to our hospital for further evaluation of weight loss and deterioration of diabetes mellitus. Contrast-enhanced computed tomography showed a solid and cystic mass with hypo-enhancement at the tail of the pancreas. The main pancreatic duct (MPD) was diffusely dilated without obstruction, accompanied by marked parenchymal atrophy. Multiple peritoneal and omental nodules were observed, suggesting tumor dissemination. Endoscopic retrograde cholangiopancreatography revealed that the mass correlated with the dilated MPD. During pancreatography, a large amount of mucus was extruded from the pancreatic orifice of the ampulla. Based on these imaging findings, intraductal papillary mucinous carcinoma was suspected. Per-oral pancreatoscopy (POPS)-guided tumor biopsies were conducted for the lesion's solid components. Histopathological examination of the biopsied material confirmed small-cell-type PanNEC with a Ki-67 labeling index of 90%. Due to his condition's rapid decline, the patient was given the best supportive care and died 28 days after diagnosis. Conclusion Although rare, PanNEC, which correlates with the MPD and is accompanied by marked dilation of the MPD, does exist as one phenotype. In such cases, POPS-guided biopsy could be a useful diagnostic modality.
• Utility of contrast-enhanced harmonic EUS for diagnosis of portal vein invasion by pancreatic cancer

  Atsushi Nakai; Ken Kamata; Tomoko Hyodo; Takaaki Chikugo; Akane Hara; Yasuo Otsuka; Hidekazu Tanaka; Tomoe Yoshikawa; Rei Ishikawa; Ayana Okamoto; Tomohiro Yamazaki; Shunsuke Omoto; Kosuke Minaga; Kentaro Yamao; Mamoru Takenaka; Yasutaka Chiba; Tomohiro Watanabe; Ippei Matsumoto; Yoshifumi Takeyama; Masatoshi Kudo

  Endoscopic Ultrasound Medknow 11 (5) 401 - 406 2303-9027 2022/07 [Refereed]
   

  BACKGROUND: The value of contrast-enhanced harmonic EUS (CH-EUS) for diagnosis of portal vein invasion in patients with pancreatic cancer was evaluated. PATIENTS AND METHODS: This single-center, retrospective study included consecutive patients with pancreatic cancer who underwent both surgical resection after preoperative EUS, CH-EUS, and contrast-enhanced computed tomography (CE-CT) examinations between April 2015 and August 2017. CH-EUS evaluation was performed during the late phase. Portal vein invasion on EUS and CH-EUS was defined as no continuity in the line of the vessel wall. Definition of portal vein invasion on CE-CT was based on the Loyer's criteria. The accuracy of three modalities for diagnosis of invasion into the portal vein was compared using the McNemar's test. RESULTS: Eighty-eight patients (mean age: 71.0 years, ratio of male to female: 48:40) were eligible. Postoperative pathological results were as follows: seven cases of portal vein invasion; 81 cases without. Diagnostic accuracy of EUS, CH-EUS, and CE-CT for diagnosing invasion into the portal vein was 72.7%, 93.2%, and 81.8%, respectively. The differences between CH-EUS and CE-CT (P = 0.0094) and CH-EUS and EUS (P = 0.0022) were significant. EUS and CE-CT were comparable. CONCLUSION: CH-EUS is useful for diagnosis of portal vein invasion by pancreatic cancer.
• 非代償性肝硬変による直腸静脈瘤出血に対して内視鏡的組織接着剤注入術を施行した1例

  加藤 弘樹; 松井 繁長; 田北 雅弘; 上中 大地; 今村 瑞貴; 原 茜; 野村 健司; 瀬海 郁衣; 高田 隆太郎; 河野 匡志; 正木 翔; 永井 知行; 本庶 元; 米田 頼晃; 上嶋 一臣; 渡邉 智裕; 西田 直生志; 辻 直子; 樫田 博史; 工藤 正俊

  日本消化器内視鏡学会近畿支部例会プログラム・抄録集 日本消化器内視鏡学会-近畿支部 108回 89 - 89 2022/06
• Case Report: New-Onset Rheumatoid Arthritis Following COVID-19 Vaccination

  Tomohiro Watanabe; Kosuke Minaga; Akane Hara; Tomoe Yoshikawa; Ken Kamata; Masatoshi Kudo

  Frontiers in Immunology Frontiers Media SA 13 859926 - 859926 2022/05 [Refereed]
   

  Efficient protection against coronavirus disease 2019 (COVID-19) has been achieved by immunization with mRNA-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, efficient immune responses against this novel virus by vaccination are accompanied by a wide variety of side effects. Indeed, flares or new-onset of autoimmune disorders have been reported soon after the COVID-19 vaccination. Although pro-inflammatory cytokine responses play pathogenic roles in the development of autoimmunity, cytokines charactering COVID-19 vaccination-related autoimmune responses have been poorly understood. Given that mRNA derived from COVID-19 vaccine is a potent inducer for pro-inflammatory cytokine responses, these cytokines might mediate autoimmune responses after COVID-19 vaccination. Here we report a case with new-onset rheumatoid arthritis (RA) following COVID-19 vaccination. Serum concentrations not only of arthrogenic cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), but also of type I interferon (IFN) were elevated at the active phase in this case. Induction of remission by methotrexate and tocilizumab was accompanied by a marked reduction in serum concentrations of type I IFN, IL-6, and TNF-α. These results suggest that production of type I IFN, IL-6, and TNF-α induced by COVID-19 vaccination might be involved in this case with new-onset RA.
• Reply to Response to “‘A Case of Ulcerative Colitis Relapse Characterized by Systemic Type I Interferon Responses After COVID-19 Vaccination’” by Mungmunpuntipantip and Wiwanitkiton

  Yasuhiro Masuta; Tomohiro Watanabe; Kosuke Minaga; Masatoshi Kudo

  Inflammatory Bowel Diseases Oxford University Press (OUP) 28 (8) e113  1078-0998 2022/04 [Refereed][Invited]
  
• A Mouse Model of Acute and Chronic Pancreatitis

  Kosuke Minaga; Tomohiro Watanabe; Ken Kamata; Masatoshi Kudo; Warren Strober

  Current Protocols Wiley 2 (4) e422  2691-1299 2022/04 [Refereed][Invited]
   

  Pancreatitis occurs in two forms defined by its chronicity. Acute pancreatitis (AP) occurs suddenly and only lasts for several days. Consequently, most patients with AP recover without permanent damage to the pancreas, and about 20% of patients with AP have severe disease. In contrast, chronic pancreatitis (CP) is a long-lasting inflammation that causes permanent damage to pancreatic tissue; consequently, this form is marked by the emergence of persistent endocrine and exocrine pancreatic insufficiency. Despite these differences, AP and CP share central mechanisms of disease: in both forms, inflammation is initiated and/or sustained by the intrapancreatic activation of pancreatic digestive enzymes followed by the autodigestion of pancreatic tissues. In addition, in both forms enzymatic damage is accompanied by changes in intestinal permeability and entry of commensal organisms into the pancreas where they elicit innate immune responses that ultimately dominate and define pancreatic inflammation. In the murine models of AP and CP described here, both of these elements of pancreatitis pathogenesis are taken into account. Thus, in one approach mice are administered high doses of cerulein, a cholecystokinin analog with the ability at this dose to induce excessive activation of the cholecystokinin receptor expressed in pancreatic acinar cells and the release of active trypsin that causes both direct and indirect acinar damages due to entry of commensal organisms and stimulation of innate immune responses. In a second approach mice are administered low doses of cerulein, which causes little or no damage to the pancreas unless given along with nucleotide-binding oligomerization domain 1 (NOD1) ligand, which in the presence of low-dose cerulein administration induces a pathologic innate immune response mediated by NOD1. These approaches are adopted to produce AP when cerulein or cerulein plus NOD1 ligand is applied only once or to produce CP when a similar regimen is applied multiple times. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Cerulein-induced acute pancreatitis Alternate Protocol 1: Acute pancreatitis induced by cerulein and NOD1 ligand Basic Protocol 2: Cerulein-induced chronic pancreatitis Alternate Protocol 2: Chronic pancreatitis induced by cerulein and NOD1 ligand Support Protocol: Isolation of pancreatic mononuclear cells.
• Cross‐wired metal stents for endoscopic bilateral stent‐in‐stent deployment in malignant hilar biliary obstruction: A multicenter, single‐arm, prospective study

  Kentaro Yamao; Takeshi Ogura; Hideyuki Shiomi; Takaaki Eguchi; Hisakazu Matsumoto; Zhao Liang Li; Hiroaki Hashimoto; Yasutaka Chiba; Mamoru Takenaka; Tomohiro Watanabe; Masatoshi Kudo; Tsuyoshi Sanuki

  DEN Open Wiley 2 (1) e20  2692-4609 2022/04 [Refereed]
   

  Objectives: The endoscopic bilateral stent-in-stent (SIS) deployment is a challenging procedure. Such difficulty is mainly caused by sticking of the tip of the delivery sheath into the self-expandable metal stents (SEMSs) mesh, requiring an additional dilating procedure. Herein, we assessed the clinical results of using cross-wired metal stent for endoscopic bilateral SIS deployment (BONASTENT M-Hilar) in patients with malignant hilar biliary obstruction (MHBO) in both high-volume and non-high-volume centers. Methods: We prospectively enrolled consecutive patients with MHBO between February 2016 and December 2018 at eight centers. Results: Forty-six patients were enrolled during the study period. The proportions of technical success were 93.5% (43/46) and clinical success (CS) on intention-to-treat and per-protocol analyses were 91.3% (42/46) and 93.0% (40/43), respectively. The proportion of an additional dilating procedure during the primary procedure was 50.0% (23/46). Recurrent biliary obstruction (RBO) on intention-to-treat analysis occurred in 32.6% (15/46) of cases. Almost all of the events were caused by stent ingrowth (14/15). The median survival time and time to RBO were 255 and 349 days, respectively. The probability of stent patency at 3, 6, and 12 months was 86.5%, 63.9%, and 47.6%, respectively. Conclusions: The cross-wired metal stent had excellent technical and CS, although non-high-volume centers were included in this study (UMIN000021441).
• 【消化器疾患と腸内細菌叢の関わり-臨床的意義と治療への影響-】自己免疫性膵炎の病態と腸内細菌

  鎌田 研; 渡邉 智裕; 吉川 智恵; 原 茜; 三長 孝輔; 工藤 正俊

  Progress in Medicine (株)ライフ・サイエンス 42 (3) 259 - 263 0287-3648 2022/03
• A Case of Ulcerative Colitis Relapse Characterized by Systemic Type I Interferon Responses after COVID-19 Vaccination

  Yasuhiro Masuta; Tomohiro Watanabe; Kosuke Minaga; Masatoshi Kudo

  Inflammatory Bowel Diseases Oxford University Press (OUP) 28 (8) e110-e111  1078-0998 2022/02 [Refereed]
  
• 制御性T細胞に依存性しない寛解導入が得られたCollagenous Colitisの一例

  瀬海 郁衣; 本庶 元; 今村 瑞貴; 松原 卓哉; 河野 匡志; 原 茜; 栗本 真之; 吉川 馨介; 益田 康弘; 大塚 康生; 高田 隆太郎; 吉川 智恵; 鎌田 研; 三長 孝輔; 松井 繁長; 木村 雅友; 渡邉 智裕; 工藤 正俊

  日本消化器病学会近畿支部例会プログラム・抄録集 日本消化器病学会-近畿支部 116回 117 - 117 2022/02
• 腸内細菌に対する炎症性サイトカイン応答の増強を示すクローン病関連脊椎関節炎の一例

  福西 香栄; 本庶 元; 岡井 夏輝; 河野 匡志; 鎌田 研; 三長 孝輔; 米田 頼晃; 辻 成佳; 渡邉 智裕; 工藤 正俊

  日本消化器病学会近畿支部例会プログラム・抄録集 日本消化器病学会-近畿支部 116回 108 - 108 2022/02
• 制御性T細胞に依存性しない寛解導入が得られたCollagenous Colitisの一例

  瀬海 郁衣; 本庶 元; 今村 瑞貴; 松原 卓哉; 河野 匡志; 原 茜; 栗本 真之; 吉川 馨介; 益田 康弘; 大塚 康生; 高田 隆太郎; 吉川 智恵; 鎌田 研; 三長 孝輔; 松井 繁長; 木村 雅友; 渡邉 智裕; 工藤 正俊

  日本消化器病学会近畿支部例会プログラム・抄録集 日本消化器病学会-近畿支部 116回 117 - 117 2022/02
• Value of artificial intelligence with novel tumor tracking technology in the diagnosis of gastric submucosal tumors by contrast‐enhanced harmonic endoscopic ultrasonography

  Hidekazu Tanaka; Ken Kamata; Rika Ishihara; Hisashi Handa; Yasuo Otsuka; Akihiro Yoshida; Tomoe Yoshikawa; Rei Ishikawa; Ayana Okamoto; Tomohiro Yamazaki; Atsushi Nakai; Shunsuke Omoto; Kosuke Minaga; Kentaro Yamao; Mamoru Takenaka; Tomohiro Watanabe; Naoshi Nishida; Masatoshi Kudo

  Journal of Gastroenterology and Hepatology Wiley 37 (5) 841 - 846 0815-9319 2022/01 [Refereed]
   

  BACKGROUND AND AIM: Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) is useful for the diagnosis of lesions inside and outside the digestive tract. This study evaluated the value of artificial intelligence (AI) in the diagnosis of gastric submucosal tumors by CH-EUS. METHODS: This retrospective study included 53 patients with gastrointestinal stromal tumors (GISTs) and leiomyomas, all of whom underwent CH-EUS between June 2015 and February 2020. A novel technology, SiamMask, was used to track and trim the lesions in CH-EUS videos. CH-EUS was evaluated by AI using deep learning involving a residual neural network and leave-one-out cross-validation. The diagnostic accuracy of AI in discriminating between GISTs and leiomyomas was assessed and compared with that of blind reading by two expert endosonographers. RESULTS: Of the 53 patients, 42 had GISTs and 11 had leiomyomas. Mean tumor size was 26.4 mm. The consistency rate of the segment range of the tumor image extracted by SiamMask and marked by the endosonographer was 96% with a Dice coefficient. The sensitivity, specificity, and accuracy of AI in diagnosing GIST were 90.5%, 90.9%, and 90.6%, respectively, whereas those of blind reading were 90.5%, 81.8%, and 88.7%, respectively (P = 0.683). The κ coefficient between the two reviewers was 0.713. CONCLUSIONS: The diagnostic ability of CH-EUS results evaluated by AI to distinguish between GISTs and leiomyomas was comparable with that of blind reading by expert endosonographers.
• Expression levels of cellular inhibitor of apoptosis proteins and colitogenic cytokines are inversely correlated with the activation of interferon regulatory factor 4

  Sho Masaki; Tomohiro Watanabe; Yasuyuki Arai; Ikue Sekai; Akane Hara; Masayuki Kurimoto; Yasuo Otsuka; Yasuhiro Masuta; Tomoe Yoshikawa; Ryutaro Takada; Ken Kamata; Kosuke Minaga; Kouhei Yamashita; Masatoshi Kudo

  Clinical and Experimental Immunology Oxford University Press (OUP) 207 (3) 340 - 350 0009-9104 2022/01 [Refereed]
   

  Cellular inhibitor of apoptosis proteins 1 (cIAP1) and 2 (cIAP2) are involved in signaling pathways mediated by Toll-like receptors (TLRs) and tumor necrosis factor (TNF)-α. Excessive activation of TLRs and TNF-αunderlies the immunopathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC). However, the roles played by cIAP1 and cIAP2 in the development of CD and UC remain poorly understood. In this study, we attempted to clarify the molecular link between cIAP1/cIAP2 and colonic inflammation. Human monocyte-derived dendritic cells (DCs) treated with siRNAs specific for cIAP1 or cIAP2 exhibited reduced pro-inflammatory cytokine responses upon stimulation with TLR ligands. Expression of cIAP1 and cIAP2 in human DCs was suppressed in the presence of interferon regulatory factor 4 (IRF4). This effect was associated with inhibition of cIAP1 and cIAP2 polyubiquitination. To verify these in vitro findings, we created mice overexpressing IRF4 in DCs and showed that these mice were resistant to trinitrobenzene sulfonic acid-induced colitis as compared with wild-type mice; these effects were accompanied by reduced expression levels of cIAP1 and cIAP2. Pro-inflammatory cytokine production by mesenteric lymph node cells upon stimulation with TLR ligands was reduced in mice with DC-specific IRF4 overexpression as compared with that in wild-type mice. Finally, in clinical samples of the colonic mucosa from patients with CD, there was a negative relationship between the percentage of IRF4 + DCs and percentages of cIAP1 + or cIAP2 + lamina propria mononuclear cells. These data suggest that the colitogenic roles of cIAP1 and cIAP2 are negatively regulated by IRF4.
• Primary Hepatic Neuroendocrine Carcinoma with Thrombocytopenia due to Diffuse Bone Marrow and Splenic Infiltration: An Autopsy Case

  Shogo Nakano; Kosuke Minaga; Yasuhiro Tani; Kohei Tonomura; Yusuke Hanawa; Hiroki Morimura; Tomoko Terashita; Hisakazu Matsumoto; Hiroyoshi Iwagami; Yasuki Nakatani; Takuji Akamatsu; Yoshito Uenoyama; Chikara Maeda; Kazuo Ono; Tomohiro Watanabe; Yukitaka Yamashita

  Internal Medicine Japanese Society of Internal Medicine 0918-2918 2022 

  An 82-year-old man with fever and back pain was referred to our hospital and was thus found to be thrombocytopenic. A bone marrow biopsy revealed the diffuse infiltration of poorly differentiated neuroendocrine carcinoma (NEC). Computed tomography revealed a large hepatic mass. Considering the risk of bleeding due to thrombocytopenia, a needle biopsy was not performed. The patient rapidly deteriorated and died 10 days after presentation. An autopsy confirmed the diagnosis of primary hepatic NEC, with diffuse metastasis to the spleen, bone marrow, and systemic lymph nodes. This is an extremely rare case of NEC presenting with thrombocytopenia due to extensive bone marrow and splenic infiltration.
• 診断に難渋した小腸GISTの一例

  福西 香栄; 永井 知行; 杉森 啓伸; 岡井 夏輝; 高田 隆太郎; 河野 匡志; 正木 翔; 米田 頼晃; 本庶 元; 松井 繁長; 渡邉 智裕; 辻 直子; 樫田 博史; 工藤 正俊

  日本消化器内視鏡学会近畿支部例会プログラム・抄録集 日本消化器内視鏡学会-近畿支部 107回 127 - 127 2021/12
• IL-33 as a Critical Cytokine for Inflammation and Fibrosis in Inflammatory Bowel Diseases and Pancreatitis

  Masayuki Kurimoto; Tomohiro Watanabe; Ken Kamata; Kosuke Minaga; Masatoshi Kudo

  Frontiers in Physiology Frontiers Media SA 12 781012 - 781012 2021/10 [Refereed][Invited]
   

  IL-33 is a pleiotropic cytokine that promotes inflammation and fibrosis. IL-33 is produced by a broad range of cells, including antigen-presenting cells (APCs), epithelial cells, and fibroblasts. IL-33 produced by the innate immune cells has been shown to activate pro-inflammatory T helper type 1 (Th1) and T helper type 2 (Th2) responses. The intestinal barrier and tolerogenic immune responses against commensal microbiota contribute to the maintenance of gut immune homeostasis. Breakdown of tolerogenic responses against commensal microbiota as a result of intestinal barrier dysfunction underlies the immunopathogenesis of inflammatory bowel diseases (IBD) and pancreatitis. Recent studies have provided evidence that IL-33 is an innate immune cytokine that bridges adaptive Th1 and Th2 responses associated with IBD and pancreatitis. In this Mini Review, we discuss the pathogenic roles played by IL-33 in the development of IBD and pancreatitis and consider the potential of this cytokine to be a new therapeutic target.
• Analysis of Progression Time in Pancreatic Cancer including Carcinoma In Situ Based on Magnetic Resonance Cholangiopancreatography Findings

  Kentaro Yamao; Masakatsu Tsurusaki; Kota Takashima; Hidekazu Tanaka; Akihiro Yoshida; Ayana Okamoto; Tomohiro Yamazaki; Shunsuke Omoto; Ken Kamata; Kosuke Minaga; Mamoru Takenaka; Takaaki Chikugo; Yasutaka Chiba; Tomohiro Watanabe; Masatoshi Kudo

  Diagnostics MDPI AG 11 (10) 1858 - 1858 2021/10 [Refereed]
   

  Background: Pancreatic cancer (PC) exhibits extremely rapid growth; however, it remains largely unknown whether the early stages of PC also exhibit rapid growth speed equivalent to advanced PC. This study aimed to investigate the natural history of early PCs through retrospectively assessing pre-diagnostic images. Methods: We examined the data of nine patients, including three patients with carcinoma in situ (CIS), who had undergone magnetic resonance cholangiopancreatography (MRCP) to detect solitary main pancreatic duct (MPD) stenosis >1 year before definitive PC diagnosis. We retrospectively analyzed the time to diagnosis and first-time tumor detection from the estimated time point of first-time MPD stenosis detection without tumor lesion. Results: The median tumor size at diagnosis and the first-time tumor detection size were 14 and 7.5 mm, respectively. The median time to diagnosis and first-time tumor detection were 26 and 49 months, respectively. Conclusions: No studies have investigated the PC history, especially that of early PCs, including CIS, based on the initial detection of MPD stenosis using MRCP. Assessment of a small number of patients showed that the time to progression can take several years in the early PC stages. Understanding this natural history is very important in the clinical setting.
• 自然免疫反応からみた自己免疫性膵炎・IgG4関連疾患の血清バイオマーカー：IFN-α・IL-33

  原茜; 三長孝輔; 吉川智恵; 鎌田研; 渡邉智裕; 工藤正俊

  肝胆膵 (株)アークメディア 83 (4) 617 - 623 0389-4991 2021/10 [Invited]
  
• TNF-αおよびIL-6の関与が考えられた好酸球性胃腸炎の1例

  瀬海 郁衣; 吉川 馨介; 高田 隆太郎; 原 茜; 吉川 智恵; 鎌田 研; 三長 孝輔; 渡邉 智裕; 工藤 正俊

  日本消化器病学会近畿支部例会プログラム・抄録集 日本消化器病学会-近畿支部 115回 81 - 81 2021/09
• EUS-FNAにて術前診断できた食道schwannomaの1例

  福西 香栄; 松井 繁長; 杉森 啓伸; 高田 隆太郎; 正木 翔; 河野 匡志; 永井 知行; 米田 頼晃; 山崎 友裕; 山雄 健太郎; 竹中 完; 本庶 元; 渡邉 智裕; 辻 直子; 樫田 博史; 工藤 正俊; 白石 治; 安田 卓司

  日本消化器病学会近畿支部例会プログラム・抄録集 日本消化器病学会-近畿支部 115回 79 - 79 2021/09
• 消化器疾患とかかわる要注意人物〜NOD様受容体〜

  渡邉智裕; 三長孝輔; 工藤正俊

  消化器病学サイエンス 5 (3) 179 - 184 2432-7549 2021/09 [Invited]
  
• NOD2 deficiency protects mice from the development of adoptive transfer colitis through the induction of regulatory T cells expressing forkhead box P3

  Ryutaro Takada; Tomohiro Watanabe; Akane Hara; Ikue Sekai; Masayuki Kurimoto; Yasuo Otsuka; Yasuhiro Masuta; Tomoe Yoshikawa; Ken Kamata; Kosuke Minaga; Masatoshi Kudo

  Biochemical and Biophysical Research Communications Elsevier BV 568 55 - 61 0006-291X 2021/09 [Refereed]
   

  Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular receptor for muramyl dipeptide derived from the intestinal microbiota. Loss-of-function mutations in Nod2 are associated with the development of Crohn's disease, suggesting that NOD2 signaling plays critical roles in the maintenance of intestinal immune homeostasis. Although NOD2 activation prevents the development of short-term experimental colitis, it remains unknown whether the sensitivity to long-term experimental colitis is influenced by NOD2. In this study, we explored the roles played by NOD2 in the development of long-term adoptive transfer colitis. Unexpectedly, we found that Rag1-/-Nod2-/- mice were more resistant to adoptive transfer colitis than Rag1-/- mice and had reduced proinflammatory cytokine responses and enhanced accumulation of regulatory T cells (Tregs) expressing forkhead box P3 in the colonic mucosa. Prevention of colitis in Rag1-/-Nod2-/- mice was mediated by TGF-β1 because neutralization of TGF-β1 resulted in the development of more severe colitis due to reduced accumulation of Tregs. Such paradoxical Treg responses in the absence of NOD2 could explain why Nod2 mutations in humans are not sufficient to cause Crohn's disease.
• Utility of contrast-enhanced harmonic endoscopic ultrasonography for T-staging of patients with extrahepatic bile duct cancer

  Yasuo Otsuka; Ken Kamata; Tomoko Hyodo; Takaaki Chikugo; Akane Hara; Hidekazu Tanaka; Tomoe Yoshikawa; Rei Ishikawa; Ayana Okamoto; Tomohiro Yamazaki; Atsushi Nakai; Shunsuke Omoto; Kosuke Minaga; Kentaro Yamao; Mamoru Takenaka; Yasutaka Chiba; Tomohiro Watanabe; Takuya Nakai; Ippei Matsumoto; Yoshifumi Takeyama; Masatoshi Kudo

  Surgical Endoscopy Springer Science and Business Media LLC 36 (5) 3254 - 3260 0930-2794 2021/08 [Refereed]
   

  BACKGROUND: The value of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for T-staging in patients with extrahepatic bile duct cancer was evaluated. METHODS: This single-center, retrospective study included consecutive patients with extrahepatic bile duct cancer who underwent surgical resection after preoperative EUS, CH-EUS, and contrast-enhanced CT (CE-CT) examinations between June 2014 and August 2017. The capacity of these modalities for T-staging of extrahepatic bile duct cancer was evaluated by assessing invasion beyond the biliary wall into the surrounding tissue, gallbladder, liver, pancreas, duodenum, portal vein system (portal vein and/or superior mesenteric vein), inferior vena cava, and hepatic arteries (proper hepatic artery, right. and/or left. hepatic artery). Blind reading of EUS, CH-EUS, and CE-CT images was performed by two expert reviewers each. RESULTS: 38 patients were eligible for analysis, of which eight had perihilar bile duct cancer and 30 had distal bile duct cancer. Postoperative T-staging was T1 in 6, T2 in 16, and T3 in 16 cases. CH-EUS was superior to CE-CT for diagnosing invasion beyond the biliary wall into surrounding tissue (92.1% vs. 45.9%, P = 0.0002); the ability to detect invasion to other organs did not differ significantly between the two modalities. The accuracy of CH-EUS for T-staging of tumors was better than that of CE-CT (73.7% vs. 39.5%, P = 0.0059). CH-EUS tended to have a better accuracy than EUS for the diagnosis of invasion beyond the biliary wall into the surrounding tissue (92.1% vs. 78.9%, P = 0.074) and T-staging (73.7% vs. 60.5%, P = 0.074). CONCLUSION: CH-EUS is useful for T-staging of extra hepatic bile duct cancer, especially in terms of invasion beyond the biliary wall into the surrounding tissue.
• Diagnostic Value of EUS-Guided Fine-Needle Aspiration Biopsy for Gastric Linitis Plastica with Negative Endoscopic Biopsy

  Ryutaro Takada; Kosuke Minaga; Akane Hara; Yasuo Otsuka; Shunsuke Omoto; Ken Kamata; Kentaro Yamao; Mamoru Takenaka; Satoru Hagiwara; Hajime Honjo; Shigenaga Matsui; Takaaki Chikugo; Tomohiro Watanabe; Masatoshi Kudo

  Journal of Clinical Medicine MDPI AG 10 (16) 3716 - 3716 2021/08 [Refereed]
   

  Due to the tendency of gastric linitis plastica (GLP) to cause extensive submucosal infiltration, a superficial endoscopic biopsy sometimes yields no evidence of malignancy, hindering definite diagnosis. The present study was a single-center retrospective analysis of 54 consecutive patients diagnosed with GLP between 2016 and 2020 to evaluate EUS-guided fine-needle aspiration (EUS-FNA) biopsy outcomes in patients with negative endoscopic biopsy findings. A pathological GLP diagnosis was achieved by endoscopic biopsy in 40 patients (74.1%). EUS-FNA biopsy with a 22-gauge needle was performed in 13 of the remaining 14 patients, and GLP diagnosis was confirmed in 10 patients, with a median of three needle passes. The remaining four patients were laparoscopically diagnosed with GLP. The diagnostic ability of EUS-FNA biopsy for GLP was 76.9%, and EUS-FNA biopsy contributed to GLP diagnosis in 18.5% (10/54) of all cases. None of the 13 patients exhibited EUS-FNA biopsy-related adverse events. Univariable and multivariable analyses revealed an absence of superficial ulcerations as a predictor of false-negative endoscopic biopsy findings in patients with GLP. These results suggest EUS-FNA biopsy as a minimally invasive and safe alternative diagnostic modality for GLP in cases where conventional endoscopic biopsy fails to verify malignancy, although prospective studies with larger cohorts are warranted to confirm these findings.
• Plasmacytoid Dendritic Cells as a New Therapeutic Target for Autoimmune Pancreatitis and IgG4-Related Disease

  Kosuke Minaga; Tomohiro Watanabe; Akane Hara; Tomoe Yoshikawa; Ken Kamata; Masatoshi Kudo

  Frontiers in Immunology Frontiers Media SA 12 713779 - 713779 2021/07 [Refereed][Invited]
   

  Although plasmacytoid dendritic cells (pDCs) able to produce large amounts of type 1 interferons (IFN-I) play beneficial roles in host defense against viral infections, excessive activation of pDCs, followed by robust production of IFN-I, causes autoimmune disorders including systemic lupus erythematosus (SLE) and psoriasis. Autoimmune pancreatitis (AIP), which is recognized as a pancreatic manifestation of systemic immunoglobulin G4-related disease (IgG4-RD), is a chronic fibroinflammatory disorder driven by autoimmunity. IgG4-RD is a multi-organ autoimmune disorder characterized by elevated serum concentrations of IgG4 antibody and infiltration of IgG4-expressing plasmacytes in the affected organs. Although the immunopathogenesis of IgG4-RD and AIP has been poorly elucidated, recently, we found that activation of pDCs mediates the development of murine experimental AIP and human AIP/IgG4-RD via the production of IFN-I and interleukin-33 (IL-33). Depletion of pDCs or neutralization of signaling pathways mediated by IFN-I and IL-33 efficiently inhibited the development of experimental AIP. Furthermore, enhanced expression of IFN-I and IL-33 was observed in the pancreas and serum of human AIP/IgG4-RD. Thus, AIP and IgG4-RD share their immunopathogenesis with SLE and psoriasis because in all these conditions, IFN-I production by pDCs contributes to the pathogenesis. Because the enhanced production of IFN-I and IL-33 by pDCs promotes chronic inflammation and fibrosis characteristic for AIP and IgG4-RD, neutralization of IFN-I and IL-33 could be a new therapeutic option for these disorders. In this Mini Review, we discuss the pathogenic roles played by the pDC-IFN-I-IL-33 axis and the development of a new treatment targeting this axis in AIP and IgG4-RD.
• Case Report: Regulatory T Cell-Independent Induction of Remission in a Patient With Collagenous Colitis

  Hajime Honjo; Tomohiro Watanabe; Mizuki Tomooka; Takuya Matsubara; Masashi Kono; Ikue Sekai; Akane Hara; Masayuki Kurimoto; Keisuke Yoshikawa; Yasuhiro Masuta; Yasuo Otsuka; Ryutaro Takada; Tomoe Yoshikawa; Ken Kamata; Kosuke Minaga; Shigenaga Matsui; Masatomo Kimura; Masatoshi Kudo

  Frontiers in Medicine Frontiers Media SA 8 678268 - 678268 2021/07 [Refereed]
   

  Collagenous colitis (CC), a prototypical microscopic colitis, is a chronic inflammatory disorder of the colon. The diagnosis of CC depends on the pathological examination. The colonic mucosa of patients with CC is characterized by the presence of a substantially thickened collagen band (>10μm) under the surface epithelium. In addition, intraepithelial and lamina propria lymphocytes are markedly increased in patients with CC. However, the roles played by the lymphocytes accumulating in the colonic mucosa of patients with CC are poorly defined. Recent studies indicate that T cells infiltrating the colonic mucosa of patients with CC are mainly represented by CD4⁺ T cells, CD8⁺ T cells, and forkhead box P3 (FOXP3)⁺ regulatory T cells (Tregs). Given that activation of CD4⁺/CD8⁺ T cells and FOXP3⁺ Tregs usually mediates pro-inflammatory and anti-inflammatory responses, respectively, alterations in the colonic numbers of these adaptive T cells might be related to the resolution of colitis in patients with CC. We determined alterations in the composition of colonic T cells by extensive immunohistochemical (IHC) analyses in a case of CC successfully treated with budesonide and metronidazole. Colonic lamina propria immune cells mainly comprised CD3⁺ T cells, CD4⁺ T cells, CD8⁺ T cells, CD68⁺ macrophages, and FOXP3⁺ Tregs, but not CD20⁺ B cells or myeloperoxidase (MPO)⁺ granulocytes in the active phase. During remission, the numbers of CD3⁺ T cells, CD4⁺ T cells, CD8⁺ T cells, and CD68⁺ macrophages did not change significantly in the colonic lamina propria, whereas FOXP3⁺ Tregs were markedly decreased, suggesting that induction of remission was achieved in a Treg-independent manner. Thus, our study indicates that accumulation of FOXP3⁺ Tregs in the colonic mucosa of patients with CC might be a counter-regulatory mechanism reflecting persistent inflammation and that induction of remission might be achieved without activation of Tregs.
• Castor oil as booster for colon capsule endoscopy preparation reduction: A prospective pilot study and patient questionnaire

  Kota Takashima; Yoriaki Komeda; Toshiharu Sakurai; Sho Masaki; Tomoyuki Nagai; Shigenaga Matsui; Satoru Hagiwara; Mamoru Takenaka; Naoshi Nishida; Hiroshi Kashida; Konosuke Nakaji; Tomohiro Watanabe; Masatoshi Kudo

  World Journal of Gastrointestinal Pharmacology and Therapeutics Baishideng Publishing Group Inc. 12 (4) 79 - 89 2150-5349 2021/07
• 内視鏡で保存的に回収できた胃石の1例

  杉森 啓伸; 本庶 元; 原 茜; 益田 康弘; 吉田 早希; 高田 隆太郎; 河野 匡志; 正木 翔; 永井 知行; 米田 頼晃; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 辻 直子; 樫田 博史; 工藤 正俊

  日本消化器内視鏡学会近畿支部例会プログラム・抄録集 日本消化器内視鏡学会-近畿支部 106回 98 - 98 2021/07
• 内視鏡で保存的に回収できた胃石の1例

  杉森 啓伸; 本庶 元; 原 茜; 益田 康弘; 吉田 早希; 高田 隆太郎; 河野 匡志; 正木 翔; 永井 知行; 米田 頼晃; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 辻 直子; 樫田 博史; 工藤 正俊

  日本消化器内視鏡学会近畿支部例会プログラム・抄録集 日本消化器内視鏡学会-近畿支部 106回 98 - 98 2021/07
• Immunohistochemical characterization of granulomatosis with polyangiitis exhibiting spontaneous regression

  Yasuhiro Masuta; Yoriaki Komeda; Ikue Sekai; Akane Hara; Masayuki Kurimoto; Keisuke Yoshikawa; Yasuo Otsuka; Ryutaro Takada; Tomoe Yoshikawa; Ken Kamata; Kosuke Minaga; Osamu Maenishi; Tomohiro Watanabe; Masatoshi Kudo

  Asian Pacific Journal of Allergy and Immunology Allergy, Asthma, and Immunology Association of Thailand 0125-877X 2021/07 [Refereed]
   

  BACKGROUND: Granulomatosis with polyangiitis (GPA) is characterized by granulomatous inflammation, vasculitis, and elevated levels of serum proteinase 3 (PR3)-anti-neutrophil cytoplasmic antibody (PR3-ANCA). OBJECTIVE: We tried to characterize immune cells accumulated into the lung lesions of a GPA patient exhibiting spontaneous regression. METHODS: Transbronchial lung biopsy (TBLB) samples were subjected to immunohistochemical analyses. RESULTS: Multiple lung nodules were detected by CT. TBLB showed granulomatous inflammation and small vessel vasculitis. This case was diagnosed as GPA based on pathological findings and elevation of PR-3 ANCA levels. Spontaneous disappearance of multiple lung nodules was observed in CT. CD3+ T cells and CD20+ B cells accumulated in the inflammatory lesions surrounding the vessels whereas granulomatous inflammation was mainly comprised of CD3+ T cells and CD68+ macrophages, but not B cells or myeloperoxidase+ neutrophils. CONCLUSIONS: We characterized immune cell compositions of the lung lesions of a patient with GPA exhibiting spontaneous regression.
• Artificial intelligence-based endoscopic diagnosis of colorectal polyps using residual networks

  Yoriaki Komeda; Hisashi Handa; Ryoma Matsui; Shohei Hatori; Riku Yamamoto; Toshiharu Sakurai; Mamoru Takenaka; Satoru Hagiwara; Naoshi Nishida; Hiroshi Kashida; Tomohiro Watanabe; Masatoshi Kudo

  PLOS ONE Public Library of Science (PLoS) 16 (6) e0253585 - e0253585 2021/06 [Refereed]
   

  Convolutional neural networks (CNNs) are widely used for artificial intelligence (AI)-based image classification. Residual network (ResNet) is a new technology that facilitates the accuracy of image classification by CNN-based AI. In this study, we developed a novel AI model combined with ResNet to diagnose colorectal polyps. In total, 127,610 images consisting of 62,510 images with adenomatous polyps, 30,443 with non-adenomatous hyperplastic polyps, and 34,657 with healthy colorectal normal mucosa were subjected to deep learning after annotation. Each validation process was performed using 12,761 stored images of colorectal polyps by a 10-fold cross validation. The efficacy of the ResNet system was evaluated by sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy. The sensitivity, specificity, PPV, NPV, and diagnostic accuracy for adenomatous polyps at WLIs were 98.8%, 94.3%, 90.5%, 87.4%, and 92.8%, respectively. Similar results were obtained for adenomatous polyps at narrow-band imagings (NBIs) and chromoendoscopy images (CEIs) (NBIs vs. CEIs: sensitivity, 94.9% vs. 98.2%; specificity, 93.9% vs. 85.8%; PPV, 92.5% vs. 81.7%; NPV, 93.5% vs. 99.9%; and overall accuracy, 91.5% vs. 90.1%). The ResNet model is a powerful tool that can be used for AI-based accurate diagnosis of colorectal polyps.
• Case Report: Concurrent Occurrence of Abdominal Double Expressor Lymphoma and Jejunum Follicular Lymphoma

  Ryutaro Takada; Tomohiro Watanabe; Ikue Sekai; Keisuke Yoshikawa; Akane Hara; Yasuo Otsuka; Tomoe Yoshikawa; Ken Kamata; Kosuke Minaga; Yoriaki Komeda; Takaaki Chikugo; Yasuyuki Arai; Kohei Yamashita; Masatoshi Kudo

  Frontiers in Oncology Frontiers Media SA 11 656219 - 656219 2021/05 [Refereed]
   

  Double expressor lymphoma (DEL), defined as overexpression of BCL2 and MYC, is an aggressive subtype of diffuse large B cell lymphoma (DLBCL). Here we report a case of a 64-year-old female diagnosed with abdominal DEL transformed from jejunum follicular lymphoma (FL). 18F-fluorodeoxyglucose (FDG)-positron emission tomography showed diffuse accumulation of FDG into the peritoneum and small bowel wall. Double balloon-assisted enteroscopy revealed whitish submucosal tumors in the proximal jejunum. Aggregation of atypical lymphocytes positive for CD20, CD79a, and BCL2 was seen in the jejunal biopsy samples. These atypical lymphocytes were monoclonal since cell surface expression of Ig light chains was limited to κ chain by flow-cytometry. Thus, immunohistochemical and flowcytometric analyses data were consistent with FL of the jejunum. Neoplastic lymphocytes obtained from ascites were positive for CD10, CD20, CD79a, BCL2, and BCL6. Fluorescence in situ hybridization (FISH) showed formation of BCL2/IgH fusion gene and extra copies of MYC, the former of which is a characteristic chromosomal abnormality of FL. These genetic alterations and protein expression profiles of ascitic fluid cells were consistent with those of DEL transformed from FL. Given that a significant population of patients with indolent FL of the gastrointestinal tract developed into aggressive DLBCL, it is likely that primary FL of the jejunum transformed into the abdominal aggressive DEL in this case. This case is unique in that concurrent occurrence of FL and DEL was confirmed by immunohistochemical and FISH analyses and that abdominal DEL transformed from jejunal FL was highly suspected.
• Biomarkers in autoimmune pancreatitis and immunoglobulin G4-related disease

  Akane Hara; Tomohiro Watanabe; Kosuke Minaga; Tomoe Yoshikawa; Ken Kamata; Masatoshi Kudo

  World Journal of Gastroenterology Baishideng Publishing Group Inc. 27 (19) 2257 - 2269 1007-9327 2021/05 [Refereed][Invited]
   

  Solitary organ autoimmune disorders, formerly known as autoimmune pancreatitis (AIP), autoimmune sialadenitis, and autoimmune sclerosing cholangitis, are now considered organ-specific manifestations of systemic immunoglobulin G4-related disease (IgG4-RD). AIP and IgG4-RD are characterized by elevated serum concentration of IgG4 antibody (Ab), accumulation of IgG4-expressing plasmacytes in the affected organs, and involvement of multiple organs. It is well established that enhanced IgG4 Ab responses are a hallmark of AIP and IgG4-RD for diagnosis and monitoring disease activity. However, a significant fraction of patients with AIP and IgG4-RD who develop chronic fibroinflammatory responses have normal serum concentrations of this IgG subtype. In addition, disease flare-up is sometimes seen even in the presence of normalized serum concentrations of IgG4 Ab after successful induction of remission by prednisolone. Therefore, it is necessary to identify new biomarkers based on the understanding of the pathophysiology of AIP and IgG4-RD. Recently, we found that activation of plasmacytoid dendritic cells producing both interferon-α (IFN-α) and interleukin-33 (IL-33) mediate murine AIP and human IgG4-RD. More importantly, we provided evidence that serum concentrations of IFN-α and IL-33 could be useful biomarkers for the diagnosis and monitoring of AIP and IgG4-RD activity after induction of remission in these autoimmune disorders. In this Frontier article, we have summarized and discussed biomarkers of AIP and IgG4-RD, including Igs, autoAbs, and cytokines to provide useful information not only for clinicians but also for researchers.
• Reply to “Contrast‐enhanced harmonic EUS: an additional tool to predict clinical behaviour of Pancreatic NENs” by Tamanini et al.

  Rei Ishikawa; Ken Kamata; Tomohiro Watanabe

  Digestive Endoscopy Wiley 33 (5) 878 - 879 0915-5635 2021/05 [Refereed][Invited]
  
• Case Report: A Case of Intestinal Behçet's Disease Exhibiting Enhanced Expression of IL-6 and Forkhead Box P3 mRNA After Treatment With Infliximab

  Keisuke Yoshikawa; Tomohiro Watanabe; Ikue Sekai; Ryutaro Takada; Akane Hara; Masayuki Kurimoto; Yasuhiro Masuta; Yasuo Otsuka; Tomoe Yoshikawa; Sho Masaki; Ken Kamata; Kosuke Minaga; Yoriaki Komeda; Takaaki Chikugo; Masatoshi Kudo

  Frontiers in Medicine Frontiers Media SA 8 679237 - 679237 2021/05 [Refereed]
   

  Behçet's disease (BD) is a rare inflammatory condition characterized by oral and genital ulcers, skin lesions, as well as ophthalmological, neurological, and gastrointestinal manifestations. BD involving the gastrointestinal tract is known as intestinal BD. The mucosa of the gastrointestinal tract of patients with intestinal BD exhibits enhanced levels of proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α. These proinflammatory cytokines play pathogenic roles in the development of BD, as evidenced by the fact that biologics targeting these cytokines effectively induce BD remission. It should be noted, however, that the molecular mechanisms by which the blockade of these cytokines suppresses chronic inflammatory responses in BD are poorly understood. Herein, we report a case of intestinal BD resistant to prednisolone that was successfully treated with infliximab (IFX). The induction of remission by IFX was accompanied by a marked elevation of IL-6 and forkhead box P3 (FOXP3) at mRNA level. This case suggests that induction of remission by IFX is mediated not only by the suppression of TNF-α-mediated signaling pathways, but also by the promotion of IL-6 expression and accumulation of regulatory T cells expressing FOXP3.
• Should Contrast-Enhanced Harmonic Endoscopic Ultrasound Be Incorporated into the International Consensus Guidelines to Determine the Appropriate Treatment of Intraductal Papillary Mucinous Neoplasm?

  Tomohiro Yamazaki; Mamoru Takenaka; Shunsuke Omoto; Tomoe Yoshikawa; Rei Ishikawa; Ayana Okamoto; Atsushi Nakai; Kosuke Minaga; Ken Kamata; Kentaro Yamao; Yoriaki Komeda; Tomohiro Watanabe; Naoshi Nishida; Keiko Kamei; Ippei Matsumoto; Yoshifumi Takeyama; Takaaki Chikugo; Yasutaka Chiba; Masatoshi Kudo

  Journal of Clinical Medicine MDPI AG 10 (9) 1818 - 1818 2021/04 [Refereed]
   

  This study aimed to investigate whether the incorporation of contrast-enhanced harmonic endoscopic ultrasound (CH-EUS) into the international consensus guidelines (ICG) for the management of intraductal papillary mucinous neoplasm (IPMN) could improve its malignancy diagnostic value. In this single-center retrospective study, 109 patients diagnosed with IPMN who underwent preoperative CH-EUS between March 2010 and December 2018 were enrolled. We analyzed each malignancy diagnostic value (sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV)) by replacing fundamental B-mode EUS with CH-EUS as the recommended test for patients with worrisome features (WF) (the CH-EUS incorporation ICG) and comparing the results to those obtained using the 2017 ICG. The malignancy diagnostic values as per the 2017 ICG were 78.9%, 42.3%, 60.0%, and 64.7% for Se, Sp, PPV, and NPV, respectively. The CH-EUS incorporation ICG plan improved the malignancy diagnostic values (Se 78.9%/Sp, 53.8%/PPV, 65.2%/NPV 70.0%). CH-EUS may be useful in determining the appropriate treatment strategies for IPMN.
• A case with Crohn's disease-associated spondyloarthritis exhibiting enhanced pro-inflammatory cytokine responses to Toll-like receptor ligands.

  Hajime Honjo; Tomohiro Watanabe; Natsuki Okai; Masashi Kono; Ken Kamata; Kosuke Minaga; Yoriaki Komeda; Shigeyoshi Tsuji; Masatoshi Kudo

  Asian Pacific journal of allergy and immunology 2021/04 [Refereed]
   

  BACKGROUND: Despite the high incidence of spondyloarthritis (SpA) as an extra-intestinal manifestation of Crohn's disease (CD), the immunopathogenesis of CD-associated SpA remains largely unknown. OBJECTIVE: We tried to explore molecular mechanisms accounting for the development of CD-associated SpA in a patient successfully treated with infliximab. METHODS: Peripheral blood mononuclear cells (PBMCs) before infliximab treatment were stimulated with Toll-like receptor (TLR) ligands to measure pro-inflammatory cytokine responses. Endoscopic biopsy samples before and after infliximab treatment were subjected to quantitative polymerase chain reaction. RESULTS: PBMCs from this CD-associated SpA patient exhibited higher production of pro-inflammatory cytokines upon stimulation with TLR ligands than PBMCs from healthy controls. Induction of remission by infliximab was associated with the downregulation of pro-inflammatory cytokine responses in the small intestinal mucosa, which is continually exposed to TLR ligands. CONCLUSIONS: Excessive pro-inflammatory cytokine responses to TLR ligands might underlie the immunopathogenesis of CD-associated SpA.
• RIPK2 as a New Therapeutic Target in Inflammatory Bowel Diseases

  Hajime Honjo; Tomohiro Watanabe; Ken Kamata; Kosuke Minaga; Masatoshi Kudo

  Frontiers in Pharmacology Frontiers Media SA 12 650403 - 650403 2021/04 [Refereed][Invited]
   

  Inflammatory bowel diseases (IBDs) are becoming more frequent worldwide. A significant fraction of patients with IBD are refractory to various types of therapeutic biologics and small molecules. Therefore, identification of novel therapeutic targets in IBD is required. Receptor-interacting serine/threonine kinase 2 (RIPK2), also known as receptor-interacting protein 2 (RIP2), is a downstream signaling molecule for nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs). RIPK2 is expressed in antigen-presenting cells, such as dendritic cells and macrophages. Recognition of microbe-associated molecular patterns by NOD1, NOD2, and TLRs leads to the interaction between RIPK2 and these innate immune receptors, followed by the release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12/23p40 through the activation of nuclear factor kappa B and mitogen-activated protein kinases. Thus, activation of RIPK2 plays a critical role in host defense against microbial infections. Recent experimental and clinical studies have provided evidence that activation of RIPK2 is involved in the development of autoimmune diseases, especially IBDs. In addition, the colonic mucosa of patients with IBD exhibits enhanced expression of RIPK2 and associated signaling molecules. Furthermore, the blockage of RIPK2 activation ameliorates the development of experimental murine colitis. Thus, activation of RIPK2 underlies IBD immunopathogenesis. In this review, we attempt to clarify the roles played by RIPK2 in the development of IBD by focusing on its associated signaling pathways. We also discuss the possibility of using RIPK2 as a new therapeutic target in IBD.
• Clinicopathological analysis of hepatic immune-related adverse events in comparison with autoimmune hepatitis and graft-versus host disease

  Satoru Hagiwara; Tomohiro Watanabe; Masatoshi Kudo; Kosuke Minaga; Yoriaki Komeda; Ken Kamata; Masatomo Kimura; Hidetoshi Hayashi; Kazuhiko Nakagawa; Kazuomi Ueshima; Yasunori Minami; Tomoko Aoki; Masahiro Takita; Masahiro Morita; Hirokazu Cishina; Hiroshi Ida; Ah-Mee Park; Naoshi Nishida

  Scientific Reports Springer Science and Business Media LLC 11 (1) 9242 - 9242 2021/04 [Refereed]
   

  Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8⁺ T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4⁺ T cells, CD8⁺ T cells, CD20⁺ B cells, and FOXP3⁺ Tregs. Overall, the activation of CD8⁺ T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs.
• A Mimicker of Intraductal Papillary Mucinous Carcinoma of the Pancreas

  Akihiro Yoshida; Kentaro Yamao; Tomohiro Watanabe

  Gastroenterology Elsevier BV 161 (5) e8-e11  0016-5085 2021/04 [Refereed]
  
• Intestinal Dysbiosis and Autoimmune Pancreatitis

  Tomoe Yoshikawa; Tomohiro Watanabe; Ken Kamata; Akane Hara; Kosuke Minaga; Masatoshi Kudo

  Frontiers in Immunology Frontiers Media SA 12 621532 - 621532 2021/03 [Refereed][Invited]
   

  Autoimmune pancreatitis (AIP) is a chronic fibro-inflammatory disorder of the pancreas. Recent clinicopathological analysis revealed that most cases of AIP are pancreatic manifestations of systemic IgG4-related disease (IgG4-RD), a newly established disease characterized by enhanced IgG4 antibody responses and the involvement of multiple organs. Although the immuno-pathogenesis of AIP and IgG4-RD has been poorly defined, we recently showed that activation of plasmacytoid dendritic cells (pDCs) with the ability to produce large amounts of IFN-α and IL-33 mediates chronic fibro-inflammatory responses in experimental and human AIP. Moreover, M2 macrophages producing a large amount of IL-33 play pathogenic roles in the development of human IgG4-RD. Interestingly, recent studies including ours provide evidence that compositional alterations of gut microbiota are associated with the development of human AIP and IgG4-RD. In addition, intestinal dysbiosis plays pathological roles in the development of chronic pancreatic inflammation as dysbiosis mediates the activation of pDCs producing IFN-α and IL-33, thereby causing experimental AIP. In this Mini Review, we focus on compositional alterations of gut microbiota in AIP and IgG4-RD to clarify the mechanisms by which intestinal dysbiosis contributes to the development of these disorders.
• A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells

  Ikue Sekai; Satoru Hagiwara; Tomohiro Watanabe; Masatoshi Kudo

  Clinical Journal of Gastroenterology Springer Science and Business Media LLC 14 (4) 1191 - 1196 1865-7257 2021/03 [Refereed]
   

  Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8⁺ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8⁺ T cells but also by defective accumulation of FOXP3⁺ Tregs.
• Akkermansia muciniphila

  三長孝輔; 渡邉智裕; 工藤正俊

  消化器病学サイエンス 5 (1) 49 - 49 2432-7549 2021/03 [Invited]
  
• Clinical characteristics of immunoglobulin IgG4-related sclerosing cholangitis: Comparison of cases with and without autoimmune pancreatitis in a large cohort

  Itaru Naitoh; Terumi Kamisawa; Atsushi Tanaka; Takahiro Nakazawa; Kensuke Kubota; Hajime Takikawa; Michiaki Unno; Atsushi Masamune; Shigeyuki Kawa; Seiji Nakamura; Kazuichi Okazaki; Keisuke Furumatsu; Shigeaki Sawai; Takuma Goto; Toshikatsu Okumura; Daisuke Suzuki; Masayuki Otsuka; Ikuhiro Kobori; Masaya Tamano; Mitsuhito Koizumi; Yoichi Hiasa; Naoto Kawabe; Yoshiki Hirooka; Satoshi Yamamoto; Yukio Asano; Kazuo Inui; Akihiko Horiguchi; Hiroyuki Watanabe; Daishu Toya; Katsuko Hatayama; Toshiharu Ueki; Norikatsu Kinoshita; Mitsuru Sugimoto; Hiromasa Ohira; Tsuyoshi Mukai; Eiichi Tomita; Keisuke Iwata; Shogo Shimizu; Jun Suetsugu; Masahito Shimizu; Keiji Tsuji; Ryoko Ishida; Masanori Ito; Ryutaro Furukawa; Naoya Sakamoto; Masahiro Araki; Satoshi Tanno; Yasunari Sakamoto; Tetsuhide Ito; Satoshi Takai; Shinichi Ikeya; Takanori Yamada; Norihiko Kudara; Akinori Shimizu; Keiji Hanada; Yasunori Ichiki; Hideki Kitada; Michio Hifumi; Hiroyuki Kimura; Masayuki Kurosaki; Namiki Izumi; Hajime Sumi; Jun-ichi Haruta; Katsumi Hayashi; Ryo Harada; Masafumi Inoue; Shinichiro Nakamura; Tetsuya Ito; Ko Tomishima; Hiroyuki Isayama; Kyoko Oura; Tsutomu Masaki; Naoto Shimokawahara; Shirou Tanoue; Kousei Maemura; Akio Ido; Ichiro Mizushima; Mitsuhiro Kawano; Katsunori Yoshida; Makoto Naganuma; Miki Murata; Akiyoshi Nishio; Yuji Fujita; Takuma Teratani; Shohei Matsubara; Hironao Tamai; Yuu Yoshida; Ryousaku Azemoto; Ken Kamata; Tomohiro Watanabe; Takahiro Kurosu; Wasaburou Koizumi; Jun Fujita; Hideyuki Seki; Yasuhiro Ueda; Takumi Fukumoto; Takuhiro Kousaki; Kazushige Uchida; Toshimasa Ochiai; Takeshi Kawasaki; Motohiko Tanaka; Etsuji Ishida; Kenji Notohara; Hideaki Mori; Toshiyuki Mori; Hideaki Kawabata; Masatoshi Miyata; Junichi Sakagami; Yoshito Itoh; Masahiro Shiokawa; Hiroshi Seno; Noriko Watanabe; Itaru Naitoh; Hiromi Kataoka; Toshinori Aoki; Mitsuhiro Fujishiro; Toru Niihara; Hiroto Nishimata; Akira Mitoro; Hitoshi Yoshiji; Motoyuki Yoshida; Masafumi Ikeda; Kengo Tomita; Ryota Hokari; Kenji Hayasaka; Yuji Amano; Kazuhiko Shioji; Kazunao Hayashi; Shuji Terai; Michiko Nakajima; Junya Yamahana; Ryusuke Matsumoto; Hideaki Kikuchi; Akira Kanamori; Seiki Kiriyama; Shinichi Iwatsu; Yuji Kato; Shigeru Horiguchi; Takahito Yagi; Hiroyuki Okada; Kazuyoshi Ohkawa; Motohiro Hirao; Naoki Hiramatsu; Noriko Oza; Haruo Imamura; Takeshi Baba; Shigeru Nakano; Tetsuya Shinobi; Shomei Ryozawa; Masayo Motoya; Hiroshi Nakase; Noboru Kinoshita; Kei Ito; Tatsuya Miyake; Naruaki Kohge; Hiroshi Tobita; Satoru Joshita; Takeji Umemura; Shinya Kawaguchi; Kazuya Ohno; Koichi Sonobe; Akihiko Satoh; Tooru Shimosegawa; Fumihiko Miura; Minami Yagi; Keiji Sano; Atsushi Tanaka; Toshifumi Kin; Akio Katanuma; Kazuhiko Koike; Shin Miura; Atsushi Masamune; Youhei Kawashima; Tatehiro Kagawa; Seishin Azuma; Mamoru Watanabe; Mitsuyoshi Honjyo; Takao Itoi; Akira Honda; Katsumasa Kobayashi; Toru Asano; Terumi Kamisawa; Suguru Mizuno; Kazuhiko Koike; Takayoshi Nishino; Hideaki Taniguchi; Kazuto Tajiri; Ichiro Yasuda; Yoshiya Tanaka; Shinji Oe; Masaru Harada; Masanao Kurata; Mituharu Fukasawa; Nobuyuki Enomoto; Yuki Kawaji; Masayuki Kitano; Yuko Nishise; Hidetoshi Hirakawa; Tetsuya Ishizawa; Yoshiyuki Ueno; Miyuki Kaino; Yuko Fujimoto; Isao Sakaida; Kensuke Kubota

  Digestive and Liver Disease Elsevier BV 53 (10) 1308 - 1314 1590-8658 2021/03 [Refereed]
   

  BACKGROUND: The clinical characteristics of IgG4-related sclerosing cholangitis (IgG4-SC) especially without autoimmune pancreatitis (AIP) have not been investigated in a large cohort. AIMS: To clarify the clinical characteristics of IgG4-SC and IgG4-SC without AIP. METHODS: We retrospectively reviewed imaging, serology, other organ involvement (OOI) and histology of 872 patients with IgG4-SC who participated in a Japanese nationwide survey in 2019, and compared these items between IgG4-SC with and without AIP. RESULTS: AIP was present in 83.7% (730/872) of IgG4-SC. In IgG4-SC, bile duct wall thickening was observed on ultrasound (528/650; 81.2%), computed tomography (375/525; 71.4%) and magnetic resonance imaging or cholangiopancreatography (290/440; 65.9%). An elevated serum IgG4 level (≥ 135 mg/dL) was found in 88.0% (322/366). IgG4-related OOI other than AIP was observed in 25.2% (211/836). The proportion of females was significantly higher in IgG4-SC without AIP (28.9% vs. 20.1%; p = 0.025). Hilar stricture was the most common cholangiographic type in IgG4-SC without AIP (39/107; 36.4%).There were no significant differences between IgG4-SC with and without AIP in the rates of bile duct wall thickening, elevated serum IgG4 level, or IgG4-related OOI. CONCLUSIONS: The clinical characteristics of IgG4-SC was similar between IgG4-SC with and without AIP in a large cohort.
• A unique profile of serum cytokines in type 1 autoimmune pancreatitis and chronic rhinosinusitis

  Tomoe Yoshikawa; Kosuke Minaga; Akane Hara; Ikue Sekai; Yasuo Otsuka; Ryutaro Takada; Ken Kamata; Tomohiro Watanabe; Masatoshi Kudo

  Asian Pacific Journal of Allergy and Immunology Allergy, Asthma, and Immunology Association of Thailand 0125-877X 2021/03 [Refereed]
   

  BACKGROUND: Type 1 autoimmune pancreatitis (AIP) is a pancreatic manifestation of IgG4-related disease (IgG4-RD). Although AIP and IgG4-RD are characterized by multiple organ involvement including salivary glands, lung, and kidney, co-occurrence of chronic rhinosinusitis (CRS) and AIP/IgG4-RD has been poorly defined. OBJECTIVE: We explored molecular mechanism accounting for the co-occurrence of CRS and AIP/IgG4-RD. METHODS: Serum concentrations of IFN-α and IL-33 were measured by enzyme-linked immune-sorbent assay. RESULTS: We encountered a patient with concurrent type 1 AIP/IgG4-RD and CRS. Induction of remission by prednisolone (PSL) for type 1 AIP/IgG4-RD led to a marked improvement of CRS. Serum cytokine analysis after PSL treatment revealed a marked reduction in serum concentrations of IFN-α and IL-33, both of which are candidate pathogenic cytokines for AIP/IgG4-RD. CONCLUSIONS: Given that IL-33 is shared as one of pathogenic cytokines by type 1 AIP/IgG4-RD and CRS, enhanced IL33 responses may cause concurrent type 1 AIP/IgG4-RD and CRS.
• Probiotic-Derived Polyphosphate Prevents Pancreatitis

  Kosuke Minaga; Tomohiro Watanabe; Masatoshi Kudo

  Digestive Diseases and Sciences Springer Science and Business Media LLC 0163-2116 2021/01 [Refereed][Invited]
  
• A case with eosinophilic gastroenteritis exhibiting enhanced TNF-α and IL-6 responses

  Ikue Sekai; Tomohiro Watanabe; Keisuke Yoshikawa; Ryutaro Takada; Akane Hara; Tomoe Yoshikawa; Ken Kamata; Kosuke Minaga; Masatoshi Kudo

  Clinical Journal of Gastroenterology Springer Science and Business Media LLC 1865-7257 2021/01 [Refereed]
   

  Eosinophilic gastroenteritis (EGE) is a chronic allergic disorder characterized by infiltration of eosinophils in the gastrointestinal (GI) tract and hypereosinophilia. Although T helper type 2 (Th2) responses play pathogenic roles in EGE, roles of innate immunity cytokines including IL-6 and TNF-α have been poorly defined. Here, we describe a case of EGE exhibiting accumulation of eosinophils in the upper GI mucosa and hypereosinophilia. Induction of remission by prednisolone reduced expression levels not only of Th2 cytokines but also of IL-6 and TNF-α in the GI mucosa. Moreover, induction of remission was accompanied by a marked reduction in serum levels of chemokine C-C motif ligand 17 (CCL17, TARC), IL-6 and TNF-α, implicating that both Th2 and innate immune responses were involved in the development of EGE in this case. Collectively, this case suggests possible involvement of IL-6 and TNF-α in the development of EGE.
• IgG4関連疾患と免疫異常ーとくに自然免疫系について

  渡邉 智裕; 工藤 正俊

  医学のあゆみ 医歯薬出版(株) 276 (2) 152 - 155 0039-2359 2021/01 [Invited]
   

  IgG4関連疾患はIgG4陽性形質細胞の罹患臓器への浸潤、血清IgG4値の上昇、多臓器病変を特色とする新規疾患概念である。IgG4関連疾患は"IgG4産生反応の亢進"を最大の免疫学的特徴としている。このため、これまでの病態研究は獲得免疫反応に重点をおいて解析を進められ、自然免疫反応については十分に解析されていなかった。最近、筆者らは形質細胞様樹状細胞(pDCs)の活性化とpDCsの産生するIFN-α・IL-33がIgG4関連疾患の病態に深く関与することを見出した。さらに、pDCsの活性化には腸内細菌叢の乱れ(dysbiosis)が関わることが明らかになった。"dysbiosisによって誘導されるpDCsの活性化とその産生するサイトカイン(IFN-α・IL-33)"がIgG4関連疾患の新規治療標的として期待される。(著者抄録)
• Utility of contrast‐enhanced harmonic endoscopic ultrasonography for predicting the prognosis of pancreatic neuroendocrine neoplasms

  Rei Ishikawa; Ken Kamata; Akane Hara; Hidekazu Tanaka; Ayana Okamoto; Tomohiro Yamazaki; Atsushi Nakai; Shunsuke Omoto; Kosuke Minaga; Kentaro Yamao; Mamoru Takenaka; Yasunori Minami; Tomohiro Watanabe; Yasutaka Chiba; Takaaki Chikugo; Ippei Matsumoto; Yoshifumi Takeyama; Yuko Matsukubo; Tomoko Hyodo; Masatoshi Kudo

  Digestive Endoscopy Wiley 33 (5) 829 - 839 0915-5635 2020/10 [Refereed]
   

  BACKGROUND AND AIMS: Pancreatic neuroendocrine neoplasms (PanNENs), including Grade 1 (G1) or G2 tumors, can have a poor prognosis. This study investigated the value of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for predicting the prognosis of PanNENs. METHODS: This single-center, retrospective study included 47 consecutive patients who underwent CH-EUS and were diagnosed with PanNEN by surgical resection or EUS-guided fine needle aspiration between December 2011 and February 2016. Patients were divided into aggressive and non-aggressive groups according to the degree of clinical malignancy. CH-EUS was assessed regarding its capacity for diagnosing aggressive PanNEN, the correspondence between contrast patterns and pathological features, and its ability to predict the prognosis of PanNEN. RESULTS: There were 19 cases of aggressive PanNEN and 28 cases of non-aggressive PanNEN. The aggressive group included three G1, four G2, three G3 tumors, three mixed neuroendocrine non-neuroendocrine neoplasms, and six neuroendocrine carcinomas. CH-EUS was superior to contrast-enhanced computed tomography for the diagnosis of aggressive PanNEN (P < 0.001): hypo-enhancement on CH-EUS was an indicator of aggressive PanNEN, with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 94.7%, 100%, 100%, 96.6%, and 97.9%, respectively. Among G1/G2 PanNENs, cases with hypo-enhancement on CH-EUS had a poorer prognosis than those with hyper/iso-enhancement (P = 0.0009). Assessment of 36 resected specimens showed that hypo-enhancement on CH-EUS was associated with smaller and fewer vessels and greater degree of fibrosis. CONCLUSION: Contrast-enhanced harmonic endoscopic ultrasonography may be useful for predicting the prognosis of PanNENs.
• 膵癌早期診断のための3D CT解析による膵実質萎縮の検討

  山雄 健太郎; 竹中 完; 石川 嶺; 沼本 勲; 鶴崎 正勝; 渡邉 智裕; 工藤 正俊

  日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増大会) A721 - A721 0446-6586 2020/10
• 消化器領域から見たIgG4関連疾患研究の進歩 IRF7-I型IFN-IL-33経路がIgG4関連疾患の病態に果たす役割とバイオマーカーとしての有用性

  三長 孝輔; 渡邉 智裕; 工藤 正俊

  日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増大会) A678 - A678 0446-6586 2020/10
• 拡大観察から見たPPI関連胃底腺ポリープの特徴

  友岡 瑞貴; 辻 直子; 高島 耕太; 正木 翔; 河野 匡志; 永井 知之; 米田 頼晃; 本庶 元; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 樫田 博史; 工藤 正俊

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 62 (Suppl.2) 2088 - 2088 0387-1207 2020/10
• 小腸内視鏡診療ガイドラインでのカプセル内視鏡検査の運用の実際

  米田 頼晃; 樫田 博史; 櫻井 俊治; 松村 まり子; 高島 耕太; 正木 翔; 河野 匡志; 山田 光成; 本庶 元; 永井 知行; 松井 繁長; 辻 直子; 渡邉 智裕; 工藤 正俊

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 62 (Suppl.2) 2113 - 2113 0387-1207 2020/10
• 消化器領域から見たIgG4関連疾患研究の進歩 IRF7-I型IFN-IL-33経路がIgG4関連疾患の病態に果たす役割とバイオマーカーとしての有用性

  三長 孝輔; 渡邉 智裕; 工藤 正俊

  日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増大会) A678 - A678 0446-6586 2020/10
• 拡大観察から見たPPI関連胃底腺ポリープの特徴

  友岡 瑞貴; 辻 直子; 高島 耕太; 正木 翔; 河野 匡志; 永井 知之; 米田 頼晃; 本庶 元; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 樫田 博史; 工藤 正俊

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 62 (Suppl.2) 2088 - 2088 0387-1207 2020/10
• 小腸内視鏡診療ガイドラインでのカプセル内視鏡検査の運用の実際

  米田 頼晃; 樫田 博史; 櫻井 俊治; 松村 まり子; 高島 耕太; 正木 翔; 河野 匡志; 山田 光成; 本庶 元; 永井 知行; 松井 繁長; 辻 直子; 渡邉 智裕; 工藤 正俊

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 62 (Suppl.2) 2113 - 2113 0387-1207 2020/10
• ATG16L1 negatively regulates RICK/RIP2-mediated innate immune responses

  Hajime Honjo; Tomohiro Watanabe; Yasuyuki Arai; Ken Kamata; Kosuke Minaga; Yoriaki Komeda; Kouhei Yamashita; Masatoshi Kudo

  International Immunology Oxford University Press (OUP) 33 (2) 91 - 105 2020/09 [Refereed]
   

  Polymorphisms in the autophagy-related protein 16 like 1 (ATG16L1) and nucleotide-binding oligomerization domain 2 (NOD2) genes are associated with Crohn’s disease (CD). Impaired interaction between ATG16L1 and NOD2 underlies CD immunopathogenesis. Although activation of the receptor-interacting serine/threonine kinase (RICK, also known as RIP2), a downstream signaling molecule for NOD2 and multiple toll-like receptors (TLRs), plays a pathogenic role in the development of inflammatory bowel disease, the molecular interaction between ATG16L1 and RICK/RIP2 remains poorly understood. In this study, we examined the physical interaction between ATG16L1 and RICK/RIP2 in human embryonic kidney 293 (HEK293) cells and human monocyte-derived dendritic cells (DCs) expressing excessive and endogenous levels of these proteins, respectively. We established that ATG16L1 binds to RICK/RIP2 kinase domain and negatively regulates TLR2-mediated nuclear factor-kappa B (NF-κB) activation and proinflammatory cytokine responses by inhibiting the interaction between TLR2 and RICK/RIP2. Binding of ATG16L1 to RICK/RIP2 suppressed NF-κB activation by downregulating RICK/RIP2 polyubiquitination. Notably, the percentage of colonic DCs expressing ATG16L1 inversely correlated with IL-6 and TNF-α expression levels in the colon of CD patients. These data suggest that the interaction between ATG16L1 and RICK/RIP2 maintains intestinal homeostasis via the downregulation of TLR-mediated proinflammatory cytokine responses.
• Gut microbiome alterations in type 1 autoimmune pancreatitis after induction of remission by prednisolone

  Ken Kamata; Tomohiro Watanabe; Kosuke Minaga; Akane Hara; Ikue Sekai; Yasuo Otsuka; Tomoe Yoshikawa; Ah‐Mee Park; Masatoshi Kudo

  Clinical & Experimental Immunology Wiley 202 (3) 308 - 320 0009-9104 2020/09 [Refereed]
  
• 直腸NENに対する治療の適応と工夫 当院での直腸NENの治療成績からみた治療方法の検討

  永井 知行; 樫田 博史; 益田 康弘; 友岡 瑞貴; 高島 耕太; 高田 隆太郎; 正木 翔; 河野 匡志; 米田 頼晃; 本庶 元; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 辻 直子; 工藤 正俊

  日本大腸肛門病学会雑誌 (一社)日本大腸肛門病学会 73 (9) A70 - A70 0047-1801 2020/09
• 直腸NENに対する治療の適応と工夫 当院での直腸NENの治療成績からみた治療方法の検討

  永井 知行; 樫田 博史; 益田 康弘; 友岡 瑞貴; 高島 耕太; 高田 隆太郎; 正木 翔; 河野 匡志; 米田 頼晃; 本庶 元; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 辻 直子; 工藤 正俊

  日本大腸肛門病学会雑誌 (一社)日本大腸肛門病学会 73 (9) A70 - A70 0047-1801 2020/09
• Identification of serum IFN-α and IL-33 as novel biomarkers for type 1 autoimmune pancreatitis and IgG4-related disease

  Kosuke Minaga; Tomohiro Watanabe; Akane Hara; Ken Kamata; Shunsuke Omoto; Atsushi Nakai; Yasuo Otsuka; Ikue Sekai; Tomoe Yoshikawa; Kentaro Yamao; Mamoru Takenaka; Yasutaka Chiba; Masatoshi Kudo

  Scientific Reports Springer Science and Business Media LLC 10 (1) 14879 - 14879 2020/09 [Refereed]
   

  IgG4-related disease (IgG4-RD) is a multi-organ autoimmune disease characterized by elevated serum IgG4 concentration. Although serum IgG4 concentration is widely used as a biomarker for IgG4-RD and type 1 autoimmune pancreatitis (AIP), a pancreatic manifestation of IgG4-RD, a significant number of patients have normal serum IgG4 levels, even in the active phase of the disease. Recently, we reported that the development of experimental AIP and human type 1 AIP is associated with increased expression of IFN-α and IL-33 in the pancreas. In this study, we assessed the utility of serum IFN-α and IL-33 levels as biomarkers for type 1 AIP and IgG4-RD. Serum IFN-α and IL-33 concentrations in patients who met the diagnostic criteria for definite type 1 AIP and/or IgG4-RD were significantly higher than in those with chronic pancreatitis or in healthy controls. Strong correlations between serum IFN-α, IL-33, and IgG4 concentrations were observed. Diagnostic performance of serum IFN-α and IL-33 concentrations as markers of type 1 AIP and/or IgG4-RD was comparable to that of serum IgG4 concentration, as calculated by the receiver operating characteristic curve analysis. Induction of remission by prednisolone treatment markedly decreased the serum concentration of these cytokines. We conclude that serum IFN-α and IL-33 concentrations can be useful as biomarkers for type 1 AIP and IgG4-RD.
• Verrucous antral gastritis in relation to Helicobacter pylori infection, nutrition, and gastric atrophy

  Naoko Tsuji; Yasuko Umehara; Mamoru Takenaka; Yasunori Minami; Tomohiro Watanabe; Naoshi Nishida; Masatoshi Kudo

  Gastroenterology Report Oxford University Press (OUP) 8 (4) 293 - 298 2020/08 [Refereed]
   

  There have been few studies in the English literature regarding verrucous gastritis (VG). The present study investigated the clinical and endoscopic features of verrucous antral gastritis, especially focusing on Helicobacter pylori infection, nutrition, and gastric atrophy. We performed a retrospective study of patients who underwent routine endoscopy with indigo carmine chromoendoscopy and a comparative study was conducted between VG-positive and VG-negative groups. VG was subdivided into classical and numerous types based on the number and distribution of verrucous lesions. Demographic, clinical, and endoscopic data including body mass index (BMI), serum albumin and cholesterol, gastric atrophy, reflux oesophagitis, Barrett’s oesophagus, and H. pylori status were collected. Univariate and multivariable analyses were performed to identify factors associated with VG. We analysed the data of 621 patients undergoing routine endoscopy and found that VG (n = 352) was significantly associated with increased BMI (1.12 [1.05–1.18], P &lt; 0.01), reflux esophagitis (1.96 [1.10–3.28], P &lt; 0.01), and H. pylori negativity with or without a history of eradication (9.94 [6.00–16.47] and 6.12 [3.51–10.68], P &lt; 0.001, respectively). Numerous-type (n = 163) VG was associated with both closed- and open-type gastric atrophy (9.9 [4.04–21.37] and 8.10 [3.41–19.24], P &lt; 0.001, respectively). There were no statistical differences between groups regarding age, sex, total cholesterol, albumin, and bile-colored gastric juice. Verrucous antral gastritis was related to increased BMI, reflux esophagitis, and H. pylori negativity. Numerous-type verrucous lesions were associated with gastric atrophy. These indicate that VG may be a physiological phenomenon due to high gastric acidity, mechanical overload, and vulnerability of background mucosa.
• 【胆膵疾患の最新画像診断】3D-CT解析を用いた膵実質萎縮による膵癌早期診断

  山雄 健太郎; 竹中 完; 田中 秀和; 田中 隆光; 吉田 晃浩; 石川 嶺; 岡本 彩那; 中井 敦; 山崎 友裕; 大本 俊介; 鎌田 研; 三長 孝輔; 渡邉 智裕; 工藤 正俊

  胆と膵 医学図書出版(株) 41 (8) 713 - 718 0388-9408 2020/08 

  膵癌は予後不良な癌腫であり、予後改善が急務である。小膵癌の場合、CTやMRIでの直接指摘が困難であるため、尾側膵管拡張を伴う主膵管狭窄などの間接所見が診断の契機となる。しかしながら主膵管狭窄は慢性膵炎などの良性疾患でも認められる。近年、上皮内癌を含む腫瘍径10mm以下の微小膵癌において膵実質の部分萎縮(やせ)が診断の指標になるとの報告が散見される。ただし膵臓は膵頭部が膨大している、門脈から腹側へ圧排を受けるなどの構造をしているため、通常のCTでは萎縮がやや評価しにくい。3D-CTは本来立体構造をした膵臓をそのまま3D画像として可視化できるため、この技術を用いて膵臓を抽出することで膵実質の萎縮を直感的かつ簡便に評価できる。3D-CTによる膵実質の萎縮評価は膵癌の早期診断および予後改善に寄与すると考える。(著者抄録)
• Purpura-free small intestinal IgA vasculitis complicated by cytomegalovirus reactivation.

  Mariko Matsumura; Yoriaki Komeda; Tomohiro Watanabe; Masatoshi Kudo

  BMJ case reports BMJ 13 (7) e235042 - e235042 2020/07 [Refereed]
   

  IgA vasculitis (Henoch-Schönlein purpura) affects various organs, including the skin, gastrointestinal (GI) tract, joints and kidneys. Its clinical course typically consists of two phases: initial appearance of purpura and delayed onset of arthralgia, GI symptoms and haematuria. We report the case of an adult patient with IgA vasculitis of the small bowel, without skin involvement, complicated by cytomegalovirus (CMV) enteritis following prednisolone administration. Single-balloon enteroscopy revealed mucosal oedema, redness, erosions and transverse ulcers of the duodenum and jejunum. Jejunal biopsy specimens showed IgA deposition in the capillary walls. CMV reactivation was confirmed by PCR and immunostaining using jejunal biopsy specimens. This case report strongly suggests that adult patients with IgA vasculitis can present with isolated GI involvement, without characteristic skin purpura. Furthermore, CMV reactivation needs to be considered in patients with IgA vasculitis showing poor response to glucocorticoids.
• 自己免疫性膵胆道疾患診療の課題と展望 転写因子IRF7の活性化からみた自己免疫性膵炎の病態解明

  三長 孝輔; 渡邉 智裕; 工藤 正俊

  日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増総会) A200 - A200 0446-6586 2020/07
• 血清IFN-α/IL-33が治療効果判定に有用と考えられた自己免疫性膵炎の1例

  原 茜; 三長 孝輔; 吉川 智恵; 鎌田 研; 渡邉 智裕; 工藤 正俊

  日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増総会) A299 - A299 0446-6586 2020/07
• 自己免疫性膵胆道疾患診療の課題と展望 転写因子IRF7の活性化からみた自己免疫性膵炎の病態解明

  三長 孝輔; 渡邉 智裕; 工藤 正俊

  日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増総会) A200 - A200 0446-6586 2020/07
• 血清IFN-α/IL-33が治療効果判定に有用と考えられた自己免疫性膵炎の1例

  原 茜; 三長 孝輔; 吉川 智恵; 鎌田 研; 渡邉 智裕; 工藤 正俊

  日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増総会) A299 - A299 0446-6586 2020/07
• Partial Pancreatic Parenchymal Atrophy Is a New Specific Finding to Diagnose Small Pancreatic Cancer (≤10 mm) Including Carcinoma in Situ: Comparison with Localized Benign Main Pancreatic Duct Stenosis Patients.

  Kentaro Yamao; Mamoru Takenaka; Rei Ishikawa; Ayana Okamoto; Tomohiro Yamazaki; Atsushi Nakai; Shunsuke Omoto; Ken Kamata; Kosuke Minaga; Ippei Matsumoto; Yoshifumi Takeyama; Isao Numoto; Masakatsu Tsurusaki; Takaaki Chikugo; Yasutaka Chiba; Tomohiro Watanabe; Masatoshi Kudo

  Diagnostics (Basel, Switzerland) MDPI AG 10 (7) 445 - 445 2020/07 [Refereed]
   

  BACKGROUND: This study aimed to evaluate and identify the specific CT findings by focusing on abnormalities in the main pancreatic duct (MPD) and pancreatic parenchyma in patients with small pancreatic cancer (PC) including carcinoma in situ (CIS). METHODS: Nine CT findings indicating abnormalities of MPD and pancreatic parenchyma were selected as candidate findings for the presence of small PC ≤ 10 mm. The proportions of patients positive for each finding were compared between small PC and benign MPD stenosis groups. Interobserver agreement between two independent image reviewers was evaluated using kappa statistics. RESULTS: The final analysis included 24 patients with small PC (including 11 CIS patients) and 28 patients with benign MPD stenosis. The proportion of patients exhibiting partial pancreatic parenchymal atrophy (PPA) corresponding to the distribution of MPD stenosis (45.8% vs. 7.1%, p < 0.01), upstream PPA arising from the site of MPD stenosis (33.3% vs. 3.6%, p = 0.01), and MPD abrupt stenosis (45.8% vs. 14.3%, p = 0.03) was significantly higher in the small PC group than in the benign MPD stenosis group. CONCLUSIONS: The presence of partial PPA, upstream PPA, and MPD abrupt stenosis on a CT image was highly suggestive of the presence of small PCs including CIS.
• IgG4関連疾患と自然免疫

  渡邉 智裕; 吉川 智恵; 原 茜; 鎌田 研; 三長 孝輔; 工藤 正俊

  炎症と免疫 28 (4) 310 - 314 2020/07
• Improved liver metastasis detection using Kupffer-phase imaging in contrast-enhanced harmonic EUS in patients with pancreatic cancer (with video).

  Kosuke Minaga; Masayuki Kitano; Atsushi Nakai; Shunsuke Omoto; Ken Kamata; Kentaro Yamao; Mamoru Takenaka; Masakatsu Tsurusaki; Takaaki Chikugo; Ippei Matsumoto; Yasutaka Chiba; Tomohiro Watanabe; Masatoshi Kudo

  Gastrointestinal endoscopy Elsevier BV 93 (2) 433 - 441 0016-5107 2020/06 [Refereed]
   

  BACKGROUND AND AIMS: Kupffer-phase imaging visualized by Sonazoid distribution into normal liver tissues upon phagocytosis by Kupffer cells, potentially aids in improving liver metastasis detection compared with fundamental B-mode EUS (FB-EUS). However, the diagnostic performance of Kupffer-phase imaging in contrast-enhanced harmonic EUS (CH-EUS) remains unclear. Hence, this study aimed to evaluate the usefulness of CH-EUS-based Kupffer-phase imaging for diagnosing liver metastasis from pancreatic cancer. METHODS: We retrospectively analyzed consecutive patients with pancreatic cancer who underwent contrast-enhanced CT (CE-CT) and FB-EUS, followed by CH-EUS, from 2011 to 2017. The diagnostic ability of CH-EUS against that of CE-CT and FB-EUS for left-lobe liver metastasis was compared. Subsequently, the influences of CH-EUS on the determination of clinical stage and patient management for pancreatic cancer were assessed. RESULTS: We enrolled 426 patients with pancreatic cancer. The left-lobe liver metastasis was present in 27.2% of patients. The diagnostic accuracy of CE-CT, FB-EUS, and CH-EUS was 90.6%, 93.4%, and 98.4%, respectively. The sensitivity and diagnostic accuracy of CH-EUS for left-lobe liver metastasis were significantly higher than those of FB-EUS or CE-CT. The sensitivity of CH-EUS for detecting small liver metastasis (<10 mm) was considerably higher than that of CE-CT or FB-EUS (P < 0.001). In 2.1% patients, only CH-EUS could detect a single distant metastasis of the left-lobe liver, thereby upgrading the tumor staging and altering the clinical management. CONCLUSIONS: CH-EUS-based Kupffer-phase imaging increased the detectability of left-lobe liver metastasis. This technique could be a reliable pretreatment imaging modality for clinical decision-making in pancreatic cancer patients.
• Diffuse Pancreas Swelling in a Patient with Multiple Myeloma

  Akane Hara; Kosuke Minaga; Tomohiro Watanabe

  Gastroenterology Elsevier BV 0016-5085 2020/06 [Refereed]
  
• Response to the Letter to the Editor 'Reply to "Clinical Safety and Efficacy of Secondary Prophylactic Pegylated G-CSF in Advanced Pancreatic Cancer Patients Treated with mFOLFIRINOX: A Single-center Retrospective Study" by Dr. Peng Chen'

  Kentaro Yamao; Tomohiro Watanabe; Masatoshi Kudo

  Internal Medicine Japanese Society of Internal Medicine 59 (6) 879 - 879 0918-2918 2020/03 [Refereed]
  
• Response to the Letter to the Editor 'Reply to "Clinical Safety and Efficacy of Secondary Prophylactic Pegylated G-CSF in Advanced Pancreatic Cancer Patients Treated with mFOLFIRINOX: A Single-center Retrospective Study" by Dr. Peng Chen'.

  Kentaro Yamao; Tomohiro Watanabe; Masatoshi Kudo

  Internal medicine (Tokyo, Japan) 59 (6) 879 - 879 2020/03
• Clinical utility of treatment method conversion during single-session endoscopic ultrasound-guided biliary drainage.

  Kosuke Minaga; Mamoru Takenaka; Kentaro Yamao; Ken Kamata; Shunsuke Omoto; Atsushi Nakai; Tomohiro Yamazaki; Ayana Okamoto; Rei Ishikawa; Tomoe Yoshikawa; Yasutaka Chiba; Tomohiro Watanabe; Masatoshi Kudo

  World journal of gastroenterology 26 (9) 947 - 959 2020/03 [Refereed]
   

  BACKGROUND: Although several techniques for endoscopic ultrasound-guided biliary drainage (EUS-BD) are available at present, an optimal treatment algorithm of EUS-BD has not yet been established. AIM: To evaluate the clinical utility of treatment method conversion during single endoscopic sessions for difficult cases in initially planned EUS-BD. METHODS: This was a single-center retrospective analysis using a prospectively accumulated database. Patients with biliary obstruction undergoing EUS-BD between May 2008 and April 2016 were included. The primary outcome was to evaluate the improvement in EUS-BD success rates by converting the treatment methods during a single endoscopic session. Secondary outcomes were clarification of the factors leading to the conversion from the initial EUS-BD and the assessment of efficacy and safety of the conversion as judged by technical success, clinical success, and adverse events (AEs). RESULTS: A total of 208 patients underwent EUS-BD during the study period. For 18.8% (39/208) of the patients, the treatment methods were converted to another EUS-BD technique from the initial plan. Biliary obstruction was caused by pancreatobiliary malignancies, other malignant lesions, biliary stones, and other benign lesions in 22, 11, 4, and 2 patients, respectively. The reasons for the difficulty with the initial EUS-BD were classified into the following 3 procedures: Target puncture (n = 13), guidewire manipulation (n = 18), and puncture tract dilation (n = 8). Technical success was achieved in 97.4% (38/39) of the cases and clinical success was achieved in 89.5% of patients (34/38). AEs occurred in 10.3% of patients, including bile leakage (n = 2), bleeding (n = 1), and cholecystitis (n = 1). The puncture target and drainage technique were altered in subsequent EUS-BD procedures in 25 and 14 patients, respectively. The final technical success rate with 95%CI for all 208 cases was 97.1% (95%CI: 93.8%-98.9%), while that of the initially planned EUS-BD was 78.8% (95%CI: 72.6%-84.2%). CONCLUSION: Among multi-step procedures in EUS-BD, guidewire manipulation appeared to be the most technically challenging. When initially planned EUS-BD is technically difficult, treatment method conversion in a single endoscopic session may result in successful EUS-BD without leading to severe AEs.
• Efficacy of a modified double-guidewire technique using an uneven double lumen cannula (uneven method) in patients with surgically altered gastrointestinal anatomy (with video).

  Mamoru Takenaka; Kosuke Minaga; Ken Kamata; Kentaro Yamao; Tomoe Yoshikawa; Rei Ishikawa; Ayana Okamoto; Tomohiro Yamazaki; Atsushi Nakai; Shunsuke Omoto; Yoriaki Komeda; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Yasutaka Chiba; Chang-Il Kwon; Seok Jeong; Tae Hoon Lee; Masatoshi Kudo

  Surgical endoscopy 34 (3) 1432 - 1441 2020/03 [Refereed]
   

  BACKGROUND: Balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (BE-ERCP) has been reported to be effective for patients with surgically altered gastrointestinal anatomy. However, selective biliary cannulation remains difficult in BE-ERCP. We examined the usefulness of a modified double-guidewire technique using an uneven double lumen cannula (the uneven method) for BE-ERCP in patients with surgically altered gastrointestinal anatomy. METHODS: To clarify the usefulness of the uneven method for selective biliary cannulation in BE-ERCP in comparison to the pancreatic guidewire (PGW) method, 40 patients with surgically altered gastrointestinal anatomy who underwent BE-ERCP with successful placement of a guidewire in the pancreatic duct were evaluated. The uneven method was used in 18 cases (uneven group) and the PGW method was used in the remaining 22 cases (PGW group). RESULTS: The technical success rate of biliary cannulation was higher in the uneven group than in the PGW group (83.3 vs. 59.0%; P = 0.165). In addition, the time to biliary cannulation were significantly shorter in the uneven group than in the PGW group (6 vs. 18 min; P = 0.004; respectively). In the PGW group, post-ERCP pancreatitis (PEP) occurred in 3 of 22 cases (13.6%). No adverse events, including PEP, occurred in the uneven group. CONCLUSIONS: The uneven method may be a useful option of selective biliary cannulation in BE-ERCP for the patients with surgically altered gastrointestinal anatomy.
• Recurrent abdominal pain caused by nephroptosis.

  Saki Yoshida; Mariko Matsumura; Kiyoshi Maekawa; Kosuke Minaga; Ken Kamata; Masahiro Nozawa; Tomohiro Watanabe; Masatoshi Kudo

  Clinical journal of gastroenterology 13 (4) 621 - 625 2020/02 [Refereed]
   

  Nephroptosis is a benign disorder defined as a significant descent of the affected kidney as the patient moves from supine to erect. Patients with nephroptosis sometimes manifest symptoms including abdominal pain, back pain, nausea and hematuria, while the majority of those are asymptomatic. Downward migration of the affected kidney induced by a postural change from the supine to the upright position underlies the pathophysiology of nephroptosis. The diagnosis of nephroptosis is difficult since routine imaging examinations are conducted in the supine position alone. Here, we report a case presenting recurrent abdominal pain due to unknown causes. This patient was successfully diagnosed as nephroptosis by ultrasonography and drip infusion pyelography, both of which were performed in both supine and upright positions. This case report strongly suggests that we need to take into consideration a possibility of nephroptosis when we encounter with patients complaining abdominal and/or back pain due to unknown causes.
• 【慢性膵炎診療2020】基礎研究・病態 腸内細菌は慢性膵炎発症に関連するのか

  渡邉 智裕; 三長 孝輔; 原 茜; 鎌田 研; 工藤 正俊

  肝・胆・膵 (株)アークメディア 80 (2) 241 - 246 0389-4991 2020/02 [Refereed]
  
• 【慢性膵炎診療2020】基礎研究・病態 腸内細菌は慢性膵炎発症に関連するのか

  渡邉 智裕; 三長 孝輔; 原 茜; 鎌田 研; 工藤 正俊

  肝・胆・膵 (株)アークメディア 80 (2) 241 - 246 0389-4991 2020/02 [Refereed]
  
• 【慢性膵炎診療2020】診断 早期慢性膵炎のEUS所見は特異的か 加齢や他疾患の影響は

  竹中 完; 中井 敦史; 大本 俊介; 三長 孝輔; 鎌田 研; 山雄 健太郎; 渡邉 智裕; 松本 逸平; 竹山 宜典; 工藤 正俊

  肝・胆・膵 (株)アークメディア 80 (2) 295 - 302 0389-4991 2020/02
• Requirement of Additional Surgery after Non-Curative Endoscopic Submucosal Dissection for Early Colorectal Cancer.

  Yoriaki Komeda; Tomohiro Watanabe; Masatoshi Kudo

  Journal of investigative surgery : the official journal of the Academy of Surgical Research 1 - 2 2020/01 [Refereed][Invited]
  
• Activation of interferon regulatory factor 7 in plasmacytoid dendritic cells promotes experimental autoimmune pancreatitis.

  Kosuke Minaga; Tomohiro Watanabe; Yasuyuki Arai; Masahiro Shiokawa; Akane Hara; Tomoe Yoshikawa; Ken Kamata; Kouhei Yamashita; Masatoshi Kudo

  Journal of gastroenterology 55 (5) 565 - 576 2020/01 [Refereed]
   

  BACKGROUND: Excessive type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs) promotes autoimmunity. Recently, we reported that a prominent feature of both experimental autoimmune pancreatitis (AIP) and human type 1 AIP is pDC activation followed by enhanced production of IFN-I and IL-33. However, the roles played by interferon regulatory factor 7 (IRF7), a critical transcription factor for IFN-I production in pDCs, in these disorders have not been clarified. METHODS: Whole and nuclear extracts were isolated from pancreatic mononuclear cells (PMNCs) from MRL/MpJ mice exhibiting AIP. Expression of phospho-IRF7 and nuclear translocation of IRF7 was examined in these extracts by immunoblotting. Pancreatic expression of IRF7 was assessed by immunofluorescence analysis in experimental AIP. Nuclear translocation of IRF7 upon exposure to neutrophil extracellular traps (NETs) was assessed in peripheral blood pDCs from type 1 AIP patients. Pancreatic IRF7 expression was examined in surgically operated specimens from type 1 AIP patients. RESULTS: IRF7 activation was induced in pancreatic pDCs in experimental AIP. siRNA-mediated knockdown of IRF7 expression prevented AIP development, which was accompanied by a marked reduction in both pancreatic accumulation of pDCs and production of IFN-α and IL-33. Notably, in peripheral blood pDCs isolated from patients with type 1 AIP, nuclear translocation of IRF7 was enhanced as compared with the translocation in pDCs from healthy controls. Furthermore, IRF7-expressing pDCs were detected in the pancreas of patients with type 1 AIP. CONCLUSIONS: These findings suggest that the IRF7-IFN-I-IL-33 axis activated in pDCs drives pathogenic innate immune responses associated with type 1 AIP.
• Possible involvement of autophagy in esophageal ulcers in anorexia nervosa.

  Sho Masaki; Tomohiro Watanabe; Kosuke Minaga; Ken Kamata; Yoriaki Komeda; Masatomo Kimura; Masatoshi Kudo

  Clinical journal of gastroenterology 13 (4) 473 - 476 2020/01 [Refereed]
   

  Although patients with anorexia nervosa (AN) present with various gastrointestinal disorders, little has been understood regarding the incidence and pathophysiology of gastrointestinal ulcers related to AN. A 20-year-old woman with a past history of AN was hospitalized for further examination of dysphagia and chest pain. Her nutritional status was very poor as evidenced by very low body mass index. Esophagogastroduodenoscopy detected longitudinal and geographical ulcers in the entire circumference of the cervical and upper esophagus. Enhanced expression of autophagy-related proteins, LC3B and p62, was seen in the esophageal epithelium surrounding the active ulcers. Expression of these autophagy markers disappeared from the esophageal epithelium soon after the nutritional rehabilitation. Given the fact that starvation and malnutrition are potent inducers for autophagy, these findings suggest that autophagy might be involved in the development of gastrointestinal ulcers in patients with AN.
• Intestinal dysbiosis mediates experimental autoimmune pancreatitis via activation of plasmacytoid dendritic cells.

  Ken Kamata; Tomohiro Watanabe; Kosuke Minaga; Akane Hara; Tomoe Yoshikawa; Ayana Okamoto; Kentaro Yamao; Mamoru Takenaka; Ah-Mee Park; Masatoshi Kudo

  International immunology 31 (12) 795 - 809 2019/11 [Refereed]
   

  Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a newly proposed disease entity, IgG4-related disease (IgG4-RD), characterized by enhanced IgG4 antibody responses and involvement of multiple organs. We have previously reported that innate immune activation contributes to the development of AIP and IgG4-RD, as these diseases are characterized by the production of IFN-α and IL-33 by plasmacytoid dendritic cells (pDCs) that mediate chronic fibroinflammatory responses. In this study, we investigated the roles played by innate immunity against intestinal microflora in experimental AIP induced in MRL/MpJ mice by repeated administrations of 100 µg of polyinosinic-polycytidylic acid [poly (I:C)]. Bowel sterilization with a broad spectrum of antibiotics inhibited pancreatic accumulation of pDCs producing IFN-α and IL-33, and thereby suppressed the development of AIP. Mice treated with 10 µg of poly (I:C) developed severe AIP equivalent to that induced by 100 µg of poly (I:C) upon co-housing with mice treated with 100 µg of poly (I:C). Fecal microbiota transplantation (FMT) from donor mice treated with 100 µg of poly (I:C) led to the development of severe AIP in the recipient mice upon injection with 10 µg of poly (I:C). Induction of severe AIP in mice with 10 µg of poly (I:C) was associated with pancreatic accumulation of pDCs producing IFN-α and IL-33 in the co-housing and FMT experiments. These data collectively suggest that innate immune responses against intestinal microflora are involved in the development of experimental AIP, and that intestinal dysbiosis increases sensitivity to experimental AIP via activation of pDCs.
• DLBCLに発症したリンパ管拡張症に対してステロイド投与、食事療法が奏効した1症例

  大塚 康生; 米田 頼晃; 正木 翔; 筑後 孝章; 吉川 馨介; 高島 耕太; 橋本 有人; 山田 光成; 本庶 元; 永井 知行; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 辻 直子; 樫田 博史; 工藤 正俊

  日本消化器病学会近畿支部例会プログラム・抄録集 日本消化器病学会-近畿支部 111回 91 - 91 2019/10
• LENVATINIB AS AN INITIAL TREATMENT IN PATIENTS WITH INTERMEDIATE-STAGE HEPATOCELLULAR CARCINOMA BEYOND UP-TO-SEVEN CRITERIA AND CHILD-PUGH A LIVER FUNCTION: A MULTICENTER PROPENSITY-SCORE MATCHED STUDY

  Kudo Masatoshi; Ueshima Kazuomi; Chan Stephen L; Minami Tomohiro; Chishina Hirokazu; Aoki Tomoko; Takita Masahiro; Hagiwara Satoru; Minami Yasunori; Ida Hiroshi; Takenaka Mamoru; Sakurai Toshiharu; Watanabe Tomohiro; Morita Masahiro; Ogawa Chikara; Wada Yoshiyuki; Ikeda Masafumi; Ishii Hiroshi; Izumi Namiki; Nishida Naoshi

  HEPATOLOGY WILEY 70 133A - 134A 0270-9139 2019/10 [Refereed]
  
• Comparison of the Diagnostic Performance of Newly Designed 21-Gauge and Standard 22-Gauge Aspiration Needles in Patients with Solid Pancreatic Masses

  Kosuke Minaga; Tomoe Yoshikawa; Yukitaka Yamashita; Hiroko Akamatsu; Maiko Ikenouchi; Tatsuya Ishii; Hisakazu Matsumoto; Hiroyoshi Iwagami; Yasuki Nakatani; Keiichi Hatamaru; Mamoru Takenaka; Takuji Akamatsu; Yoshito Uenoyama; Tomohiro Watanabe; Kazuo Ono; Yasutaka Chiba; Masatoshi Kudo

  Digestive Diseases and Sciences Springer Science and Business Media LLC 64 (10) 2982 - 2991 0163-2116 2019/10 [Refereed]
  
• RICK/RIP2 is a NOD2-independent nodal point of gut inflammation

  Tomohiro Watanabe; Kosuke Minaga; Ken Kamata; Toshiharu Sakurai; Yoriaki Komeda; Tomoyuki Nagai; Atsushi Kitani; Masaki Tajima; Ivan J Fuss; Masatoshi Kudo; Warren Strober

  International Immunology Oxford University Press (OUP) 31 (10) 669 - 683 2019/09 [Refereed]
   

  Previous studies have shown that inhibition of receptor-interacting serine/threonine kinase (RICK) (also known as RIP2) results in amelioration of experimental colitis. This role has largely been attributed to nucleotide-binding oligomerization domain 2 (NOD2) signaling since the latter is considered a major inducer of RICK activation. In this study, we explored the molecular mechanisms accounting for RICK-mediated inhibition of inflammatory bowel disease (IBD). In an initial series of studies focused on trinitrobenzene sulfonic acid (TNBS)-colitis and dextran sodium sulfate (DSS)-colitis we showed that down-regulation of intestinal RICK expression in NOD2-intact mice by intra-rectal administration of a plasmid expressing RICK-specific siRNA was accompanied by down-regulation of pro-inflammatory cytokine responses in the colon and protection of the mice from experimental colitis. Somewhat surprisingly, intra-rectal administration of RICK-siRNA also inhibited TNBS-colitis and DSS-colitis in NOD2-deficient and in NOD1/NOD2-double deficient mice. In complementary studies of humans with IBD we found that expression of RICK, cellular inhibitor of apoptosis protein 2 (cIAP2) and downstream signaling partners were markedly increased in inflamed tissue of IBD compared to controls without marked elevations of NOD1 or NOD2 expression. In addition, the increase in RICK expression correlated with disease activity and pro-inflammatory cytokine responses. These studies thus suggest that NOD1- or NOD2-independenent activation of RICK plays a major role in both murine experimental colitis and human IBD.
• 【IgG4関連疾患病態解明への挑戦-臓器横断的研究からみえてきたもの!】IgG4とはどのような分子か?

  渡邉 智裕; 三長 孝輔; 吉川 智恵; 原 茜; 鎌田 研; 工藤 正俊

  消化器病学サイエンス (株)先端医学社 3 (3) 142 - 148 2432-7549 2019/09 [Invited]
   

  IgG4関連疾患は、全身性のIgG4産生反応の亢進・罹患臓器へのIgG4陽性細胞の浸潤・多臓器病変を特色とする自己免疫疾患である。定常状態では免疫グロブリンの5%以下であるIgG4が、全身性・局所性に増加することがIgG4関連疾患の最大の免疫学的特徴である。IgG4は補体活性化能が他のIgG分画とくらべてきわめて低いことから、IgG4関連疾患における「IgG4の病原性」については疑問視されてきた。最近、IgG4関連疾患の標的抗原が同定され、「IgG4は炎症反応を誘導する方向ではなく、むしろ抑制する方向で作用している」ことが明らかになりつつある。IgG4の病原性については否定されつつあるものの、IgG4産生反応の亢進メカニズムの解明は、IgG4関連疾患の病態解明さらには新規治療法の開発に有用である。(著者抄録)
• Contrast-enhanced harmonic endoscopic ultrasonography for evaluating the response to chemotherapy in pancreatic cancer.

  Hidekazu Tanaka; Ken Kamata; Mamoru Takenaka; Tomoe Yoshikawa; Rei Ishikawa; Ayana Okamoto; Tomohiro Yamazaki; Atsushi Nakai; Shunsuke Omoto; Kosuke Minaga; Kentaro Yamao; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Yasutaka Chiba; Masayuki Kitano; Masatoshi Kudo

  Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 51 (8) 1130 - 1134 2019/08 [Refereed]
   

  BACKGROUND AND AIMS: Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) is used for the diagnosis of pancreatic cancer (PC). Here, we examined the usefulness of CH-EUS for evaluating therapeutic responses in PC. METHODS: The study included 23 patients with PC who received chemotherapy. Patients underwent contrast-enhanced computed tomography (CE-CT) and CH-EUS before chemotherapy and at the time of evaluation of the therapeutic response. Patients with a ≧50% reduction in serum carbohydrate antigen 19-9 levels after chemotherapy were defined as "super responders". The incidence of an avascular area in the tumor on CH-EUS after chemotherapy was compared between "super responders" and non-super responders. RESULTS: Nine patients were included in the "super responders" group.Tumor reduction rates did not differ significantly between CE-CT and CH-EUS in the "super responders". The appearance of an avascular area was detected in 7 of 9 super responders (77.8%) and in 4 of 14 non-super responders (28.6%), and the difference was significant (P = 0.036). The mean survival time of patients with an avascular area after chemotherapy was longer than that of without an avascular area. CONCLUSIONS: Detection of avascular areas by CH-EUS after chemotherapy may predict long-term survival of patients with PC.
• Hepatic portal venous gas associated with Klebsiella oxytoca infection in the absence of preceding antibiotic treatment

  Hidekazu Tanaka; Tomohiro Watanabe; Tomoyuki Nagai; Kosuke Minaga; Ken Kamata; Yoriaki Komeda; Masatoshi Kudo

  Clinical Journal of Gastroenterology Springer Science and Business Media LLC 12 (4) 316 - 319 1865-7257 2019/08 [Refereed]
  
• Lenvatinib as an Initial Treatment in Patients with Intermediate-Stage Hepatocellular Carcinoma Beyond Up-To-Seven Criteria and Child-Pugh A Liver Function: A Proof-Of-Concept Study.

  Masatoshi Kudo; Kazuomi Ueshima; Stephan Chan; Tomohiro Minami; Hirokazu Chishina; Tomoko Aoki; Masahiro Takita; Satoru Hagiwara; Yasunori Minami; Hiroshi Ida; Mamoru Takenaka; Toshiharu Sakurai; Tomohiro Watanabe; Masahiro Morita; Chikara Ogawa; Yoshiyuki Wada; Masafumi Ikeda; Hiroshi Ishii; Namiki Izumi; Naoshi Nishida

  Cancers 11 (8) pii: E1084  2019/07 [Refereed]
   

  Although transcatheter arterial chemoembolization (TACE) is the standard of care for intermediate-stage hepatocellular carcinoma (HCC), this is a largely heterogeneous disease that includes a subgroup of patients who do not benefit from TACE. The treatment strategy for this subgroup of patients currently remains an unmet need in clinical practice. Here, we performed a proof-of-concept study that lenvatinib may be a more favorable treatment option over TACE as an initial treatment in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-seven criteria. This proof-of-concept study included 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria (unresectable, beyond the up-to-seven criteria, no prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child-Pugh A liver function) were selected for the study. Propensity score matching was used to adjust for patient demographics. After propensity-score matching, the outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials, one in an early access program and 15 in real world settings) and 60 patients treated with cTACE as the initial treatment was compared. The change of albumin-bilirubin (ALBI) score from baseline to the end of treatment were -2.61 to -2.61 for 30 patients in the lenvatinib group (p = 0.254) and -2.66 to -2.09 in the cTACE group (p < 0.01), respectively. The lenvatinib group showed a significantly higher objective response rate (73.3% vs. 33.3%; p < 0.001) and significantly longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months; p < 0.001). Overall survival was significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months; hazard ratio: 0.48, p < 0.01). In patients with large or multinodular intermediate-stage HCC exceeding the up-to-seven criteria with Child-Pugh A liver function, who usually do not benefit from TACE, lenvatinib provides a more favorable outcome than TACE.
• Clinical Safety and Efficacy of Secondary Prophylactic Pegylated G-CSF in Advanced Pancreatic Cancer Patients Treated with mFOLFIRINOX: A Single-center Retrospective Study.

  Kentaro Yamao; Mamoru Takenaka; Tomoe Yoshikawa; Rei Ishikawa; Ayana Okamoto; Tomohiro Yamazaki; Atsushi Nakai; Shunsuke Omoto; Ken Kamata; Kosuke Minaga; Satoru Hagiwara; Toshiharu Sakurai; Naoshi Nishida; Yasutaka Chiba; Tomohiro Watanabe; Masatoshi Kudo

  Internal medicine (Tokyo, Japan) 58 (14) 1993 - 2002 2019/07 [Refereed]
   

  Objective Although modified FOLFIRINOX (mFOLFIRINOX, mFFX) is widely used for patients with advanced pancreatic ductal adenocarcinoma (PDAC), maintenance of the standard dose intensity is often difficult due to the high incidence of neutropenic events. Pegylated granulocyte colony-stimulating factor (G-CSF) (Peg G) is a long-lasting G-CSF agent that is applicable for prophylaxis against neutropenic complications. The aim of this study was to assess the clinical safety and efficacy of mFFX combined with secondary prophylaxis using Peg G in advanced PDAC patients. Methods Advanced PDAC patients who had received more than two cycles of mFFX were analyzed. The clinical safety and efficacy were compared between patients in the Peg G group and those in the non-Peg G group in a retrospective manner. Results Among 45 patients treated with mFFX, 28 exhibited grade 3-4 neutropenia or febrile neutropenia. Among these 28 patients, 4 who received only 1 or 2 mFFX cycles were excluded from this study. Finally, 11 patients in the Peg G group and 13 in the non-Peg G group were enrolled. The combination therapy with Peg G and mFFX markedly prolonged the progression-free survival compared with the non-Peg G group, and its effects were associated with a reduced incidence of neutropenic events as well as lower rates of dosage reduction, delayed chemotherapy due to neutropenic events and altered blood cell counts after chemotherapy. Conclusion The scheduled administration of secondary prophylactic Peg G prolonged the progression-free survival in patients treated with mFFX. The combination therapy of Peg G and mFFX may be recommended in patients who exhibit grade 3-4 neutropenic events after prior mFFX cycles.
• Usefulness of Ustekinumab for Treating a Case of Myelodysplastic Syndrome-associated Inflammatory Bowel Disease.

  Masashi Kono; Toshiharu Sakurai; Kazuki Okamoto; Tomoyuki Nagai; Yoriaki Komeda; Hiroshi Kashida; Kosuke Minaga; Ken Kamata; Mamoru Takenaka; Satoru Hagiwara; Tomohiro Watanabe; Naoshi Nishida; Eisuke Enoki; Hiroaki Inoue; Itaru Matsumura; Masatoshi Kudo

  Internal medicine (Tokyo, Japan) 58 (14) 2029 - 2033 2019/07 [Refereed]
   

  Autoimmune diseases including inflammatory bowel disease (IBD) occur in association with myelodysplastic syndrome (MDS). MDS-associated IBD frequently demonstrates a complicated course. We herein report the first case with MDS-associated IBD that was successfully treated with ustekinumab (UST), an anti-interleukin (IL) 12/23p40 monoclonal antibody. A 63-year-old man with a 7-year history of MDS was referred for examination of diarrhea, abdominal pain and fever. A blood examination revealed a marked elevation of C-reactive protein. Colonoscopy showed multiple ulcers in the terminal ileum. He was resistant to anti-tumor necrosis factor (TNF)-α antibody and azacitidine. Subsequently, UST treatment reduced colonic IL-17 and IL-6 expression and the patient currently maintains a state of remission.
• Impact of Baseline ALBI Grade on the Outcomes of Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Study.

  Kazuomi Ueshima; Naoshi Nishida; Satoru Hagiwara; Tomoko Aoki; Tomohiro Minami; Hirokazu Chishina; Masahiro Takita; Yasunori Minami; Hiroshi Ida; Mamoru Takenaka; Toshiharu Sakurai; Tomohiro Watanabe; Masahiro Morita; Chikara Ogawa; Atsushi Hiraoka; Philip Johnson; Masatoshi Kudo

  Cancers 11 (7) pii: E952.  2019/07 [Refereed]
   

  BACKGROUND: This study investigated the impact of baseline liver function according to the Child-Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular carcinoma treated with lenvatinib. METHODS: A total of 82 lenvatinib treated patients were included. The correlations of baseline liver function according to the Child-Pugh score and ALBI grade with treatment outcomes, including objective response rate per mRECIST (modified Response Evaluation Criteria in the Solid Tumor), time to treatment failure, treatment duration, and likelihood of treatment discontinuation due to adverse events, were assessed in patients with hepatocellular carcinoma treated with lenvatinib. Patients were divided into four groups: (1) Child-Pugh score 5 and ALBI grade 1 (group 1), (2) Child-Pugh score 5 and ALBI grade 2 (group 2), (3) Child-Pugh score 6 (group 3), and (4) Child-Pugh score ≥7 (group 4). Univariate and multivariate analyses were performed to identify the factors contributing to the objective response rate and likelihood of discontinuation due to adverse events. Results: Among the 82 patients analyzed, group 1 had the highest objective response rate (57.1%) and the lowest likelihood of treatment discontinuation because of adverse events (11.1%) among the four groups (p < 0.05 and p < 0.05). Multivariate analysis identified ALBI grade 1 and baseline AFP level <200 ng/mL as the significant predictors of a high objective response rate (p < 0.05 and p < 0.01), and confirmed that patients with ALBI grade 1 had the lowest probability of treatment discontinuation due to adverse events (p < 0.01). Conclusions: Patients with Child-Pugh score of 5 and ALBI grade 1 predicted a higher response rate and lower treatment discontinuation due to adverse events by lenvatinib treatment.
• Tu1955 COMPUTER-AIDED DIAGNOSIS BASED ON CONVOLUTIONAL NEURAL NETWORK SYSTEM USING ARTIFICIAL INTELLIGENCE FOR COLORECTAL POLYP CLASSIFICATION

  Yoriaki Komeda; Hisashi Handa; Ryoma Matsui; Toshiharu Sakurai; Tomohiro Watanabe; Hiroshi Kashida; Masatoshi Kudo

  Gastrointestinal Endoscopy Elsevier BV 89 (6) AB631 - AB631 0016-5107 2019/06
• The IFN-α-IL-33 Axis as Possible Biomarkers in IgG4-Related Disease

  Kosuke Minaga; Tomohiro Watanabe; Ken Kamata; Mamoru Takenaka; Satoru Yasukawa; Masatoshi Kudo

  The American Journal of Gastroenterology Ovid Technologies (Wolters Kluwer Health) 114 (6) 1002 - 1003 0002-9270 2019/06 [Refereed]
  
• Recent Updates on the Relationship between Cancer and Autoimmune Pancreatitis

  Ayana Okamoto; Tomohiro Watanabe; Ken Kamata; Kosuke Minaga; Masatoshi Kudo

  Internal Medicine Japanese Society of Internal Medicine 58 (11) 1533 - 1539 0918-2918 2019/06 [Refereed]
  
• Autoimmune hepatitis and IgG4-related disease

  Kosuke Minaga; Tomohiro Watanabe; Hobyung Chung; Masatoshi Kudo

  World Journal of Gastroenterology Baishideng Publishing Group Inc. 25 (19) 2308 - 2314 1007-9327 2019/05 [Refereed]
  
• 好酸球性食道炎の臨床的特徴の検討

  正木 翔; 松井 繁長; 工藤 正俊; 大塚 康生; 松村 まり子; 高島 耕太; 河野 辰哉; 岡元 寿樹; 河野 匡志; 山田 光成; 永井 知行; 米田 頼晃; 櫻井 俊治; 渡邉 智裕; 辻 直子; 樫田 博史

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 61 (Suppl.1) 963 - 963 0387-1207 2019/05
• Efficacy and Safety of Chemotherapy Following Anti-PD-1 Antibody Therapy for Gastric Cancer: A Case of Sclerosing Cholangitis

  Masashi Kono; Toshiharu Sakurai; Kazuki Okamoto; Shou Masaki; Tomoyuki Nagai; Yoriaki Komeda; Ken Kamata; Kosuke Minaga; Kentarou Yamao; Mamoru Takenaka; Tomohiro Watanabe; Naoshi Nishida; Masatoshi Kudo

  Internal Medicine Japanese Society of Internal Medicine 58 (9) 1263 - 1266 0918-2918 2019/05 [Refereed]
  
• Risk factors for local recurrence and appropriate surveillance interval after endoscopic resection

  Yoriaki Komeda; Tomohiro Watanabe; Toshiharu Sakurai; Masashi Kono; Kazuki Okamoto; Tomoyuki Nagai; Mamoru Takenaka; Satoru Hagiwara; Shigenaga Matsui; Naoshi Nishida; Naoko Tsuji; Hiroshi Kashida; Masatoshi Kudo

  World Journal of Gastroenterology Baishideng Publishing Group Inc. 25 (12) 1502 - 1512 1007-9327 2019/03 [Refereed]
  
• Cytokines produced by innate immune cells in IgG4-related disease

  Tomoe Yoshikawa; Tomohiro Watanabe; Kosuke Minaga; Ken Kamata; Masatoshi Kudo

  Modern Rheumatology Informa UK Limited 29 (2) 219 - 225 1439-7595 2019/03 [Refereed]
  
• Clinical efficacy and safety of endoscopic ultrasound‐guided gallbladder drainage replacement of percutaneous drainage: A multicenter retrospective study

  Kosuke Minaga; Yukitaka Yamashita; Takeshi Ogura; Mamoru Takenaka; Yuzo Shimokawa; Takeshi Hisa; Masahiro Itonaga; Hironari Kato; Hidefumi Nishikiori; Atsushi Okuda; Hisakazu Matsumoto; Yoshito Uenoyama; Tomohiro Watanabe; Yasutaka Chiba; Kazuhide Higuchi; Masatoshi Kudo; Masayuki Kitano

  Digestive Endoscopy Wiley 31 (2) 180 - 187 0915-5635 2019/03 [Refereed]
  
• 【自己免疫性膵炎2019】AIPの病因・病態 腸内細菌叢からみた発症機序

  渡邉 智裕; 鎌田 研; 吉川 智恵; 三長 孝輔; 工藤 正俊

  肝・胆・膵 (株)アークメディア 78 (2) 189 - 195 0389-4991 2019/02 [Invited]
  
• 慢性膵炎

  渡邉 智裕; 三長 孝輔; 工藤 正俊

  検査と技術 47 (10) 1160 - 1165 2019 [Invited]
  
• 慢性膵炎と自己免疫性膵炎の発症に関わる自然免疫反応

  渡邉 智裕; 工藤 正俊

  近畿大学医学雑誌 44 (1・2) 3 - 7 2019 [Invited]
  
• VALUE OF ADDITIONAL ENDOSCOPIC ULTRASONOGRAPHY FOR SURVEILLANCE AFTER SURGICAL REMOVAL OF INTRADUCTAL PAPILLARY MUCINOUS NEOPLASMS

  KAMATA Ken; CHIBA Yasutaka; WATANABE Tomohiro; SAKURAI Toshiharu; NISHIDA Naoshi; CHIKUGO Takaaki; MATSUMOTO Ippei; TAKEYAMA Yoshifumi; KITANO Masayuki; KUDO Masatoshi; TAKENAKA Mamoru; MINAGA Kosuke; OMOTO Shunsuke; MIYATA Takeshi; YAMAO Kentaro; IMAI Hajime; NAKAI Atsushi; TANAKA Hidekazu

  GASTROENTEROLOGICAL ENDOSCOPY Japan Gastroenterological Endoscopy Society 61 (4) 417 - 426 0387-1207 2019 [Refereed]
   

  Background and Aim: This study evaluated the utility of endoscopic ultrasonography (EUS) combined with contrast-enhanced harmonic EUS (CH-EUS) for surveillance of the remnant pancreas after surgery for intraductal papillary mucinous neoplasm (IPMN).

  Methods: This was a single-center, retrospective, descriptive study. A total of 134 consecutive patients who underwent surgical resection for IPMN between April 2009 and March 2015 were evaluated. Rates of recurrence and development of IPMN-concomitant pancreatic ductal adenocarcinoma (PDAC) during follow up were assessed. Clinical findings of patients with recurrence or development of PDAC were also evaluated.

  Results: Of 134 resected IPMN 56 (41.8%) and 78 (58.2%) were classified as benign and malignant, respectively. Patients were followed up for a median of 29 months, 33 (24.6%) by both contrast-enhanced computed tomography (CE-CT) and EUS, and 101 (75.4%) by computed tomography (CT) alone. Thirteen patients (9.7%) showed tumor recurrence, five with intra-pancreatic recurrence and eight with extra-pancreatic metastases. An enhancing mural nodule within the dilated main pancreatic duct was successfully detected by EUS in one patient, but not by CE-CT. Two patients developed IPMN-concomitant PDAC during follow up. EUS combined with CH-EUS successfully detected small IPMN-concomitant PDAC in two patients, whereas these lesions were not detected by CT. CH-EUS was useful for better visualization of the margins of IPMN-concomitant PDAC in one of these two patients.

  Conclusion: Endoscopic ultrasonography combined with CH-EUS may improve follow up of patients with resected IPMN.

• Gankyrin Contributes to Tumorigenesis and Chemoresistance in Sporadic Colorectal Cancer

  Toshiharu Sakurai; Yoriaki Komeda; Tomoyuki Nagai; Ken Kamata; Kosuke Minaga; Kentarou Yamao; Mamoru Takenaka; Satoru Hagiwara; Tomohiro Watanabe; Naoshi Nishida; Hiroshi Kashida; Kazuhiko Nakagawa; Masatoshi Kudo

  Digestion S. Karger AG 100 (3) 1 - 9 0012-2823 2018/12 [Refereed]
  
• 【EUSによる消化管疾患の診断-現状と最新の話題】造影ハーモニックEUSによる消化管粘膜下腫瘍の診断

  鎌田 研; 竹中 完; 石川 嶺; 吉川 智恵; 岡本 彩那; 山崎 友裕; 中井 敦史; 大本 俊介; 三長 孝輔; 山雄 健太郎; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 西田 直生志; 樫田 博史; 工藤 正俊

  胃と腸 (株)医学書院 53 (13) 1795 - 1799 0536-2180 2018/12 [Invited]
   

  ＜文献概要＞EUSは上部消化管粘膜下腫瘍(SMT)の診断に用いられているが,上部消化管SMTの良悪性鑑別には限界がある.本稿では,造影ハーモニックEUSによる上部消化管粘膜下腫瘍の診断に関する前向き研究1報と後ろ向き研究6報の合計7報の研究をもとに上部消化管SMTの鑑別診断について調べた.造影ハーモニックEUSによるGISTとそれ以外の上部消化管SMTの鑑別診断に関する3つの報告では,hyper-enhancementがGISTの造影ハーモニックEUS所見であり,診断能は感度84.5〜100%,特異度73.3〜100%であった.一方,low-grade malignancy GISTとhigh-grade malignancy GISTの鑑別診断に関する4つの報告では,造影ハーモニックEUSによるhigh-grade malignancy GISTの診断能は感度53.8〜100%,特異度63〜100%であった.またhigh-grade malignancy GISTでは造影ハーモニックEUSにおいてirregular vesselsが高率に認められた.hyper-enhancementか否かおよびirregular vesselsの有無を確認することで上部消化管SMTの鑑別診断が可能であることが示唆された.
• Acute Pancreatitis with Disturbed Consciousness Caused by Hyperparathyroidism

  Yasuo Otsuka; Ken Kamata; Kosuke Minaga; Mamoru Takenaka; Tomohiro Watanabe; Masatoshi Kudo

  Internal Medicine Japanese Society of Internal Medicine 57 (21) 3075 - 3078 0918-2918 2018/11 [Refereed]
  
• Mechanistic Insights into Autoimmune Pancreatitis and IgG4-Related Disease

  Tomohiro Watanabe; Kosuke Minaga; Ken Kamata; Masatoshi Kudo; Warren Strober

  Trends in Immunology Elsevier BV 39 (11) 874 - 889 1471-4906 2018/11 [Refereed]
  
• Molecular Scoring of Hepatocellular Carcinoma for Predicting Metastatic Recurrence and Requirements of Systemic Chemotherapy

  Naoshi Nishida; Takafumi Nishimura; Toshimi Kaido; Kosuke Minaga; Kentaro Yamao; Ken Kamata; Mamoru Takenaka; Hiroshi Ida; Satoru Hagiwara; Yasunori Minami; Toshiharu Sakurai; Tomohiro Watanabe; Masatoshi Kudo

  Cancers MDPI AG 10 (10) 367 - 367 2018/09 [Refereed]
   

  Hepatocellular carcinoma (HCC) causes one of the most frequent cancer-related deaths; an HCC subset shows rapid progression that affects survival. We clarify molecular features of aggressive HCC, and establish a molecular scoring system that predicts metastasis after curative treatment. In total, 125 HCCs were examined for TP53, CTNNB1, and TERT promoter mutation, methylation of 8 tumor suppressor genes, and 3 repetitive DNA sequences to estimate promoter hypermethylation and global hypomethylation. A fractional allelic loss (FAL) was calculated to represent chromosomal instability through microsatellite analysis. Molecular subclasses were determined using corresponding and hierarchical clustering analyses. Next, twenty-five HCC patients who underwent liver transplantation were analyzed for associations between molecular characteristics and metastatic recurrence; survival analyses were validated using a publicly available dataset of 376 HCC cases from the Cancer Genome Atlas (TCGA). An HCC subtype characterized by TP53 mutation, high FAL, and global hypomethylation was associated with aggressive tumor characteristics, like vascular invasion; CTNNB1 mutation was a feature of the less-progressive phenotype. A number of molecular risk factors, including TP53 mutation, high FAL, significant global hypomethylation, and absence of CTNNB1 mutation, were noted to predict shorter recurrence-free survival in patients who underwent liver transplantation (p = 0.0090 by log-rank test). These findings were validated in a cohort of resected HCC cases from TCGA (p = 0.0076). We concluded that molecular risks determined by common genetic and epigenetic alterations could predict metastatic recurrence after curative treatments, and could be a marker for considering systemic therapy for HCC patients.
• 瀉血治療が奏効した骨髄性プロトポルフィリン症関連肝障害(Erythropoietic Protoporphyria-related Hepatopathy Successfully Treated with Phlebotomy)

  Yoshida Akihiro; Hagiwara Satoru; Watanabe Tomohiro; Nishida Naosihi; Ida Hiroshi; Sakurai Toshiharu; Komeda Yoriaki; Yamao Kentaro; Takenaka Mamoru; Enoki Eisuke; Kimura Masatomo; Miyake Masako; Kawada Akira; Kudo Masatoshi

  Internal Medicine (一社)日本内科学会 57 (17) 2505 - 2509 0918-2918 2018/09 [Refereed]
   

  症例は27歳男性で、小児期から光線性皮膚症に罹患しており、約1年前に全身性エリテマトーデスと診断されていた。この時点で肝胆道酵素値などが著明に上昇しており、最終的に骨髄性プロトポルフィリン症(EPP)関連肝障害と診断された。今回、全身疲労と血清中のAST、ALT、GGT、総ビリルビン値が再び上昇した。肝生検により、EPP関連肝障害の増悪であると診断した。血漿交換を計5回施行したが血中のAST、ALT、プロトポルフィリン値が低下しなかったため、200〜400mLの瀉血を毎週行ったところ、血清中の肝酵素値、AST、ALT、プロトポルフィリン値は著明に減少し、症状も軽減した。
• Value of additional endoscopic ultrasonography for surveillance after surgical removal of intraductal papillary mucinous neoplasms

  Ken Kamata; Mamoru Takenaka; Kosuke Minaga; Shunsuke Omoto; Takeshi Miyata; Kentaro Yamao; Hajime Imai; Atsushi Nakai; Hidekazu Tanaka; Yasutaka Chiba; Tomohiro Watanabe; Toshiharu Sakurai; Naoshi Nishida; Takaaki Chikugo; Ippei Matsumoto; Yoshifumi Takeyama; Masayuki Kitano; Masatoshi Kudo

  Digestive Endoscopy Wiley 30 (5) 659 - 666 0915-5635 2018/09 [Refereed]
  
• Outcomes of endoscopic biliary drainage in pancreatic cancer patients with an indwelling gastroduodenal stent: a multicenter cohort study in West Japan

  Kentaro Yamao; Masayuki Kitano; Mamoru Takenaka; Kosuke Minaga; Toshiharu Sakurai; Tomohiro Watanabe; Takahisa Kayahara; Tomoe Yoshikawa; Yukitaka Yamashita; Masanori Asada; Yoshihiro Okabe; Keiji Hanada; Yasutaka Chiba; Masatoshi Kudo

  Gastrointestinal Endoscopy Elsevier BV 88 (1) 66 - 75.e2 0016-5107 2018/07 [Refereed]
  
• Chemokine CXCL16 mediates acinar cell necrosis in cerulein induced acute pancreatitis in mice.

  Yojiro Sakuma; Yuzo Kodama; Takaaki Eguchi; Norimitsu Uza; Yoshihisa Tsuji; Masahiro Shiokawa; Takahisa Maruno; Katsutoshi Kuriyama; Yoshihiro Nishikawa; Yuki Yamauchi; Motoyuki Tsuda; Tatsuki Ueda; Tomoaki Matsumori; Toshihiro Morita; Teruko Tomono; Nobuyuki Kakiuchi; Atsushi Mima; Yuko Sogabe; Saiko Marui; Takeshi Kuwada; Akihiko Okada; Tomohiro Watanabe; Hiroshi Nakase; Tsutomu Chiba; Hiroshi Seno

  Scientific reports 8 (1) 8829 - 8829 2018/06 [Refereed]
   

  Severe acute pancreatitis is a lethal inflammatory disease frequently accompanied by pancreatic necrosis. We aimed to identify a key regulator in the development of pancreatic necrosis. A cytokine/chemokine array using sera from patients with acute pancreatitis (AP) revealed that serum CXCL16 levels were elevated according to the severity of pancreatitis. In a mouse model of AP, Cxcl16 expression was induced in pancreatic acini in the late phase with the development of pancreatic necrosis. Cxcl16-/- mice revealed similar sensitivity as wild-type (WT) mice to the onset of pancreatitis, but better resisted development of acinar cell necrosis with attenuated neutrophil infiltration. A cytokine array and immunohistochemistry revealed lower expression of Ccl9, a neutrophil chemoattractant, in the pancreatic acini of Cxcl16-/- mice than WT mice. Ccl9 mRNA expression was induced by stimulation with Cxcl16 protein in pancreatic acinar cells in vitro, suggesting a Cxcl16/Ccl9 cascade. Neutralizing antibody against Cxcl16 ameliorated pancreatic injury in the mouse AP model with decreased Ccl9 expression and less neutrophil accumulation. In conclusion, Cxcl16 expressed in pancreatic acini contributes to the development of acinar cell necrosis through the induction of Ccl9 and subsequent neutrophil infiltration. CXCL16 could be a new therapeutic target in AP.
• Dysbiosis-Associated Polyposis of the Colon—Cap Polyposis

  Kazuki Okamoto; Tomohiro Watanabe; Yoriaki Komeda; Ayana Okamoto; Kosuke Minaga; Ken Kamata; Kentaro Yamao; Mamoru Takenaka; Satoru Hagiwara; Toshiharu Sakurai; Tomonori Tanaka; Hiroki Sakamoto; Kiyoshige Fujimoto; Naoshi Nishida; Masatoshi Kudo

  Frontiers in Immunology Frontiers Media SA 9 2018/05 [Refereed]
  
• Pouch functional outcomes after restorative proctocolectomy with ileal-pouch reconstruction in patients with ulcerative colitis: Japanese multi-center nationwide cohort study.

  Motoi Uchino; Hiroki Ikeuchi; Akira Sugita; Kitaro Futami; Toshiaki Watanabe; Kouhei Fukushima; Kenji Tatsumi; Kazutaka Koganei; Hideaki Kimura; Keisuke Hata; Kenichi Takahashi; Kazuhiro Watanabe; Tsunekazu Mizushima; Yuji Funayama; Daijiro Higashi; Toshimitsu Araki; Masato Kusunoki; Takeshi Ueda; Fumikazu Koyama; Michio Itabashi; Riichiro Nezu; Yasuo Suzuki

  Journal of gastroenterology 53 (5) 642 - 651 0944-1174 2018/05 [Refereed]
   

  BACKGROUND: Although several complications capable of causing pouch failure may develop after restorative proctocolectomy (RPC) for ulcerative colitis (UC), the incidences and causes are conflicting and vary according to country, race and institution. To avoid pouch failure, this study aimed to evaluate the rate of pouch failure and its risk factors in UC patients over the past decade via a nationwide cohort study. METHODS: We conducted a retrospective, observational, multicenter study that included 13 institutions in Japan. Patients who underwent RPC between January 2005 and December 2014 were included. The characteristics and backgrounds of the patients before and during surgery and their postoperative courses and complications were reviewed. RESULTS: A total of 2376 patients were evaluated over 6.7 ± 3.5 years of follow-up. Twenty-seven non-functional pouches were observed, and the functional pouch rate was 98.9% after RPC. Anastomotic leakage (odds ratio, 9.1) was selected as a risk factor for a non-functional pouch. The cumulative pouch failure rate was 4.2%/10 years. A change in diagnosis to Crohn's disease/indeterminate colitis (hazard ratio, 13.2) was identified as an independent risk factor for pouch failure. CONCLUSION: The significant risk factor for a non-functional pouch was anastomotic leakage. The optimal staged surgical procedure should be selected according to a patient's condition to avoid anastomotic failure during RPC. Changes in diagnosis after RPC confer a substantial risk of pouch failure. Additional cohort studies are needed to obtain an understanding of the long-standing clinical course of and proper treatment for pouch failure.
• Risk-stratified therapy for children with FLT3-ITD-positive acute myeloid leukemia: results from the JPLSG AML-05 study.

  Akira Shimada; Yuka Iijima-Yamashita; Akio Tawa; Daisuke Tomizawa; Miho Yamada; Shiba Norio; Tomoyuki Watanabe; Takashi Taga; Shotaro Iwamoto; Kiminori Terui; Hiroshi Moritake; Akitoshi Kinoshita; Hiroyuki Takahashi; Hideki Nakayama; Katsuyoshi Koh; Hiroaki Goto; Yoshiyuki Kosaka; Akiko Moriya Saito; Nobutaka Kiyokawa; Keizo Horibe; Yusuke Hara; Kentaro Oki; Yasuhide Hayashi; Shiro Tanaka; Souichi Adachi

  International journal of hematology 107 (5) 586 - 595 0925-5710 2018/05 [Refereed]
   

  Acute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis. We evaluated the results of the AML-05 study, in which all AMLFLT3-ITD patients were assigned to receive hematopoietic stem cell transplantation (HSCT) in the first remission (1CR). We also investigated the effects of additional genetic alterations on FLT3-ITD. The 5-year overall survival (OS) and event-free survival (EFS) rates among the 47 AMLFLT3-ITD patients were 42.2 and 36.8%, respectively. The 5-year disease-free survival rate among 29 patients without induction failure was 58.4%. We defined the allelic ratio (AR) of FLT3-ITD to WT > 0.7 as high. Significant differences were found in OS (AR-high, 20% vs. AR-low, 66%, p < 0.001) and EFS (13 vs. 50%, p = 0.004). All five patients with concurrent NPM1 mutations survived, while seven of eight patients who expressed the NUP98-NSD1 chimera failed to achieve 1CR and died. Multivariate analysis revealed that AR > 0.7 and expression of the NUP98-NSD1 chimera strongly impacted OS and EFS. Although all the AMLFLT3-ITD patients received HSCT at 1CR, the treatment outcome of AMLFLT3-ITD patients did not improve compared with those in a previous study. Heterogeneity was observed among AMLFLT3-ITD patients.
• Nucleotide-binding oligomerization domain 1 and Helicobacter pylori infection: A review

  Kosuke Minaga; Tomohiro Watanabe; Ken Kamata; Naoki Asano; Masatoshi Kudo

  World Journal of Gastroenterology Baishideng Publishing Group Inc. 24 (16) 1725 - 1733 1007-9327 2018/04 [Refereed]
  
• Induction of Complete Remission by Azacitidine in a Patient with Myelodysplastic Syndrome-Associated Inflammatory Bowel Disease

  Masashi Kono; Yoriaki Komeda; Toshiharu Sakurai; Ayana Okamoto; Kosuke Minaga; Ken Kamata; Satoru Hagiwara; Hiroaki Inoue; Eisuke Enoki; Itaru Matsumura; Tomohiro Watanabe; Masatoshi Kudo

  Journal of Crohn's and Colitis Oxford University Press (OUP) 12 (4) 499 - 502 1873-9946 2018/03 [Refereed]
  
• パンクレリパーゼ摂取による腸管内および便の腸内細菌叢に対する影響の検討

  永井 知行; 櫻井 俊治; 工藤 正俊; 西山 拓輝; 岡崎 能久; 東 慶直; 渡邉 智裕; 五斗 進; 緒方 博之

  日本消化器病学会雑誌 (一財)日本消化器病学会 115 (臨増総会) A335 - A335 0446-6586 2018/03
• The relationship between the use of statins and mortality, severity, and pancreatic cancer in Danish patients with chronic pancreatitis

  Ulrich C. Bang; Tomohiro Watanabe; Flemming Bendtsen

  European Journal of Gastroenterology & Hepatology Ovid Technologies (Wolters Kluwer Health) 30 (3) 346 - 351 0954-691X 2018/03 [Refereed]
  
• IgG4関連疾患の病因と自然免疫

  渡邉 智裕; 鎌田 研; 三長 康輔; 工藤 正俊

  リウマチ科 60 (4) 347 - 352 2018 [Invited]
  
• IgG4

  渡邉 智裕; 工藤正俊

  消化器病学サイエンス 2 (3) 41 - 41 2018 [Invited]
  
• 自然免疫反応が膵臓の慢性炎症に果たす役割

  渡邉 智裕; 三長 孝輔; 鎌田 研; 工藤 正俊

  膵臓 33 (4) 737 - 741 2018 [Refereed][Invited]
  
• Cystic duct antegrade stenting for cholangitis after the long-term deployment of lumen-apposing metal stents for calculous cholecystitis

  Mamoru Takenaka; Ken Kamata; Kosuke Minaga; Atsushi Nakai; Shunsuke Omoto; Takeshi Miyata; Kentaro Yamao; Hajime Imai; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Masatoshi Kudo

  Endoscopic Ultrasound Medknow 7 (5) 349 - 349 2303-9027 2018 [Refereed]
  
• Autoimmune Pancreatitis Mouse Model

  Ken Kamata; Tomohiro Watanabe; Kosuke Minaga; Warren Strober; Masatoshi Kudo

  Current Protocols in Immunology Wiley 120 (1) 1934-3671 2018/01 [Refereed]
  
• Sustained antiviral effects and clearance of hepatitis surface antigen after combination therapy with entecavir and pegylated interferon in chronic hepatitis B

  Satoru Hagiwara; Naoshi Nishida; Tomohiro Watanabe; Hiroshi Ida; Toshiharu Sakurai; Kazuomi Ueshima; Masahiro Takita; Yoriaki Komeda; Norihiro Nishijima; Yukio Osaki; Masatoshi Kudo

  Antiviral Therapy International Medical Press 23 (6) 513 - 521 1359-6535 2018 [Refereed]
  
• A case of successful transluminal drainage of walled-off necrosis under contrast-enhanced harmonic endoscopic ultrasonography guidance

  Kosuke Minaga; Mamoru Takenaka; Shunsuke Omoto; Takeshi Miyata; Ken Kamata; Kentaro Yamao; Hajime Imai; Tomohiro Watanabe; Masayuki Kitano; Masatoshi Kudo

  Journal of Medical Ultrasonics Springer Science and Business Media LLC 45 (1) 161 - 165 1346-4523 2018/01 [Refereed]
  
• Supplementation of pancreatic digestive enzymes alters the composition of intestinal microbiota in mice

  Hiroki Nishiyama; Tomoyuki Nagai; Masatoshi Kudo; Yoshihisa Okazaki; Yoshinao Azuma; Tomohiro Watanabe; Susumu Goto; Hiroyuki Ogata; Toshiharu Sakurai

  Biochemical and Biophysical Research Communications Elsevier BV 495 (1) 273 - 279 0006-291X 2018/01 [Refereed]
  
• Rescue EUS-guided intrahepatic biliary drainage for malignant hilar biliary stricture after failed transpapillary re-intervention

  Kosuke Minaga; Mamoru Takenaka; Masayuki Kitano; Yasutaka Chiba; Hajime Imai; Kentaro Yamao; Ken Kamata; Takeshi Miyata; Shunsuke Omoto; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Masatoshi Kudo

  SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES SPRINGER 31 (11) 4764 - 4772 0930-2794 2017/11 [Refereed]
   

  Treatment of unresectable malignant hilar biliary stricture (UMHBS) is challenging, especially after failure of repeated transpapillary endoscopic stenting. Endoscopic ultrasonography-guided intrahepatic biliary drainage (EUS-IBD) is a recent technique for intrahepatic biliary decompression, but indications for its use for complex hilar strictures have not been well studied. The aim of this study was to assess the feasibility and safety of EUS-IBD for UMHBS after failed transpapillary re-intervention. Retrospective analysis of all consecutive patients with UMHBS of Bismuth II grade or higher who, between December 2008 and May 2016, underwent EUS-IBD after failed repeated transpapillary interventions. The technical success, clinical success, and complication rates were evaluated. Factors associated with clinical ineffectiveness of EUS-IBD were explored. A total of 30 patients (19 women, median age 66 years [range 52-87]) underwent EUS-IBD for UMHBS during the study period. Hilar biliary stricture morphology was classified as Bismuth II, III, or IV in 5, 13, and 12 patients, respectively. The median number of preceding endoscopic interventions was 4 (range 2-14). EUS-IBD was required because the following procedures failed: duodenal scope insertion (n = 4), accessing the papilla after duodenal stent insertion (n = 5), or achieving desired intrahepatic biliary drainage (n = 21). Technical success with EUS-IBD was achieved in 29 of 30 patients (96.7%) and clinical success was attained in 22 of these 29 (75.9%). Mild peritonitis occurred in three of 30 (10%) and was managed conservatively. Stent dysfunction occurred in 23.3% (7/30). There was no procedure-related mortality. On multivariable analysis, Bismuth IV stricture predicted clinical ineffectiveness (odds ratio = 12.7, 95% CI 1.18-135.4, P = 0.035). EUS-IBD may be a feasible and effective rescue alternative with few major complications after failed transpapillary endoscopic re-intervention in patients with UMHBS, particularly for Bismuth II or III strictures.
• A case of small invasive gastric cancer arising from Helicobacter pylori- negative gastric mucosa: Fundic gland-type adenocarcinoma

  Yoriaki Komeda; Tomohiro Watanabe; Shigenaga Matsui; Hiroshi Kashida; Toshiharu Sakurai; Masashi Kono; Kosuke Minaga; Tomoyuki Nagai; Satoru Hagiwara; Eisuke Enoki; Masatoshi Kudo

  JGH Open Wiley 1 (2) 74 - 75 2397-9070 2017/10 [Refereed]
  
• Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of submucosal tumors of the upper gastrointestinal tract

  Ken Kamata; Mamoru Takenaka; Masayuki Kitano; Shunsuke Omoto; Takeshi Miyata; Kosuke Minaga; Kentaro Yamao; Hajime Imai; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Takaaki Chikugo; Yasutaka Chiba; Haruhiko Imamoto; Takushi Yasuda; Andrea Lisotti; Pietro Fusaroli; Masatoshi Kudo

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY WILEY 32 (10) 1686 - 1692 0815-9319 2017/10 [Refereed]
   

  Background and Aim: The study aims to evaluate contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for the differential diagnosis of submucosal tumors (SMT) of the upper gastrointestinal tract. Methods: Between June 2008 and May 2015, 157 consecutive patients with submucosal lesions of the upper gastrointestinal tract were evaluated by CH-EUS. This was a single-center retrospective analysis of prospectively collected data in a registry. The data from 73 patients who later underwent surgical resection were analyzed in this study. Surgical specimens served as the final diagnoses. The two CH-EUS variables of blood flow (hyper-enhancement vs hypo-enhancement) and homogeneity of enhancement pattern were evaluated. Results: The final diagnoses were 58 gastrointestinal stromal tumors (GISTs) and 15 benign SMTs (two lipomas, five leiomyomas, five schwannomas, two glomus tumors, and one ectopic pancreas). On CH-EUS, 49 of 58 (84.5%) GISTs presented with hyper-enhancement, whereas 4 of 15 (26.7%) benign SMTs showed hyper-enhancement; 21 of 58 (36.2%) GISTs showed inhomogeneous contrast enhancement, while only 2 of 15 (13.3%) benign SMTs demonstrated inhomogeneous contrast enhancement. If hyper-enhancement was considered to indicate GISTs, the sensitivity, specificity, and accuracy were 84.5%, 73.3%, and 82.2%, respectively. If inhomogeneous enhancement was considered to indicate GISTs, the sensitivity, specificity, and accuracy were 36.2%, 86.7%, and 46.6%, respectively. In lesions of less than 2cm, hyper-enhancement was a more sensitive indicator of GISTs than inhomogeneous enhancement. Conclusions: Hyper-enhancement and inhomogeneous enhancement were found to be a characteristic of GISTs. CH-EUS was useful for discrimination of benign SMTs from GISTs.
• Gankyrin induces STAT3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma

  Toshiharu Sakurai; Norihisa Yada; Satoru Hagiwara; Tadaaki Arizumi; Kosuke Minaga; Ken Kamata; Mamoru Takenaka; Yasunori Minami; Tomohiro Watanabe; Naoshi Nishida; Masatoshi Kudo

  CANCER SCIENCE WILEY 108 (10) 1996 - 2003 1349-7006 2017/10 [Refereed]
   

  Most hepatocellular carcinomas (HCC) develop as a result of chronic liver inflammation. We have shown that the oncoprotein gankyrin is critical for inflammation-induced tumorigenesis in the colon. Although the invitro function of gankyrin is well known, its role invivo remains to be elucidated. We investigated the effect of gankyrin in the tumor microenvironment of mice with liver parenchymal cell-specific gankyrin ablation (Alb-Cre;gankyrin(f/f)) and gankyrin deletion both in liver parenchymal and non-parenchymal cells (Mx1-Cre;gankyrin(f/f)). Gankyrin upregulates vascular endothelial growth factor expression in tumor cells. Gankyrin binds to Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1), mainly expressed in liver non-parenchymal cells, resulting in phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3). Gankyrin deficiency in non-parenchymal cells, but not in parenchymal cells, reduced STAT3 activity, interleukin (IL)-6 production, and cancer stem cell marker (Bmi1 and epithelial cell adhesion molecule [EpCAM]) expression, leading to attenuated tumorigenic potential. Chronic inflammation enhances gankyrin expression in the human liver. Gankyrin expression in the tumor microenvironment is negatively correlated with progression-free survival in patients undergoing sorafenib treatment for HCC. Thus, gankyrin appears to play a critical oncogenic function in tumor microenvironment and may be a potential target for developing therapeutic and preventive strategies against HCC.
• EUS-guided approaches for bile duct stones: A single-center experience

  Minaga Kosuke; Takenaka Mamoru; Kamata Ken; Miyata Takeshi; Yamao Kentaro; Imai Hajime; Omoto Shunsuke; Nakai Atsushi; Yoshikawa Tomoe; Watanabe Tomohiro; Kudo Masatoshi

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 32 240  0815-9319 2017/09 [Refereed]
  
• Contribution of C1485T mutation in the HBx gene to human and murine hepatocarcinogenesis

  Satoru Hagiwara; Naoshi Nishida; Ah-Mee Park; Yoriaki Komeda; Toshiharu Sakurai; Tomohiro Watanabe; Masatoshi Kudo

  SCIENTIFIC REPORTS NATURE PUBLISHING GROUP 7 (1) 10440  2045-2322 2017/09 [Refereed]
   

  Although Hepatitis B virus (HBV) X gene mutations are frequently detected in HBV-related human hepatocellular carcinoma (HCC) patients, causative HBx mutations in the development of HCC have not yet been determined. We herein identified C1485T and C1653T mutations in the HBx gene as independent risk of HCC for HBV through the analysis using serum from chronic hepatitis B patients. We generated transgenic mice expressing wild-type (WT-HBxTg) and mutant (C1485T-HBxTg) HBx to assess the carcinogenic potential of mutated HBx. C1485T-HBxTg mice were more susceptible to diethylnitrosamine-induced hepatocarcinogenesis than WT-HBxTg mice and control non-Tg mice. The promotion of hepatocarcinogenesis in C1485T-HBxTg mice was accompanied by the activation of beta-catenin and Jun N-terminal kinase (JNK) signaling pathways as well as the production of reactive oxygen species, whereas the activation of nuclear factor-kappa B in the livers of C1485T-HBxTg mice was attenuated. These results demonstrate that the HBx C1485T mutation contributes to human and murine hepatocarcinogenesis.
• A Case of Type II Enteropathy-Associated T-Cell Lymphoma in a Patient With Ulcerative Colitis

  Yoriaki Komeda; Hiroshi Kashida; Toshiharu Sakurai; Masashi Kono; Tomoyuki Nagai; Yutaka Asakuma; Satoru Hagiwara; Shigenaga Matsui; Tomohiro Watanabe; Takaaki Chikugo; Masatoshi Kudo

  AMERICAN JOURNAL OF GASTROENTEROLOGY NATURE PUBLISHING GROUP 112 (6) 833 - 833 0002-9270 2017/06 [Refereed]
  
• Chronic Fibro-Inflammatory Responses in Autoimmune Pancreatitis Depend on IFN-α and IL-33 Produced by Plasmacytoid Dendritic Cells

  Tomohiro Watanabe; Kouhei Yamashita; Yasuyuki Arai; Kosuke Minaga; Ken Kamata; Tomoyuki Nagai; Yoriaki Komeda; Mamoru Takenaka; Satoru Hagiwara; Hiroshi Ida; Toshiharu Sakurai; Naoshi Nishida; Warren Strober; Masatoshi Kudo

  The Journal of Immunology The American Association of Immunologists 198 (10) 3886 - 3896 0022-1767 2017/05 [Refereed]
  
• 超音波内視鏡を用いた膵疾患診療 基本から応用まで EUSガイド下神経ブロックの成績と治療効果予測因子の検討

  三長 孝輔; 竹中 完; 宮田 剛; 中井 敦史; 大本 俊介; 鎌田 研; 山雄 健太郎; 今井 元; 渡邉 智裕; 工藤 正俊

  膵臓 (一社)日本膵臓学会 32 (3) 329 - 329 0913-0071 2017/05
• Follow-Up Examination of the Recurrence After Endoscopic Treatment of Colorectal Tumors

  Yoriaki Komeda; Hiroshi Kashida; Toshiharu Sakurai; Yutaka Asakuma; Tomoyuki Nagai; Shigenaga Matsui; Tomohiro Watanabe; Masatoshi Kudo

  GASTROINTESTINAL ENDOSCOPY MOSBY-ELSEVIER 85 (5) AB392 - AB392 0016-5107 2017/05 [Refereed]
  
• The oncoprotein gankyrin promotes the development of colitis-associated cancer through activation of STAT3

  Toshiharu Sakurai; Hiroaki Higashitsuji; Hiroshi Kashida; Tomohiro Watanabe; Yoriaki Komeda; Tomoyuki Nagai; Satoru Hagiwara; Masayuki Kitano; Naoshi Nishida; Takaya Abe; Hiroshi Kiyonari; Katsuhiko Itoh; Jun Fujita; Masatoshi Kudo

  ONCOTARGET IMPACT JOURNALS LLC 8 (15) 24762 - 24776 1949-2553 2017/04 [Refereed]
   

  Although long-standing colonic inflammation due to refractory inflammatory bowel disease (IBD) promotes the development of colitis-associated cancer (CAC), the molecular mechanisms accounting for the development of CAC remains largely unknown. In this study, we investigated the role of gankyrin in the development of CAC since gankyrin is overexpressed in sporadic colorectal cancers. We analyzed gene expression of colon tissues obtained from 344 patients with IBD and CAC and found that expression of gankyrin was much higher in colonic mucosa of patients with refractory IBD than in those with IBD in remission. Expression of gankyrin was upregulated in inflammatory cells as well as tumor cells in colonic mucosa of patients with CAC. Over-expressing studies utilizing tagged ganlyrin-cDNA identified physical interaction between ganlyrin and Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1). Importantly, the interaction between ganlyrin and SHP1 leads to inhibition of STAT3 activation and to enhancement of TNF-alpha and IL-17 in inflammatory cells. To further address the role of gankyrin in the development of CAC, we created mice with intestinal epithelial cell-specific gankyrin ablation (Vil-Cre; Gankyrin(f/f)) and deletion of gankyrin in myeloid and epithelial cells (Mx1Cre; Gankyrin(f/f)). Gankyrin deficiency in myeloid cells, but not in epithelial cells, reduced the activity of mitogen activated protein kinase and the expression of stem cell markers, leading to attenuated tumorigenic potential. These findings provide important insights into the pathogenesis of CAC and suggest that gankyrin is a promising target for developing therapeutic and preventive strategies against CAC.
• Immunopathogenesis of pancreatitis

  T. Watanabe; M. Kudo; W. Strober

  Mucosal Immunology Nature Publishing Group 10 (2) 283 - 298 1935-3456 2017/03 [Refereed]
   

  The conventional view of the pathogenesis of acute and chronic pancreatitis is that it is due to a genetic-or environment-based abnormality of intracellular acinar trypsinogen activation and thus to the induction of acinar cell injury that, in turn, sets in motion an intra-pancreatic inflammatory process. More recent studies, reviewed here, present strong evidence that while such trypsinogen activation is likely a necessary first step in the inflammatory cascade underlying pancreatitis, sustained pancreatic inflammation is dependent on damage-Associated molecular patterns-mediated cytokine activation causing the translocation of commensal (gut) organisms into the circulation and their induction of innate immune responses in acinar cells. Quite unexpectedly, these recent studies reveal that the innate responses involve activation of responses by an innate factor, nucleotide-binding oligomerization domain 1 (NOD1), and that such NOD1 responses have a critical role in the activation/production of nuclear factor-kappa B and type I interferon. In addition, they reveal that chronic inflammation and its accompanying fibrosis are dependent on the generation of IL-33 by injured acinar cells and its downstream induction of T cells producing IL-13. These recent studies thus establish that pancreatitis is quite a unique form of inflammation and one susceptible to newer, more innovative therapy.
• Hepatocarcinogenesis Is Associated with Serum Albumin Levels after Sustained Virological Responses with Interferon-Based Therapy in Patients with Hepatitis C

  Yasuko Umehara; Satoru Hagiwara; Naoshi Nishida; Toshiharu Sakurai; Hiroshi Ida; Yasunori Minami; Masahiro Takita; Tomohiro Minami; Hirokazu Chishina; Kazuomi Ueshima; Yoriaki Komeda; Tadaaki Arizumi; Tomohiro Watanabe; Masatoshi Kudo

  DIGESTIVE DISEASES KARGER 35 (6) 548 - 555 0257-2753 2017 [Refereed]
   

  Objective: It is a generally accepted fact that eradication of hepatitis virus C inhibits the subsequent development of hepatocellular carcinoma (HCC). On the contrary, a significant population of patients developed HCC despite sustained virological responses (SVRs) to interferon (IFN) therapy. Methods: A total of 415 patients with chronic hepatitis C, who were treated at our hospital between 2004 and 2014, were enrolled for this study. We examined the risk factors for HCC development after IFN therapy. Results: After analyzing various clinical parameters, it was concluded that a serum albumin (ALB) level <4.0 g/dL and the presence or absence of SVR achievement were risk factors for the development of HCC. When analyzing pre-and posttreatment factors, only a serum ALB level <4.0 g/dL was considered a significant risk factor. The presence or absence of liver fibrosis progression was not identified as a risk factor. Conclusions: In patients with a serum ALB level <4.0 g/dL before IFN therapy, hepatic carcinogenesis after SVR achievement need to be considered. Furthermore, the serum ALB level may be more useful than the degree of fibrosis for the prediction of HCC after SVR in chronic hepatitis C. (C) 2017 S. Karger AG, Basel
• 内視鏡所見からみた腸炎の鑑別診断.

  樫田博史; 米田頼晃; 岡元寿樹; 足立哲平; 永井知行; 朝隈豊; 櫻井俊治; 渡邉智裕

  消化器内視鏡 29 20 - 30 2017
• Malignant Transformation of Hepatocellular Adenoma

  Wing Yee Kwok; Satoru Hagiwara; Naoshi Nishida; Tomohiro Watanabe; Toshiharu Sakurai; Hiroshi Lda; Yasunori Minami; Masahiro Takita; Tomohiro Minami; Mina Lwanishi; Hirokazu Chishina; Masashi Kono; Kazuomi Ueshima; Yoriaki Komeda; Tadaaki Arizumi; Eisuke Enoki; Takuya Nakai; Tsutomu Kumabe; Osamu Nakashima; Fukuo Kondo; Masatoshi Kudo

  ONCOLOGY KARGER 92 (Suppl 1) 16 - 28 0030-2414 2017 

  The patient was a 20-year-old male in whom a hepatic hyper vascular mass accompanied by intratumoral hemorrhage was detected on examination for epigastric pain. Based on the enlargement of the mass and diagnostic imaging, hepatocellular adenoma (HCA) was suspected and hepatectomy was performed. The lesion was diagnosed as malignant transformation of P-catenin-activated HCA. There are only few reports of cases with malignant transformation of HCA in Japan; it is necessary to accumulate cases to investigate it. (C) 2016 S. Karger AG, Basel
• アミロイドーシスを疑う胃病変

  松井繁長; 樫田博史; 河野匡司; 岡元寿樹; 米田頼晃; 永井知行; 朝隈豊; 櫻井俊治; 渡邉智裕; 工藤正俊

  消化器内視鏡 29 (4) 756 - 758 0915-3217 2017
• 膵炎における腸管免疫機構破綻と重症化機序

  渡邉智裕; 三長孝輔; 鎌田研; 山雄健太郎; 竹中完; 工藤正俊

  肝•胆•膵 75 991 - 996 2017 [Invited]
  
• パターン認識受容体

  渡邉智裕; 工藤正俊

  消化器病学 サイエンス 1 150 - 152 2017 [Invited]
  
• Outcome of Combination Therapy with Sofosbuvir and Ledipasvir for Chronic Type C Liver Disease

  Satoru Hagiwara; Naoshi Nishida; Tomohiro Watanabe; Toshiharu Sakurai; Hiroshi Ida; Yasunori Minami; Masahiro Takita; Tomohiro Minami; Mina Iwanishi; Hirokazu Chishina; Kazuomi Ueshima; Yoriaki Komeda; Tadaaki Arizumi; Masatoshi Kudo

  ONCOLOGY KARGER 92 (Suppl 1) 3 - 9 0030-2414 2017 

  Introduction: Recently, the treatment of chronic hepatitis C has markedly advanced. A phase III clinical study of combination therapy with sofosbuvir (SOF) and ledipasvir (LDV) was conducted in Japan, and the additive therapeutic effects were reported. In this study, we report the results of treatment in our hospital. Methods: Of 147 patients with chronic type C liver disease who had consulted our hospital since September 2015 and received SOF/LDV therapy, in 91 subjects a sustained virological response of 12 weeks (SVR12) could be evaluated. Results: In all 91 patients, end treatment response was achieved. Subsequently, recrudescence was noted in 1 before the completion of treatment (week 12); an SVR12 was achieved in 90 patients (99%). The following adverse reactions were observed in 3 patients (3.3%): bradycardia, paroxysmal atrial fibrillation, and heart failure with QT prolongation, which were associated with heart disease. Conclusion: A favorable SVR was achieved by SOF/LDV therapy even in elderly patients, those with liver cirrhosis, or those having undergone radical treatment of liver cancer. Furthermore, a high tolerance was demonstrated, but adverse reactions associated with the heart may appear in patients with heart disease as an underlying disease; strict management during treatment is necessary. (C) 2016 S. KargerAG, Basel
• Malignant Transformation of Hepatocellular Adenoma

  Wing Yee Kwok; Satoru Hagiwara; Naoshi Nishida; Tomohiro Watanabe; Toshiharu Sakurai; Hiroshi Lda; Yasunori Minami; Masahiro Takita; Tomohiro Minami; Mina Lwanishi; Hirokazu Chishina; Masashi Kono; Kazuomi Ueshima; Yoriaki Komeda; Tadaaki Arizumi; Eisuke Enoki; Takuya Nakai; Tsutomu Kumabe; Osamu Nakashima; Fukuo Kondo; Masatoshi Kudo

  ONCOLOGY KARGER 92 (Suppl 1) 16 - 28 0030-2414 2017 

  The patient was a 20-year-old male in whom a hepatic hyper vascular mass accompanied by intratumoral hemorrhage was detected on examination for epigastric pain. Based on the enlargement of the mass and diagnostic imaging, hepatocellular adenoma (HCA) was suspected and hepatectomy was performed. The lesion was diagnosed as malignant transformation of P-catenin-activated HCA. There are only few reports of cases with malignant transformation of HCA in Japan; it is necessary to accumulate cases to investigate it. (C) 2016 S. Karger AG, Basel
• Unique Characteristics Associated with Sustained Liver Damage in Chronic Hepatitis C Patients Treated with Direct Acting Antivirals

  Masashi Kono; Naoshi Nishida; Satoru Hagiwara; Tomohiro Minami; Hirokazu Chishina; Tadaaki Arizumi; Kosuke Minaga; Ken Kamata; Yoriaki Komeda; Toshiharu Sakurai; Mamoru Takenaka; Masahiro Takita; Norihisa Yada; Hiroshi Ida; Yasunori Minami; Kazuomi Ueshima; Tomohiro Watanabe; Masatoshi Kudo

  DIGESTIVE DISEASES KARGER 35 (6) 556 - 564 0257-2753 2017 

  Background and Aims: Direct-acting antivirals (DAAs) dramatically improve the sustained virological response (SVR) of chronic hepatitis C (CHC) patients. However, continuous liver damage after SVR may be a risk of hepatocellular carcinoma (HCC). We clarified pretreatment characteristics related to sustained liver damage after SVR. Methods: A total of 286 CHC patients were treated with an interferon-free DAA regimen. Among them, 250 patients achieved SVR for 12 weeks after the end of treatment (SVR12); these individuals were classified based on a-fetoprotein (AFP) and alanine transaminase (ALT) levels posttreatment. Baseline characteristics significantly associated with AFP > 5 ng/mL and ALT level >= 20 IU/L after SVR were clarified using multivariate analyses. Results: Among the pretreatment factors examined, serum AFP values and the presence of fatty liver (FL) were significantly associated with abnormal AFP (p < 0.0001) and ALT levels 12 weeks after SVR12 (SVR24; p = 0.0109). For 126 patients who showed an increase in baseline AFP level, FL, fibrosis-4 (FIB-4) index, and albumin levels before treatment were related to abnormal AFP at SVR24 (p = 0.0005, 0.0232, and 0.0400 for FL, FIB-4 index, and albumin, respectively). Similarly, for 150 patients with abnormal baseline ALT levels, FL was associated with an ALT level = 30 IU/L after SVR (p = 0.0430). Conclusions: High FIB-4 index, low albumin level, and FL before DAA treatment were associated with a risk of sustained liver damage with AFP and ALT elevation after SVR; patients with these factors should be carefully monitored for emergence of HCC. (C) 2017 S. Karger AG, Basel
• Impact of Tumor Factors on Survival in Patients with Hepatocellular Carcinoma Classified Based on Kinki Criteria Stage B2

  Tadaaki Arizumi; Tomohiro Minami; Hirokazu Chishina; Masashi Kono; Masahiro Takita; Norihisa Yada; Satoru Hagiwara; Yasunori Minami; Hiroshi Ida; Kazuomi Ueshima; Ken Kamata; Kosuke Minaga; Yoriaki Komeda; Mamoru Takenaka; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Masatoshi Kudo

  DIGESTIVE DISEASES KARGER 35 (6) 583 - 588 0257-2753 2017 

  Background: Tumors classified based on the Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) are heterogeneous in nature. Previously, the Kinki criterion was proposed for a more precise subclassification of tumors in BCLC-stage B. However, tumors in sub-stage B2 include various size and number of HCCs even with the Kinki criteria, which could lead to heterogeneity for overall survival (OS). In this study, we assessed how the size and number of tumors affect the OS and time to progression (TTP) in patients with Kinki criteria stage B2 tumors and treated with transarterial chemoembolization (TACE). Methods: Of 906 HCC patients treated with TACE at Kindai University Hospital, 236 patients with HCC considered as Kinki criteria stage B2 were examined. They were classified into the following 4 groups according to the maximum tumor diameter and number of tumors: B2a group, tumor size <= 6 cm and total number of tumors <= 6; B2b group, size <= 6 cm and number >6; B2c group, size >6 cm and number <= 6; and B2d group, size >6 cm and number >6. The OS and TTP of patients in each group were compared. Results: There were 131 patients (55.5%) in the B2a group, 58 (24.6%) in the B2b group, 41 (17.4%) in the B2c group, and 6 (0.03%) in the B2d group. Comparison of the survivals revealed that the median OS was 2.8 years (95% CI 2.0-3.5) in the B2a group, 2.8 years (95% CI 2.0-3.3) in the B2b group, 1.9 years (95% CI 0.8-4.0) in the B2c group, and 2.3 years (95% CI 1.2-ND [no data]) in the B2d group, respectively (p = 0.896). The median TTP in B2a, B2b, B2c, and B2d sub-substage HCC were13.2, 12.1, 13.8, and 11.5 months, respectively (p = 0.047). The median TTP in B2a + B2c sub-substage patients was longer than that in B2b + B2d sub-substage HCC patients (14.0 months and 10.4 months; p = 0.002). Conclusion: No significant differences were observed in the OS among HCC patients subclassified based on the maximum tumor diameter and tumor number in Kinki criteria stage B2. Consequently, Kinki criteria stage B2 HCC is a homogeneous subgroup in terms of OS prediction. However, shorter TTP in B2b + B2c sub-substage HCC patients than that in B2a + B2c sub-substage HCC patients suggests that different treatment strategy, such as systemic therapy with targeted agents instead of TACE, may be suitable to preserve the liver function. (C) 2017 S. Karger AG, Basel
• Detection of High-Grade Pancreatic Intraepithelial Neoplasia without Morphological Changes of the Main Pancreatic Duct over a Long Period: Importance for Close Follow-Up for Confirmation

  Kentaro Yamao; Mamoru Takenaka; Atsushi Nakai; Shunske Omoto; Ken Kamata; Kosuke Minaga; Takeshi Miyata; Hajime Imai; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Ippei Matsumoto; Yosihumi Takeyama; Takaaki Chikugo; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 81 - 86 0030-2414 2017 [Refereed]
  
• Characterization of Pancreatic Tumors with Quantitative Perfusion Analysis in Contrast-Enhanced Harmonic Endoscopic Ultrasonography

  Shunsuke Omoto; Mamoru Takenaka; Masayuki Kitano; Takeshi Miyata; Ken Kamata; Kosuke Minaga; Tadaaki Arizumi; Kentaro Yamao; Hajime Imai; Hiroki Sakamoto; Yogesh Harwani; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Yoshifumi Takeyama; Yasutaka Chiba; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 55 - 60 0030-2414 2017 [Refereed]
  
• Utility of Endoscopic Ultrasound-Guided Hepaticogastrostomy with Antegrade Stenting for Malignant Biliary Obstruction after Failed Endoscopic Retrograde Cholangiopancreatography

  Hajime Imai; Mamoru Takenaka; Shunsuke Omoto; Ken Kamata; Takeshi Miyata; Kosuke Minaga; Kentaro Yamao; Toshiharu Sakurai; Naoshi Nishida; Tomohiro Watanabe; Masayuki Kitano; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 69 - 75 0030-2414 2017 [Refereed]
  
• Needle Tract Seeding: An Overlooked Rare Complication of Endoscopic Ultrasound-Guided Fine-Needle Aspiration

  Kosuke Minaga; Mamoru Takenaka; Akio Katanuma; Masayuki Kitano; Yukitaka Yamashita; Ken Kamata; Kentaro Yamao; Tomohiro Watanabe; Hiroyuki Maguchi; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 107 - 112 0030-2414 2017 [Refereed]
  
• Primary Hepatic Adenosquamous Carcinoma Associated with Primary Sclerosing Cholangitis

  Kentaro Yamao; Mamoru Takenaka; Hajime Imai; Atsushi Nakai; Shunske Omoto; Ken Kamata; Kosuke Minaga; Takeshi Miyata; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Ippei Matsumoto; Yosihumi Takeyama; Takaaki Chikugo; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 76 - 80 0030-2414 2017 [Refereed]
  
• Computer-Aided Diagnosis Based on Convolutional Neural Network System for Colorectal Polyp Classification: Preliminary Experience

  Yoriaki Komeda; Hisashi Handa; Tomohiro Watanabe; Takanobu Nomura; Misaki Kitahashi; Toshiharu Sakurai; Ayana Okamoto; Tomohiro Minami; Masashi Kono; Tadaaki Arizumi; Mamoru Takenaka; Satoru Hagiwara; Shigenaga Matsui; Naoshi Nishida; Hiroshi Kashida; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 30 - 34 0030-2414 2017 [Refereed]
  
• Magnifying Narrow Band Imaging (NBI) for the Diagnosis of Localized Colorectal Lesions Using the Japan NBI Expert Team (JNET) Classification

  Yoriaki Komeda; Hiroshi Kashida; Toshiharu Sakurai; Yutaka Asakuma; George Tribonias; Tomoyuki Nagai; Masashi Kono; Kosuke Minaga; Mamoru Takenaka; Tadaaki Arizumi; Satoru Hagiwara; Shigenaga Matsui; Tomohiro Watanabe; Naoshi Nishida; Takaaki Chikugo; Yasutaka Chiba; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 49 - 54 0030-2414 2017 [Refereed]
  
• Clinical Analysis of Esophageal Stricture in Patients Treated with Intralesional Triamcinolone Injection after Endoscopic Submucosal Dissection for Superficial Esophageal Cancer

  Kazuki Okamoto; Shigenaga Matsui; Tomohiro Watanabe; Yutaka Asakuma; Yoriaki Komeda; Ayana Okamoto; Ishikawa Rei; Masashi Kono; Mitsunari Yamada; Tomoyuki Nagai; Tadaaki Arizumi; Kosuke Minaga; Ken Kamata; Kentaro Yamao; Mamoru Takenaka; Toshiharu Sakurai; Naoshi Nishida; Hiroshi Kashida; Takaaki Chikugo; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 9 - 14 0030-2414 2017 [Refereed]
  
• EUS-Guided Pancreatic Duct Drainage for Repeat Pancreatitis in a Patient with Pancreatic Cancer

  Ken Kamata; Mamoru Takenaka; Kosuke Minaga; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 87 - 88 0030-2414 2017 [Refereed]
  
• Time to Transcatheter Arterial Chemoembolization Refractoriness in Patients with Hepatocellular Carcinoma in Kinki Criteria Stages B1 and B2

  Tadaaki Arizumi; Tomohiro Minami; Hirokazu Chishina; Masashi Kono; Masahiro Takita; Norihisa Yada; Satoru Hagiwara; Yasunori Minami; Hiroshi Ida; Kazuomi Ueshima; Ken Kamata; Kosuke Minaga; Yoriaki Komeda; Mamoru Takenaka; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Masatoshi Kudo

  DIGESTIVE DISEASES KARGER 35 (6) 589 - 597 0257-2753 2017 

  Background: Transarterial chemoembolization (TACE) is recommended for patients with hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) stage B. However, because of the heterogeneity of HCC in BCLC stage B; various subclassification systems have been proposed to predict the prognosis of patients. Previously, we proposed the Kinki criteria for precise classification of HCC cases in BCLC stage B. In this study, we compared the time to TACE refractoriness in HCC patients with Kinki criteria substages B1 and B2-HCC. Summary: Between January 2006 and December 2013, 592 HCC patients (substage B1, n = 118; substage B2, n = 170) underwent TACE. Time to progression under TACE treatment was defined as the time to untreatable progression (TTUP). TTUP and changes in liver function were analyzed in patients with substages B1 and B2-HCC. The median TTUP was 25.7 months (95% CI 19.3-37.3) and 16.4 months (95% CI 13.1-20.2) in patients with substage B1-HCC and substage B2-HCC, respectively (p = 0.0050). In patients with substage B2-HCC, median Child-Pugh scores after the first TACE session was significantly different from those after third and fifth TACE sessions (first-third, p = 0.0020; first-fifth, p = 0.0008). Key Message: TACE refractoriness occurred earlier in patients with substage B2-HCC than those with substage B1-HCC; deterioration of liver function with repeated TACE was more obvious in HCC cases with stage-B1 tumor. Shorter TTUP and impaired liver function due to repeated TACE could be responsible for the shorter survival in patients with substage B2-HCC. (C) 2017 S. Karger AG, Basel
• Prophylactic Suturing Closure Is Recommended after Endoscopic Treatment of Colorectal Tumors in Patients with Antiplatelet/Anticoagulant Therapy

  Toshiharu Sakurai; Teppei Adachi; Masashi Kono; Tadaaki Arizumi; Ken Kamata; Kosuke Minaga; Kentaro Yamao; Yoriaki Komeda; Mamoru Takenaka; Satoru Hagiwara; Tomohiro Watanabe; Naoshi Nishida; Hiroshi Kashida; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 27 - 29 0030-2414 2017 [Refereed]
  
• Comparative Study of Clarithromycin- versus Metronidazole-Based Triple Therapy as First-Line Eradication for Helicobacter pylori

  Teppei Adachi; Shigenaga Matsui; Tomohiro Watanabe; Kazuki Okamoto; Ayana Okamoto; Masashi Kono; Mitsunari Yamada; Tomoyuki Nagai; Yoriaki Komeda; Kosuke Minaga; Ken Kamata; Kentaro Yamao; Mamoru Takenaka; Yutaka Asakuma; Toshiharu Sakurai; Naoshi Nishida; Hiroshi Kashida; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 15 - 19 0030-2414 2017 [Refereed]
  
• Clinical Significance of Bmi1 Expression in Inflammatory Bowel Disease

  Mitsunari Yamada; Toshiharu Sakurai; Yoriaki Komeda; Tomoyuki Nagai; Ken Kamata; Kosuke Minaga; Kentaro Yamao; Mamoru Takenaka; Satoru Hagiwara; Shigenaga Matsui; Tomohiro Watanabe; Naoshi Nishida; Hiroshi Kashida; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 20 - 26 0030-2414 2017 [Refereed]
  
• Association between the Risk Factors for Pancreatic Ductal Adenocarcinoma and Those for Malignant Intraductal Papillary Mucinous Neoplasm

  Ken Kamata; Mamoru Takenaka; Atsushi Nakai; Shunsuke Omoto; Takeshi Miyata; Kosuke Minaga; Tomohiro Matsuda; Kentaro Yamao; Hajime Imai; Yasutaka Chiba; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Takaaki Chikugo; Ippei Matsumoto; Yoshifumi Takeyama; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 102 - 106 0030-2414 2017 [Refereed]
  
• Risk Factors for Postoperative Bleeding in Endoscopic Submucosal Dissection of Colorectal Tumors

  Kazuki Okamoto; Tomohiro Watanabe; Yoriaki Komeda; Tatsuya Kono; Kouta Takashima; Ayana Okamoto; Masashi Kono; Mitsunari Yamada; Tadaaki Arizumi; Ken Kamata; Kosuke Minaga; Kentaro Yamao; Tomoyuki Nagai; Yutaka Asakuma; Mamoru Takenaka; Toshiharu Sakurai; Shigenaga Matsui; Naoshi Nishida; Takaaki Chikugo; Hiroshi Kashida; Masatoshi Kudo

  Oncology S. Karger AG 93 (1) 35 - 42 0030-2414 2017 [Refereed]
  
• Removal of diminutive colorectal polyps: A prospective randomized clinical trial between cold snare polypectomy and hot forceps biopsy

  Yoriaki Komeda; Hiroshi Kashida; Toshiharu Sakurai; George Tribonias; Kazuki Okamoto; Masashi Kono; Mitsunari Yamada; Teppei Adachi; Hiromasa Mine; Tomoyuki Nagai; Yutaka Asakuma; Satoru Hagiwara; Shigenaga Matsui; Tomohiro Watanabe; Masayuki Kitano; Takaaki Chikugo; Yasutaka Chiba; Masatoshi Kudo

  WORLD JOURNAL OF GASTROENTEROLOGY BAISHIDENG PUBLISHING GROUP INC 23 (2) 328 - 335 1007-9327 2017/01 [Refereed]
   

  AIM To compare the efficacy and safety of cold snare polypectomy (CSP) and hot forceps biopsy (HFB) for diminutive colorectal polyps. METHODS This prospective, randomized single-center clinical trial included consecutive patients >= 20 years of age with diminutive colorectal polyps 3-5 mm from December 2014 to October 2015. The primary outcome measures were en-bloc resection (endoscopic evaluation) and complete resection rates (pathological evaluation). The secondary outcome measures were the immediate bleeding or immediate perforation rate after polypectomy, delayed bleeding or delayed perforation rate after polypectomy, use of clipping for bleeding or perforation, and polyp retrieval rate. Prophylactic clipping after polyp removal wasn't routinely performed. RESULTS Two hundred eight patients were randomized into the CSP (102), HFB (106) and 283 polyps were evaluated (CSP: 148, HFB: 135). The en-bloc resection rate was significantly higher with CSP than with HFB [99.3% (147/148) vs 80.0% (108/135), P < 0.0001]. The complete resection rate was significantly higher with CSP than with HFB [80.4% (119/148) vs 47.4% (64/135), P < 0.0001]. The immediate bleeding rate was similar between the groups [8.6% (13/148) vs 8.1% (11/135), P = 1.000], and endoscopic hemostasis with hemoclips was successful in all cases. No cases of perforation or delayed bleeding occurred. The rate of severe tissue injury to the pathological specimen was higher HFB than CSP [52.6% (71/135) vs 1.3% (2/148), P < 0.0001]. Polyp retrieval failure was encountered CSP (7), HFB (2). CONCLUSION CSP is more effective than HFB for resecting diminutive polyps. Further long-term follow-up study is required.
• Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis: Long-term outcomes after removal of a self-expandable metal stent

  Ken Kamata; Mamoru Takenaka; Masayuki Kitano; Shunsuke Omoto; Takeshi Miyata; Kosuke Minaga; Kentaro Yamao; Hajime Imai; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Masatoshi Kudo

  WORLD JOURNAL OF GASTROENTEROLOGY BAISHIDENG PUBLISHING GROUP INC 23 (4) 661 - 667 1007-9327 2017/01 [Refereed]
   

  AIM To assess the long-term outcomes of this procedure after removal of self-expandable metal stent (SEMS). The efficacy and safety of endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) with SEMS were also assessed. METHODS Between January 2010 and April 2015, 12 patients with acute calculous cholecystitis, who were deemed unsuitable for cholecystectomy, underwent EUS-GBD with a SEMS. EUS-GBD was performed under the guidance of EUS and fluoroscopy, by puncturing the gallbladder with a needle, inserting a guidewire, dilating the puncture hole, and placing a SEMS. The SEMS was removed and/or replaced with a 7-Fr plastic pigtail stent after cholecystitis improved. The technical and clinical success rates, adverse event rate, and recurrence rate were all measured. RESULTS The rates of technical success, clinical success, and adverse events were 100%, 100%, and 0%, respectively. After cholecystitis improved, the SEMS was removed without replacement in eight patients, whereas it was replaced with a 7-Fr pigtail stent in four patients. Recurrence was seen in one patient (8.3%) who did not receive a replacement pigtail stent. The median follow-up period after EUS-GBD was 304 d (78-1492). CONCLUSION EUS-GBD with a SEMS is a possible alternative treatment for acute cholecystitis. Long-term outcomes after removal of the SEMS were excellent. Removal of the SEMS at 4-wk after SEMS placement and improvement of symptoms might avoid migration of the stent and recurrence of cholecystitis due to food impaction.
• Stress Response Protein RBM3 Promotes the Development of Colitis-associated Cancer

  Toshiharu Sakurai; Hiroshi Kashida; Yoriaki Komeda; Tomoyuki Nagai; Satoru Hagiwara; Tomohiro Watanabe; Masayuki Kitano; Naoshi Nishida; Jun Fujita; Masatoshi Kudo

  Inflammatory Bowel Diseases Oxford University Press (OUP) 23 (1) 57 - 65 1078-0998 2017/01 [Refereed]
  
• The Overall Survival of Patients with Hepatocellular Carcinoma Correlates with the Newly Defined Time to Progression after Transarterial Chemoembolization

  Tadaaki Arizumi; Kazuomi Ueshima; Mina Iwanishi; Tomohiro Minami; Hirokazu Chishina; Masashi Kono; Masahiro Takita; Norihisa Yada; Satoru Hagiwara; Yasunori Minami; Hiroshi Ida; Yoriaki Komeda; Mamoru Takenaka; Toshiharu Sakurai; Tomohiro Watanabe; Naoshi Nishida; Masatoshi Kudo

  LIVER CANCER KARGER 6 (3) 227 - 235 2235-1795 2017 [Refereed]
   

  Aim/Background: The ultimate aim of any treatment for hepatocellular carcinoma (HCC) is to improve overall survival (OS); however, the clinical significance of time to progression (TTP) after transarterial chemoembolization (TACE) is unclear. This retrospective study examined the association between OS and the newly defined time to TACE progression (TTTP) to assess whether TTTP can be an alternative to OS in HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage B. Methods: Between January 2006 and December 2013, 592 patients with HCC (BCLC B1, n = 118; BCLC B2, n = 170) underwent TACE. TTTP was then redefined as time to progression from the first image taken after TACE. The relationship between TTTP and OS was then examined based on survival time. Results: Survival analysis revealed significant differences in the OS of patients with BCLC B1 and those with BCLC B2 (median OS: 42.3 months, 95% confidence interval [CI] 34.4-50.7; and 29.3 months, 95% CI 26.1-37.6, respectively, p = 0.0348). The median TTTP values were 9.5 months (95% CI 7.0-10.9) and 5.3 months (95% CI 4.6-6.7), respectively (p = 0.0078). There was a moderate positive correlation between OS and TTTP for both B1 (R-2 = 0.6563, p = 0.0045) and B2 (R-2 = 0.6433, p = 0.0052) substages. There was also a positive correlation between OS and TTTP for the combined B1 and B2 substages (R-2 = 0.6590, p = 0.0024). Conclusions: There was a moderate correlation between the TTTP and OS of patients with HCC after TACE therapy, where the patients with short TTTP represented short OS, indicating that TTTP is an alternative parameter for survival analysis of HCC patients with BCLC stage B tumors who undergo TACE. (C) 2017 S. Karger AG, Basel
• IgG4-Related Disease and Innate Immunity

  Tomohiro Watanabe; Kouhei Yamashita; Masatoshi Kudo

  IGG4-RELATED DISEASE SPRINGER INT PUBLISHING AG 401 115 - 128 0070-217X 2017 [Refereed][Invited]
   

  An increased number of clinicopathological studies on autoimmune pancreatitis, cholangitis, and sialoadenitis have led to the recognition of immunoglobulin G4-related disease (IgG4-RD) as a novel disorder, characterized by elevated levels of serum IgG4 and infiltration of IgG4-expressing plasma cells in the affected organs. Although the immunological background associated with the development of IgG4-RD remains poorly understood, recent studies have suggested involvement of the innate immune response in its pathogenesis. Peripheral blood innate immune cells, such as plasmacytoid dendritic cells and monocytes isolated from patients with IgG4-RD, promote IgG4 production by B cells. Activation of the innate immune response by microbe-and/or damage-associated molecular patterns stimulates production of type I interferon and B cell-activating factor by innate immune cells and results in IgG4 production by B cells. Elucidation of the innate immune response associated with IgG4-RD may help identify a new therapeutic target for this immune disorder.
• Nucleotide-binding oligomerization domain 1 and gastrointestinal disorders

  Tomohiro Watanabe; Naoki Asano; Masatoshi Kudo; Warren Strober

  Proceedings of the Japan Academy Series B: Physical and Biological Sciences Japan Academy 93 (8) 578 - 599 1349-2896 2017 [Refereed]
   

  Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular sensor that detects small peptides derived from the cell wall component of intestinal microflora. NOD1 is expressed in both non-hematopoietic cells such as epithelial cells and hematopoietic cells such as antigen-presenting cells. Detection of its ligand by NOD1 leads to innate immune responses through activation of nuclear factor kappa B and type I interferon as well as induction of autophagy. Innate immune responses through NOD1 activation play an indispensable role both in host defense against microbial infection and in the development of gastrointestinal disorders. Of particular importance, NOD1-mediated innate immune responses are associated with mucosal host defenses against Helicobacter pylori (H. pylori) infection of the stomach and with the development of pancreatitis. In this review, we discuss the molecular mechanisms by which NOD1 activation leads to the development of H. pylori-related gastric diseases and pancreatitis.
• A validation study of the Japan NBI Expert Team (JNET) of NBI magnifying endoscopy classification for the treatment of colorectal tumors

  Yoriaki Komeda; Hiroshi Kashida; Toshiharu Sakurai; Yutaka Asakuma; Tomoyuki Nagai; Hiromasa Mine; Teppei Adachi; Shigenaga Matsui; Tomohiro Watanabe; Masatoshi Kudo

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY WILEY-BLACKWELL 31 307 - 308 0815-9319 2016/11 [Refereed]
  
• Nucleotide-binding oligomerization domain 1 acts in concert with the cholecystokinin receptor agonist, cerulein, to induce IL-33-dependent chronic pancreatitis

  T. Watanabe; Y. Sadakane; N. Yagama; T. Sakurai; H. Ezoe; M. Kudo; T. Chiba; W. Strober

  MUCOSAL IMMUNOLOGY NATURE PUBLISHING GROUP 9 (5) 1234 - 1249 1933-0219 2016/09 [Refereed]
   

  Nucleotide-binding oligomerization domain 1 (NOD1) fulfills important host-defense functions via its responses to a variety of gut pathogens. Recently, however, we showed that in acute pancreatitis caused by administration of cholecystokinin receptor (CCKR) agonist ( cerulein) NOD1 also has a role in inflammation via its responses to gut commensal organisms. In the present study, we explored the long-term outcome of such NOD1 responsiveness in a new model of chronic pancreatitis induced by repeated administration of low doses of cerulein in combination with NOD1 ligand. We found that the development of chronic pancreatitis in this model requires intact NOD1 and type I IFN signaling and that such signaling mediates a macrophage-mediated inflammatory response that supports interleukin (IL)-33 production by acinar cells. The IL-33, in turn, has a necessary role in the induction of IL-13 and TGF-beta 1, factors causing the fibrotic reaction characteristic of chronic pancreatitis. Interestingly, the Th2 effects of IL-33 were attenuated by the concomitant type I IFN response since the inflammation was marked by clear increases in IFN-gamma and TNF-alpha production but only marginal increases in IL-4 production. These studies establish chronic pancreatitis as an IL-33-dependent inflammation resulting from synergistic interactions between the NOD1 and CCKR signaling pathways.
• Pathogenicity of IgG in patients with IgG4-related disease

  Masahiro Shiokawa; Yuzo Kodama; Katsutoshi Kuriyama; Kenichi Yoshimura; Teruko Tomono; Toshihiro Morita; Nobuyuki Kakiuchi; Tomoaki Matsumori; Atsushi Mima; Yoshihiro Nishikawa; Tatsuki Ueda; Motoyuki Tsuda; Yuki Yamauchi; Ryuki Minami; Yojiro Sakuma; Yuji Ota; Takahisa Maruno; Akira Kurita; Yugo Sawai; Yoshihisa Tsuji; Norimitsu Uza; Kazuyoshi Matsumura; Tomohiro Watanabe; Kenji Notohara; Tatsuaki Tsuruyama; Hiroshi Seno; Tsutomu Chiba

  GUT BMJ PUBLISHING GROUP 65 (8) 1322 - 1332 0017-5749 2016/08 [Refereed]
   

  Objective IgG4-related disease (IgG4-RD) is a systemic disease characterised by elevated serum IgG4 and IgG4-positive lymphoplasmacytic infiltration in the affected tissues. The pathogenic role of IgGs, including IgG4, in patients with IgG4-RD, however, is unknown. Design We examined the pathogenic activity of circulating IgGs in patients with IgG4-RD by injecting their IgGs into neonatal male Balb/c mice. Binding of patient IgGs to pancreatic tissue was also analysed in an ex vivo mouse organ culture model and in tissue samples from patients with autoimmune pancreatitis (AIP). Results Subcutaneous injection of patient IgG, but not control IgG, resulted in pancreatic and salivary gland injuries. Pancreatic injury was also induced by injecting patient IgG1 or IgG4, with more destructive changes induced by IgG1 than by IgG4. The potent pathogenic activity of patient IgG1 was significantly inhibited by simultaneous injection of patient IgG4. Binding of patient IgG, especially IgG1 and IgG4, to pancreatic tissue was confirmed in both the mouse model and AIP tissue samples. Conclusions IgG1 and IgG4 from patients with IgG4-RD have pathogenic activities through binding affected tissues in neonatal mice.
• Cdx2 Expression and Intestinal Metaplasia Induced by H. pylori Infection of Gastric Cells Is Regulated by NOD1-Mediated Innate Immune Responses

  Naoki Asano; Akira Imatani; Tomohiro Watanabe; Jun Fushiya; Yutaka Kondo; Xiaoyi Jin; Nobuyuki Ara; Kaname Uno; Katsunori Iijima; Tomoyuki Koike; Warren Strober; Tooru Shimosegawa

  CANCER RESEARCH AMER ASSOC CANCER RESEARCH 76 (5) 1135 - 1145 0008-5472 2016/03 [Refereed]
   

  Chronic infection with the bacterial Helicobacter pylori is a major cause of gastric and duodenal ulcer disease, gastric mucosal atrophy, and cancer. H. pylori-induced expression of the intestinal epithelial-specific transcription factor caudal-related homeobox 2 (Cdx2) contributes to intestinal metaplasia, a precursor event to gastric cancer. Given a role for the bacterial pattern recognition molecule nucleotide-binding oligomerization domain 1 (NOD1) in the innate immune response to bacterial infection, we investigated mechanisms used by NOD1 to regulate H. pylori infection and its propensity towards the development of intestinal metaplasia. We found that Cdx2 was induced by H. pylori infection in both normal and neoplastic gastric epithelial cells in a manner that was inversely related to NOD1 signaling. Mechanistic investigations revealed that Cdx2 induction relied upon activation of NF-kappa B but was suppressed by NOD1-mediated activation of TRAF3, a negative regulator of NF-kappa B. In vivo, prolonged infection of NOD1-deficient mice with H. pylori led to increased Cdx2 expression and intestinal metaplasia. Furthermore, gastric epithelial cells from these mice exhibited increased nuclear expression of the NF-kappa B p65 subunit and decreased expression of TRAF3. Overall, our findings illuminated a role for NOD1 signaling in attenuating H. pylori-induced Cdx2 expression in gastric epithelial cells, suggesting a rationale to augment NOD1 signaling in H. pylori-infected patients to limit their risks of accumulating precancerous gastric lesions. (C)2016 AACR.
• Outcome of Asunaprevir/Daclatasvir Combination Therapy for Chronic Liver Disease Type C

  Satoru Hagiwara; Naoshi Nishida; Tomohiro Watanabe; Toshiharu Sakurai; Hiroshi Ida; Yasunori Minami; Masahiro Takita; Tomohiro Minami; Mina Iwanishi; Hirokazu Chishina; Kazuomi Ueshima; Yoriaki Komeda; Tadaaki Arizumi; Masatoshi Kudo

  DIGESTIVE DISEASES KARGER 34 (6) 620 - 626 0257-2753 2016 

  Objective: Treatment for chronic hepatitis C has recently developed in a very rapid manner. In Japan, in September 2014, IFN-free asunaprevir (ASV) and daclatasvir (DCV) became available for combination therapy. We report the treatment outcomes achieved at our hospital using this combination therapy. Methods: Sustained virological response (SVR) 24 could be evaluated in 120 of 125 patients with chronic liver disease type C who visited our hospital and were treated with ASV/DCV after September 2014, and these patients were analyzed. Results: SVR24 was achieved in 106 patients (88%). End-of-treatment response was not achieved in 10 patients (8.3%). Five of them carried multiple-resistant NS3/4A or NS5A region, and administration was discontinued early in 4 patients due to adverse effects. After ASV/DCV treatment, hepatocellular carcinoma (HCC) developed in 2 patients (1.7%) and recurred in 5 (4.2%). Conclusions: ASV/DCV treatment achieved favorable SVR in elderly and hepatic cirrhosis patients and patients in whom HCC was cured. However, an increase in the incidence of HCC development in patients who markedly respond to direct-acting antivirals treatment is expected and surveillance of HCC becomes more important. (C) 2016 S. Karger AG, Basel
• Clinical Factors Predicting the Effect of Tolvaptan for Refractory Ascites in Patients with Decompensated Liver Cirrhosis

  Hirokazu Chishina; Satoru Hagiwara; Naoshi Nishida; Kazuomi Ueshima; Toshiharu Sakurai; Hiroshi Ida; Yasunori Minami; Masahiro Takita; Masashi Kono; Tomohiro Minami; Mina Iwanishi; Yasuko Umehara; Tomohiro Watanabe; Yoriaki Komeda; Tadaaki Arizumi; Masotoshi Kudo

  DIGESTIVE DISEASES KARGER 34 (6) 659 - 664 0257-2753 2016 

  Objective: Refractory ascites reduces the quality of life of liver cirrhosis patients. Albumin preparation and diuretics, such as furosemide, have been used to treat refractory ascites, but the effect was poor in many patients. In this study, we analyzed patients treated with tolvaptan (TLV) at our hospital and investigated predictors of the effect. Methods: The subjects were 70 patients for whom TLV was introduced to treat refractory ascites who could be analyzed between November 2013 and March 2015 at our hospital. Patient background before initiation of oral TLV treatment, the dose of diuretics, and each item of biochemical tests of blood and urine were investigated, and factors correlated with the treatment effect were analyzed. An increase of >= 1,000 ml in the daily urine volume from the day before oral treatment or a decrease of kg in the body weight within 7 days as an early effect was observed in 33 patients and not observed in 37 patients. TLV treatment was continued for 60 days or longer in 12 of the 37 patients in whom no early effect was observed, and the presence or absence of a delayed effect and predictors of the effect were investigated. A decrease in as cites on abdominal CT with improvement of subjective symptoms at 60 days was defined as a delayed effect. Results: When early predictors of the effect were investigated by univariate analysis, serum blood urea nitrogen (BUN) and serum creatinine (Cr) were significantly higher in the non responder group (BUN: p = 0.03, Cr: p = 0.04), but no factor independently associated with the treatment effect was extracted on multivariate analysis. The delayed effect was noted in 4 (33.3%) of the 12 patients, but no predictor of the effect before treatment was identified. However, reactions, such as an increase in serum Na and reduction of urinary osmotic pressure, were observed early after TLV administration in some patients in whom the delayed effect was observed. Conclusions: The diuretic effect of TLV may decrease in renal hypofunction patients. Since the delayed effect was noted in a specific ratio of patients, continuation of TLV administration is an option even though the early treatment effect is poor unless ascites aggravates or adverse effects develop. (C) 2016 S. Karger AG, Basel
• IgG4関連疾患に関わる自然免疫反応

  渡邉智裕; 千葉勉

  アレルギーの臨床 36 145 - 147 2016 [Invited]
  
• Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

  Yasuyuki Arai; Kouhei Yamashita; Katsutoshi Kuriyama; Masahiro Shiokawa; Yuzo Kodama; Toshiharu Sakurai; Kiyomi Mizugishi; Kazushige Uchida; Norimitsu Kadowaki; Akifumi Takaori-Kondo; Masatoshi Kudo; Kazuichi Okazaki; Warren Strober; Tsutomu Chiba; Tomohiro Watanabe

  The Journal of Immunology The American Association of Immunologists 195 (7) 3033 - 3044 0022-1767 2015/10 [Refereed]
  
• Immune Mechanisms of Pancreatitis

  Tomohiro Watanabe; Warren Strober; Tsutomu Chiba

  Mucosal Immunology: Fourth Edition Elsevier Inc. 2-2 1719 - 1736 2015/04 [Refereed]
   

  Pancreatitis is classified into acute pancreatitis and chronic pancreatitis. Acute pancreatitis is sudden inflammation of the exocrine pancreas, whereas chronic pancreatitis is long-standing inflammation of both the exocrine and the endocrine pancreas. Pathologic intra-acinar trypsinogen activation followed by autodigestion of the pancreas has been hypothesized to be the central mechanism of pancreatitis. In addition to this view, accumulating evidence suggested the involvement of innate and adaptive immune responses in the development of pancreatitis. Microbial antigens derived from intestinal microflora and endogenous antigens from necrotic pancreatic tissue activate pathogen recognition receptors expressed in pancreatic innate immune cells to induce acute pancreatitis through the production of proinflammatory cytokines and chemokines. Enhanced immunoglobulin G4 responses and the accumulation of regulatory T cells are associated with the development of chronic pancreatitis. Thus, although autodigestion by activated pancreatic enzymes is a necessary component for pancreatic injury, pathogenic immune responses have key roles in the development of pancreatitis.
• NOD2 Downregulates Colonic Inflammation Through IRF-4 Mediated Inhibition of K63 Directed Polyubiquitination of RICK and TRAF6 Molecules

  Tomohiro Watanabe; Naoki Asano; Atsushi Kitani; Ivan J. Fuss; Warren Strober

  GASTROENTEROLOGY W B SAUNDERS CO-ELSEVIER INC 148 (4) S722 - S722 0016-5085 2015/04 [Refereed]
  
• Cold-inducible RNA-binding protein promotes the development of liver cancer

  Toshiharu Sakurai; Norihisa Yada; Tomohiro Watanabe; Tadaaki Arizumi; Satoru Hagiwara; Kazuomi Ueshima; Naoshi Nishida; Jun Fujita; Masatoshi Kudo

  CANCER SCIENCE WILEY-BLACKWELL 106 (4) 352 - 358 1347-9032 2015/04 [Refereed]
   

  Most hepatocellular carcinomas (HCCs) develop in the context of chronic liver inflammation. Oxidative stress is thought to play a major role in the pathogenesis of HCC development. In this study, we examined whether cold-inducible RNA-binding protein (Cirp) controls reactive oxygen species (ROS) accumulation and development of HCC by using murine models of hepatocarcinogenesis and human liver samples. Cirp expression, ROS accumulation, and CD133 expression were increased in the liver of tumor-harboring mice. Cirp deficiency reduced production of interleukin-1 and interleukin-6 in Kupffer cells, ROS accumulation, and CD133 expression, leading to attenuated hepatocarcinogenesis. Thioacetamide treatment enhanced hepatic expression of CD133 and phosphorylated signal transducer and activator of transcription 3 (STAT3), which was prevented by treatment with the antioxidant butylated hydroxyanisole. Intriguingly, the risk of human HCC recurrence is positively correlated with Cirp expression in liver. Cirp appears to play a critical carcinogenic function and its expression might be a useful biomarker for HCC risk prediction.
• Heat Shock Protein A4 Controls Cell Migration and Gastric Ulcer Healing

  Toshiharu Sakurai; Hiroshi Kashida; Satoru Hagiwara; Naoshi Nishida; Tomohiro Watanabe; Jun Fujita; Masatoshi Kudo

  DIGESTIVE DISEASES AND SCIENCES SPRINGER 60 (4) 850 - 857 0163-2116 2015/04 [Refereed]
   

  Aims and Methods Heat shock protein A4 (HSPA4, also called Apg-2), a member of the HSP110 family, regulates the immune response in the gut. Here, we assessed the involvement of HSPA4 in gastric ulcer healing by using fibroblasts from wild-type and HSPA4-deficient mice, a murine gastric ulcer model, and samples from 65 patients with gastric cancer. Results HSPA4 expression was inversely correlated with gastric ulcer healing following endoscopic resection of gastric cancer. In the human gastric mucosa, the expression of HSPA4 was inversely correlated with the expression of stromal cell-derived factor 1 (SDF-1), its cognate receptor CXC chemokine receptor 4(CXCR4), the stromal cell marker vimentin, and the epithelial-mesenchymal transition regulator Twist. HSPA4 was overexpressed in stromal cells as well as in human gastric cancer cells. HSPA4 deficiency increased the expression of SDF-1 and CXCR4, as well as the number of fibroblast-specific protein 1-positive cells, leading to accelerated ulcer healing in the murine gastric ulcer model. Deletion of HSPA4 promoted cell migration in mouse fibroblasts through increased expression of SDF-1 and Twist. Conclusion HSPA4 regulates the expression of SDF-1 and Twist in fibroblasts, thereby controlling gastric ulcer healing.
• Involvement of Heat Shock Protein A4/Apg-2 in Refractory Inflammatory Bowel Disease

  Teppei Adachi; Toshiharu Sakurai; Hiroshi Kashida; Hiromasa Mine; Satoru Hagiwara; Shigenaga Matsui; Koji Yoshida; Naoshi Nishida; Tomohiro Watanabe; Katsuhiko Itoh; Jun Fujita; Masatoshi Kudo

  INFLAMMATORY BOWEL DISEASES LIPPINCOTT WILLIAMS & WILKINS 21 (1) 31 - 39 1078-0998 2015/01 [Refereed]
   

  Background: Expression of heat shock protein A4 (HSPA4, also called Apg-2), a member of the HSP110 family, is induced by several forms of stress. The physiological and pathological functions of HSPA4 in the intestine remain to be elucidated. Methods: We assessed HSPA4 expression and function by generating HSPA4-deficient mice and using 214 human intestinal mucosa samples from patients with inflammatory bowel disease (IBD). Results: In the colonic mucosa of patients with IBD, a significant correlation was observed between the expression of HSPA4 and antiapoptotic protein Bcl-2, a T-cell-derived cytokine IL-17 or stem cell markers, such as Sox2. In refractory ulcerative colitis, a condition associated with increased cancer risk, expression of HSPA4 and Bcl-2 was increased in inflammatory cells of colonic mucosae. HSPA4 was overexpressed both in cancer cells and immune cells of human colorectal cancers. Patients with high expression of HSPA4 or Bmi1 showed significantly lower response rates upon subsequent steroid therapy as compared with patients with low expression of each gene. HSPA4-deficient mice exhibit more apoptosis and less expression of IL-17/IL-23 in inflammatory cells and less number of Sox(2+) cells after administration of dextran sodium sulfate than control mice. Transduction of HspaA4(+/-) bone marrow into wild-type mice reduced the immune response. Conclusions: Upregulation of Bcl-2 and IL-17 by HSPA4 would control apoptosis of inflammatory cells and immune response in the gut, which might develop treatment resistance in IBD. HSPA4 and Bmi1 would be a useful biomarker for refractory clinical course and a promising approach for a therapeutic strategy in patients with IBD.
• NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6

  T. Watanabe; N. Asano; G. Meng; K. Yamashita; Y. Arai; T. Sakurai; M. Kudo; I. J. Fuss; A. Kitani; T. Shimosegawa; T. Chiba; W. Strober

  Mucosal Immunology Nature Publishing Group 7 (6) 1312 - 1325 1935-3456 2014/11 [Refereed]
   

  It is well established that polymorphisms of the caspase activation and recruitment domain 15 (CARD15) gene, a major risk factor in Crohn's disease (CD), lead to loss of nucleotide-binding oligomerization domain 2 (NOD2) function. However, a molecular explanation of how such loss of function leads to increased susceptibility to CD has remained unclear. In a previous study exploring this question, we reported that activation of NOD2 in human dendritic cells by its ligand, muramyl dipeptide (MDP), negatively regulates Toll-like receptor (TLR)-mediated inflammatory responses. Here we show that NOD2 activation results in increased interferon regulatory factor 4 (IRF4) expression and binding to tumor necrosis factor receptor associated factor 6 (TRAF6) and RICK (receptor interacting serine-threonine kinase). We then show that such binding leads to IRF4-mediated inhibition of Lys63-linked polyubiquitination of TRAF6 and RICK and thus to downregulation of nuclear factor (NF)-κB activation. Finally, we demonstrate that protection of mice from the development of experimental colitis by MDP or IRF4 administration is accompanied by similar IRF4-mediated effects on polyubiquitination of TRAF6 and RICK in colonic lamina propria mononuclear cells. These findings thus define a mechanism of NOD2-mediated regulation of innate immune responses to intestinal microflora that could explain the relation of CARD15 polymorphisms and resultant NOD2 dysfunction to CD.
• Stress Response Protein Cirp Links Inflammation and Tumorigenesis in Colitis-Associated Cancer

  Toshiharu Sakurai; Hiroshi Kashida; Tomohiro Watanabe; Satoru Hagiwara; Tsunekazu Mizushima; Hideki Iijima; Naoshi Nishida; Hiroaki Higashitsuji; Jun Fujita; Masatoshi Kudo

  CANCER RESEARCH AMER ASSOC CANCER RESEARCH 74 (21) 6119 - 6128 0008-5472 2014/11 [Refereed]
   

  Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and is reported to be associated with refractory inflammatory bowel disease (IBD). Defective apoptosis of inflammatory cell populations seems to be a relevant pathogenetic mechanism in refractory IBD. We assessed the involvement of stress response protein cold-inducible RNA-binding protein (Cirp) in the development of intestinal inflammation and CAC. In the colonic mucosa of patients with ulcerative colitis, expression of Cirp correlated significantly with the expression of TNF alpha, IL23/IL17, antiapoptotic proteins Bcl-2 and Bcl-xL, and stem cell markers such as Sox2, Bmi1, and Lgr5. The expression of Cirp and Sox2 was enhanced in the colonic mucosae of refractory ulcerative colitis, suggesting that Cirp expression might be related to increased cancer risk. In human CAC specimens, inflammatory cells expressed Cirp protein. Cirp(-/-) mice given dextran sodium sulfate exhibited decreased susceptibility to colonic inflammation through decreased expression of TNF alpha, IL23, Bcl-2, and Bcl-xL in colonic lamina propria cells compared with similarly treated wild-type (WT) mice. In the murine CAC model, Cirp deficiency decreased the expression of TNF alpha, IL23/IL17, Bcl-2, Bcl-xL, and Sox2 and the number of Dclk1(+) cells, leading to attenuated tumorigenic potential. Transplantation of Cirp(-/-) bone marrow into WT mice reduced tumorigenesis, indicating the importance of Cirp in hematopoietic cells. Cirp promotes the development of intestinal inflammation and colorectal tumors through regulating apoptosis and production of TNF alpha and IL23 in inflammatory cells. (C) 2014 AACR.
• Cellular and molecular mechanisms underlying NOD2 risk-associated polymorphisms in Crohn's disease

  Warren Strober; Naoki Asano; Ivan Fuss; Atsushi Kitani; Tomohiro Watanabe

  Immunological Reviews Wiley 260 (1) 249 - 260 0105-2896 2014/07 [Refereed][Invited]
  
• Uric acid induces NADPH oxidase-independent neutrophil extracellular trap formation

  Yasuyuki Arai; Yoko Nishinaka; Toshiyuki Arai; Makiko Morita; Kiyomi Mizugishi; Souichi Adachi; Akifumi Takaori-Kondo; Tomohiro Watanabe; Kouhei Yamashita

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ACADEMIC PRESS INC ELSEVIER SCIENCE 443 (2) 556 - 561 0006-291X 2014/01 [Refereed]
   

  Neutrophil extracellular traps (NETs) are composed of extracellular DNA fibers with antimicrobial peptides that capture and kill microbes. NETs play a critical role in innate host defense and in autoimmune and inflammatory diseases. While the mechanism of NET formation remains unclear, reactive oxygen species (ROS) produced via activation of NADPH oxidase (Nox) are known to be an important requirement. In this study, we investigated the effect of uric acid (UA) on NET formation. UA, a well-known ROS scavenger, was found to suppress Nox-dependent ROS release in a dose-dependent manner. Low concentrations of UA significantly inhibited Nox-dependent NET formation. However, high concentrations of UA unexpectedly induced, rather than inhibited, NET formation. NETs were directly induced by UA alone in a Nox-independent manner, as revealed by experiments using control neutrophils treated with ROS inhibitors or neutrophils of patients with chronic granulomatous disease who have a congenital defect in ROS production. Furthermore, we found that UA-induced NET formation was partially mediated by NF-kappa B activation. Our study is the first to demonstrate the novel function of UA in NET formation and may provide insight into the management of patients with hyperuricemia. (C) 2013 Elsevier Inc. All rights reserved.
• The molecular basis of NOD2 risk polymorphisms

  Watanabe T; Asano N; Strober W

  Autoantibodies and Autoimmunity 医学生物学研究所 21 31 - 36 1344-3372 2014
• 良性膵疾患と腸内細菌

  森田敏広; 児玉裕三; 大田悠司; 辻喜久; 渡邉智裕

  肝•胆•膵 70 895 - 900 2014
• 急性膵炎におけるInnate Immunity

  渡邉智裕; 辻喜久; 千葉勉

  膵臓 29 (1) 45 - 50 0913-0071 2014 [Refereed][Invited]
  
• Serum Neutrophil Extracellular Trap Levels Predict Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation

  Yasuyuki Arai; Kouhei Yamashita; Kiyomi Mizugishi; Tomohiro Watanabe; Soichiro Sakamoto; Toshiyuki Kitano; Tadakazu Kondo; Hiroshi Kawabata; Norimitsu Kadowaki; Akifumi Takaori-Kondo

  Biology of Blood and Marrow Transplantation Elsevier BV 19 (12) 1683 - 1689 1083-8791 2013/12 [Refereed]
  
• Association of gankyrin and stemness factor expression in human colorectal cancer

  Hiromasa Mine; Toshiharu Sakurai; Hiroshi Kashida; Shigenaga Matsui; Naoshi Nishida; Tomoyuki Nagai; Satoru Hagiwara; Tomohiro Watanabe; Masatoshi Kudo

  Digestive Diseases and Sciences Springer Science and Business Media LLC 58 (8) 2337 - 2344 0163-2116 2013/08 [Refereed]
   

  Background: It is widely accepted that the adenoma-carcinoma sequence represents the process by which most colorectal cancers (CRCs) arise. Although gankyrin is overexpressed in CRC tissues, its roles in the initiation step of colorectal carcinogenesis remain largely unexplored. Aim: We investigated the expression of gankyrin and stemness factors in human colorectal adenomas, precancerous lesions, as well as CRC tissues to assess its involvement in colorectal carcinogenesis. Methods: Expression of several molecules including gankyrin and certain stemness factors was compared in 50 pairs of adenoma and surrounding normal mucosa using real-time quantitative polymerase chain reaction and in 30 CRC tissues using immunohistochemistry. Results: In CRC specimens, expression of CD133, a cancer stem cell marker, was significantly correlated with gankyrin expression. Gankyrin knockdown decreased the expression of vascular endothelial growth factor (VEGF) and stemness factors such as Nanog and Oct-4 in colorectal cancer cells. Expression of gankyrin and these stemness factors was significantly higher in adenomas than in the surrounding normal mucosa. Importantly, a significant correlation was observed between the expression of gankyrin, VEGF, and Nanog in colorectal adenomas. Conclusion: In CRC development, gankyrin would control stem cell behavior by regulating the expression of stemness factors. © 2013 Springer Science+Business Media New York.
• The implications of myelodysplastic syndrome - associated chromosomal abnormalities in the development of graft-versus-host disease

  Yasuyuki Arai; Kouhei Yamashita; Kiyomi Mizugishi; Akifumi Takaori-Kondo; Tsutomu Chiba; Tomohiro Watanabe

  European Journal of Haematology Wiley 90 (6) 525 - 530 0902-4441 2013/06 [Refereed]
  
• Risk of Cancer in Patients With Autoimmune Pancreatitis

  Masahiro Shiokawa; Yuzo Kodama; Kenichi Yoshimura; Chiharu Kawanami; Jun Mimura; Yukitaka Yamashita; Masanori Asada; Masataka Kikuyama; Yoshihiro Okabe; Tetsuro Inokuma; Masaya Ohana; Hiroyuki Kokuryu; Kazuo Takeda; Yoshihisa Tsuji; Ryuki Minami; Yojiro Sakuma; Katsutoshi Kuriyama; Yuji Ota; Wataru Tanabe; Takahisa Maruno; Akira Kurita; Yugo Sawai; Norimitsu Uza; Tomohiro Watanabe; Hironori Haga; Tsutomu Chiba

  AMERICAN JOURNAL OF GASTROENTEROLOGY NATURE PUBLISHING GROUP 108 (4) 610 - 617 0002-9270 2013/04 [Refereed]
   

  OBJECTIVES: Although simultaneous occurrences of autoimmune pancreatitis (AIP) and cancer are occasionally observed, it remains largely unknown whether cancer and AIP occur independently or these disorders are interrelated. The aim of this study was to examine the relationship between AIP and cancer. METHODS: We conducted a multicenter, retrospective cohort study. One hundred and eight patients who met the Asian diagnostic criteria for AIP were included in the study. We calculated the proportion, standardized incidence ratio (SIR), relative risk, and time course of cancer development in patients with AIP. We also analyzed the clinicopathological characteristics of AIP patients with cancer in comparison with those without cancer. RESULTS: Of the 108 AIP patients, 18 cancers were found in 15 patients (13.9%) during the median follow-up period of 3.3 years. The SIR of cancer was 2.7 (95% confidence interval (CI) 1.4-3.9), which was stratified into the first year (6.1 (95% CI 2.3-9.9)) and subsequent years (1.5 (95% CI 0.3-2.8)) after AIP diagnosis. Relative risk of cancer among AIP patients at the time of AIP diagnosis was 4.9 (95% CI 1.7-14.9). In six of eight patients whose cancer lesions could be assessed before corticosteroid therapy for AIP, abundant IgG4-positive plasma cell infiltration was observed in the cancer stroma. These six patients experienced no AIP relapse after successful cancer treatment. CONCLUSIONS: Patients with AIP are at high risk of having various cancers. The highest risk for cancer in the first year after AIP diagnosis and absence of AIP relapse after successful treatment of the coexisting cancers suggest that AIP may develop as a paraneoplastic syndrome in some patients.
• Familial Mediterranean fever mutations in a patient with recurrent episodes of acute respiratory distress syndrome

  Yasuyuki Arai; Kouhei Yamashita; Kiyomi Mizugishi; Tomohiro Watanabe; Tadakazu Kondo; Toshiyuki Kitano; Hiroshi Kawabata; Norimitsu Kadowaki; Akifumi Takaori-Kondo

  CLINICAL IMMUNOLOGY ACADEMIC PRESS INC ELSEVIER SCIENCE 147 (1) 58 - 60 1521-6616 2013/04 [Refereed]
  
• Toll-like receptor activation in basophils contributes to the development of IgG4-related disease

  Tomohiro Watanabe; Kouhei Yamashita; Toshiharu Sakurai; Masatoshi Kudo; Masahiro Shiokawa; Norimitsu Uza; Yuzo Kodama; Kazushige Uchida; Kazuichi Okazaki; Tsutomu Chiba

  Journal of Gastroenterology 48 (2) 247 - 253 0944-1174 2013/02 [Refereed]
   

  Background IgG4-related disease (IRD) is characterized by systemic IgG4 antibody responses and by infiltration of IgG4-expressing plasma cells into the affected organs. Although T helper type 2 (Th2) cytokines are implicated in enhanced IgG4 responses, molecular mechanisms accounting for the development of IgG4 antibody responses are poorly defined. Since basophils function as antigenpresenting cells for Th2 responses, we tried to clarify the role of basophils in the development of IgG4 responses in this study. Methods IgG4 and cytokine responses to various nucleotide- binding oligomerization domain-like receptor and Toll-like receptor (TLR) ligands were examined by using basophils isolated from healthy controls and from patients with IgG4-related disease. Results Activation of TLRs in basophils from healthy controls induced IgG4 production by B cells, which effect was associated with enhanced production of B cell activating factor (BAFF) and IL-13. In addition, activation of TLRs in basophils from patients with IRD induced a large amount of IgG4 by B cells from healthy controls. This enhancement of IgG4 production was again associated with BAFF and IL-13. Conclusions These data suggest that innate immune responses mediated through TLRs may play a role in the development of IgG4-related disease, in part by production of BAFF from basophils. © Springer 2012.
• Hypothermia Protects against Fulminant Hepatitis in Mice by Reducing Reactive Oxygen Species Production

  Toshiharu Sakurai; Masatoshi Kudo; Tomohiro Watanabe; Katsuhiko Itoh; Hiroaki Higashitsuji; Tadaaki Arizumi; Tatsuo Inoue; Satoru Hagiwara; Kazuomi Ueshima; Naoshi Nishida; Manabu Fukumoto; Jun Fujita

  DIGESTIVE DISEASES KARGER 31 (5-6) 440 - 446 0257-2753 2013 [Refereed]
   

  Objective: Mild hypothermia (32-33 degrees C) shows protective effects in patients with brain damage and cardiac arrest. Although cold-inducible RNA-binding protein (CIRP) contributes to the protective effects of hypothermia through extracellular signal-regulated kinase activation in fibroblasts, the effects of hypothermia in the liver remain unclear. Methods: We analysed the effects of cold temperature on fulminant hepatitis, a potentially fatal disease, using the D-galactosamine (GalN)/lipopolysaccharide (LPS) and concanavalin (con) A-induced hepatitis models in mice. After GalN/LPS administration and anaesthesia, mice in the hypothermia group were kept at 25 degrees C and those in control group were kept at 35 degrees C. After concanavalin A (con A) administration, the mice in the hypothermia group were placed in a chamber with an ambient temperature of 6 degrees C for 1.5 h. Results: Hypothermia attenuated liver injury and prolonged survival. Activation of c-Jun N-terminal kinase and Akt, which are involved in reactive oxygen species (ROS) accumulation, was suppressed by low temperature. Hypothermia significantly decreased oxidized protein levels, and treatment with N-acetyl-L-cysteine, an antioxidant, attenuated GalN/LPS-induced liver injury. In con A-induced hepatitis, CIRP expression was upregulated and Bid expression was downregulated, resulting in decreased apoptosis of hepatocytes in the hypothermia group. Conclusions: These data suggest that hypothermia directly protects hepatocytes from cell death via reduction of ROS production in fulminant hepatitis. (C) 2013 S. Karger AG, Basel
• Autoimmune Hepatitis and Immunoglobulin G4-Associated Autoimmune Hepatitis

  Norihisa Yada; Masatoshi Kudo; Hobyung Chung; Tomohiro Watanabe

  DIGESTIVE DISEASES KARGER 31 (5-6) 415 - 420 0257-2753 2013 [Refereed]
   

  Autoimmune hepatitis (AIH) is a disease that is characterized by the presence of autoantibodies and elevated levels of serum immunoglobulin G (IgG) and hepatic enzymes. Its characteristic findings in the liver include interface hepatitis, infiltration of lymphocytes and plasma cells, and rosette formation, and is treated with immunosuppressive drugs. Autoimmune pancreatitis, a pancreatic disease caused by an autoimmune mechanism, is associated with elevated levels of serum IgG4 and the infiltration of IgG4-positive cells into the pancreatic parenchyma, and it is occasionally accompanied by systemic features. This systemic inflammatory disease characterized by the infiltration of IgG4-positive plasma cells and elevated serum IgG4 levels was recently classified as an IgG4-related disease. A few studies have reported AIH cases with infiltrated IgG4-positive plasma cells in the liver, suggesting the involvement of IgG4 in the pathogenesis of AIH. This feature was called IgG4-associated AIH and only two studies have been published. However, the diagnostic criteria of IgG4-associated AIH has not been defined and the epidemiology and clinical features remain uncertain. The degree of IgG4-positive plasma cell infiltration in the liver was different in each article. The serum IgG4 level was not elevated in one study, whereas it was severely elevated in the other. Corticosteroid therapy normalized liver enzymes in both studies. Further studies are needed to define the epidemiological features or diagnostic criteria. (C) 2013 S. Karger AG, Basel
• IgG4関連疾患の研究の動向

  千葉勉; 児玉裕三; 塩川雅広; 渡邉智裕

  胆と膵 34 751 - 755 2013
• NOD1と膵炎

  渡邉智裕; 千葉勉

  医学のあゆみ 246 1115 - 1116 2013 [Invited]
  
• Intestinal microflora and pancreatitis

  渡邉智裕; 辻喜久; 千葉勉

  臨床免疫•アレルギー科 科学評論社 60 (4) 435 - 438 1881-1930 2013 [Invited]
  
• 自己免疫性肝炎とIgG4関連病態

  矢田典久; 工藤正俊; 鄭浩柄; 渡邉智裕

  肝•胆•膵 67 381 - 387 2013
• NOD2と腸管炎症

  渡邉智裕; 千葉勉

  細胞 45 385 - 387 2013 [Invited]
  
• Sensing of commensal organisms by the intracellular sensor nod1 mediates experimental pancreatitis

  Yoshihisa Tsuji; Tomohiro Watanabe; Masatoshi Kudo; Hidenori Arai; Warren Strober; Tsutomu Chiba

  Immunity Elsevier BV 37 (2) 326 - 338 1074-7613 2012/08 [Refereed]
   

  The intracellular sensor NOD1 has important host-defense functions relating to a variety of pathogens. Here, we showed that this molecule also participates in the induction of a noninfectious pancreatitis via its response to commensal organisms. Pancreatitis induced by high-dose cerulein (a cholecystokinin receptor agonist) administration depends on NOD1 stimulation by gut microflora. To analyze this NOD1 activity, we induced pancreatitis by simultaneous administration of a low dose of cerulein (that does not itself induce pancreatitis) and FK156, an activator of NOD1 that mimics the effect of gut bacteria that have breached the mucosal barrier. The pancreatitis was dependent on acinar cell production of the chemokine MCP-1 and the intrapancreatic influx of CCR2+ inflammatory cells. Moreover, MCP-1 production involved activation of the transcription factors NF-κB and STAT3, each requiring complementary NOD1 and cerulein signaling. These studies indicate that gut commensals enable noninfectious pancreatic inflammation via NOD1 signaling in pancreatic acinar cells. © 2012 Elsevier Inc.
• Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma

  S. Hagiwara; M. Kudo; T. Nagai; T. Inoue; K. Ueshima; N. Nishida; T. Watanabe; T. Sakurai

  BRITISH JOURNAL OF CANCER NATURE PUBLISHING GROUP 106 (12) 1997 - 2003 0007-0920 2012/06 [Refereed]
   

  BACKGROUND: Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer deaths worldwide. While sorafenib, a multikinase inhibitor targeting the Raf/extracellular signal-regulated protein kinase (ERK) pathway, has been shown recently to provide a survival advantage to patients with advanced HCC, a predictive biomarker has not been developed. We studied whether c-Jun N-terminal kinase (JNK), which promotes liver carcinogenesis in mice, affects therapeutic response to sorafenib in HCC patients. METHODS: We collected pathological specimens from 39 patients with advanced HCC before starting sorafenib treatment, and measured JNK activity in HCCs. RESULTS: In patients treated with sorafenib, the expression of phospho-c-Jun in HCC, as a read out of JNK activity, was significantly higher (P<0.001) in the non-responder group than in the responder group. c-Jun N-terminal kinase activation in HCC was associated with a decreased time to progression and a poor overall survival (P = 0.0028 and P = 0.0008, respectively). CONCLUSION: In addition, JNK activity was significantly correlated with CD133 expression level. Correspondingly, high expression level of CD133 was linked to a poor response to sorafenib. Furthermore, D-JNKi, a specific JNK inhibitor, reduced the growth of xenografted CD133(+) cells in athymic mice. In conclusion, JNK activation was positively correlated with CD133 expression level and inversely correlated with the therapeutic response to sorafenib, suggesting that JNK activity may be considered as a new predictive biomarker for response to sorafenib treatment. British Journal of Cancer (2012) 106, 1997-2003. doi:10.1038/bjc.2012.145 www.bjcancer.com Published online 17 May 2012 (C) 2012 Cancer Research UK
• p38MAPK suppresses chronic pancreatitis by regulating HSP27 and BAD expression

  Ah-Mee Park; Masatoshi Kudo; Satoru Hagiwara; Masaki Tabuchi; Tomohiro Watanabe; Hiroshi Munakata; Toshiharu Sakurai

  FREE RADICAL BIOLOGY AND MEDICINE ELSEVIER SCIENCE INC 52 (11-12) 2284 - 2291 0891-5849 2012/06 [Refereed]
   

  Mitogen-activated protein kinases (MAPKs) are ubiquitous proteins that function in both normal and stress-related pathophysiological states of the cell. This study aimed to analyze the importance of p38MAPK in pancreatic injury using WBN/Kob rats with spontaneous chronic pancreatitis. Male WBN/Kob rats were injected with the p38MAPK inhibitor SB203580, starting at the age of 4 weeks, and sacrificed 6 weeks later. Compared with vehicle-treated rats, p38 inhibitor-treated rats exhibited a significant increase in pancreatic cell death and inflammation as assessed by histologic examination and myeloperoxidase activity, respectively. p38 inhibition decreased the expression of heat shock protein 27 (HSP27), an antioxidant protein, and enhanced accumulation of reactive oxygen species (ROS). In addition, the proapoptotic protein BAD was increased in the pancreas of rats treated with p38 inhibitor. In a pancreatic cell line (PANC-1), HSP27 knockdown augmented reactive oxygen species accumulation and cell death induced by tumor necrosis factor-alpha plus actinomycin D. In conclusion, p38MAPK suppresses chronic pancreatitis by upregulating HSP27 expression and downregulating BAD expression. (C) 2012 Elsevier Inc. All rights reserved.
• Activation of c-Jun N-terminal kinase in non-cancerous liver tissue predicts a high risk of recurrence after hepatic resection for hepatocellular carcinoma

  Satoru Hagiwara; Masatoshi Kudo; Hobyung Chung; Kazuomi Ueshima; Tatsuo Inoue; Seiji Haji; Tomohiro Watanabe; Ah-Mee Park; Hiroshi Munakata; Toshiharu Sakurai

  HEPATOLOGY RESEARCH WILEY-BLACKWELL 42 (4) 394 - 400 1386-6346 2012/04 [Refereed]
   

  Aim: Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer deaths worldwide. Hepatic resection is the mainstay of curative treatment for early stage HCC. Although c-Jun N-terminal kinase (JNK) activation contributes to hepatocyte proliferation and HCC development in mice, the extent of involvement of JNK in human HCC development is unknown. The aim of this study is to assess the predictive value of JNK for postoperative recurrence in HCC. Methods: From April 2005 to March 2008, 159 patients underwent curative resection for HCC. From the 159 patients, 20 patients each matched for age, gender and etiology were registered as three groups: (i) without recurrence (no recurrence group), (ii) with recurrence within one year after surgery (early recurrence group), and (iii) with recurrence at one year or more after surgery (late recurrence group) (a cross- sectional control study). We investigated factors contributing to postoperative early and late phase recurrence. Results: Multivariate analysis using a Logistic regression model showed that JNK activity in non- cancerous liver tissue was correlated with postoperative late recurrence. (P = 0.02, odds ratio; 5.79, 95% confidence interval [CI]; 1.33- 25.36). Conclusions: JNK activity in non- cancerous liver tissue is considered as a reliable predictive biomarker for postoperative recurrence in HCC.
• Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation

  A. Takai; H. Marusawa; Y. Minaki; T. Watanabe; H. Nakase; K. Kinoshita; G. Tsujimoto; T. Chiba

  Oncogene Springer Science and Business Media LLC 31 (13) 1733 - 1742 0950-9232 2012/03 [Refereed]
   

  Inflammatory bowel disease (IBD) is an important etiologic factor in the development of colorectal cancer. However, the mechanism underlying carcinogenesis through chronic inflammation is still unknown. Activation-induced cytidine deaminase (AID) is induced by the inflammation and involved in various human carcinogenesis via its mutagenic activity. In the current study, we investigated whether the inflammation/AID axis plays an integral role in the development of colitis-associated cancers. Inflammation in the cecum was more severe than that in other colonic regions, and endogenous AID expression was enhanced most prominently in the inflamed cecal mucosa of interleukin (IL)-10 -/- mice. Blockade of tumor necrosis factor (TNF)-α and IL-12 significantly suppressed AID expression. Although proinflammatory cytokine expression was comparable between IL-10 -/-AID +/+ and IL-10 -/-AID -/- mice, sequencing analyses revealed a significantly lower incidence of somatic mutations in Trp53 gene in the colonic mucosa of IL-10 -/-AID -/- than IL-10 -/-AID +/+ mice. Colon cancers spontaneously developed in the cecum in 6 of 22 (27.2%) IL-10 -/-AID +/+ mice. In contrast, none of the IL-10 -/-AID +/+ mice developed cancers except only one case of neoplasia in the distal colon. These findings suggest that the proinflammatory cytokine-induced aberrant production of AID links colonic inflammation to an enhanced genetic susceptibility to oncogenic mutagenesis. Targeting AID could be a novel strategy to prevent colitis-associated colon carcinogenesis irrespective of ongoing colonic inflammation. © 2012 Macmillan Publishers Limited All rights reserved.
• Involvement of activation of toll-like receptors and nucleotide-binding oligomerization domain-like receptors in enhanced IgG4 responses in autoimmune pancreatitis

  Tomohiro Watanabe; Kouhei Yamashita; Saori Fujikawa; Toshiharu Sakurai; Masatoshi Kudo; Masahiro Shiokawa; Yuzo Kodama; Kazushige Uchida; Kazuichi Okazaki; Tsutomu Chiba

  ARTHRITIS AND RHEUMATISM WILEY-BLACKWELL 64 (3) 914 - 924 0004-3591 2012/03 [Refereed]
   

  Objective IgG4-related disease is a recently recognized entity affecting multiple organs, including the pancreas, biliary tracts, and salivary glands. Although IgG4-related disease is characterized by systemic IgG4 antibody responses and by infiltration of IgG4-expressing plasma cells, the innate immune responses leading to adaptive IgG4 antibody responses are poorly understood. The aim of this study was to clarify the innate immune responses leading to IgG4 antibody production. Methods. IgG4 and cytokine responses to various nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) and Toll-like receptor (TLR) ligands were examined using peripheral blood mononuclear cells (PBMCs) from healthy control subjects and patients with IgG4-related autoimmune pancreatitis. Results. Activation of NOD-2 in monocytes from healthy control subjects induced IgG4 production by B cells in a BAFF-dependent and T cell-independent manner. In addition, PBMCs from patients with IgG4-related disease produced a large amount of IgG4 upon stimulation with NLR and TLR ligands; this enhanced IgG4 production was associated with the induction of BAFF by NLR and TLR ligands. Monocytes from patients with IgG4-related disease induced IgG4 production by B cells from healthy control subjects upon stimulation with NLR and TLR ligands. Conclusion. The results of these studies suggest that abnormal innate immune responses against microbial antigens may underlie the immunopathogenesis of IgG4-related disease.
• IBDと炎症性サイトカイン；TGF-β

  渡邉智裕; 千葉勉

  GI Research 20 75 - 80 2012 [Invited]
  
• NOD2変異からみたCrohn病の発症機序

  渡邉智裕; 千葉勉

  医学のあゆみ 241 191 - 195 2012 [Invited]
  
• IgG4関連疾患における自然免疫の関与

  渡邉智裕; 千葉勉

  胆と膵 33 479 - 483 2012
• Helicobacter pylori 感染免疫防御におけるNOD1の役割

  渡邉智裕; 千葉勉

  炎症と免疫 20 508 - 512 2012 [Invited]
  
• 自己免疫性膵炎(1型)の免疫学的解析における最近の知見 —自然免疫系の関与 −

  渡邉智裕; 千葉勉

  最新医学 67 1873 - 1879 2012 [Invited]
  
• 自然免疫系による腸管炎症の制御機構

  渡邉智裕; 千葉勉

  IBD Research 6 150 - 156 2012 [Invited]
  
• NOD1の活性化による急性膵炎の発症機序の解明

  渡邉智裕; 千葉勉

  分子消化器病 9 379 - 381 2012 [Invited]
  
• Correlation between hyporesponsiveness to Toll-like receptor ligands and liver dysfunction in patients with chronic hepatitis C virus infection

  H. Chung; T. Watanabe; M. Kudo; T. Chiba

  JOURNAL OF VIRAL HEPATITIS WILEY-BLACKWELL 18 (10) E561 - E567 1352-0504 2011/10 [Refereed]
   

  Hepatitis C virus (HCV)-associated antigens, such as the core and nonstructural antigens, activate host innate immune systems via Toll-like receptors (TLRs). We previously showed that chronic exposure to the core antigen induces hyporesponsiveness to TLR ligands in antigen-presenting cells via activation of TLR2 and that stimulation with TLR ligands results in impaired IL-6 production by peripheral blood monocytes from HCV-infected patients. In the present study, peripheral blood mononuclear cells (PBMCs) isolated from patients with chronic HCV or hepatitis B virus (HBV) infection were stimulated with TLR ligands to determine the production of IL-6 and IL-8 and to identify the clinical parameters associated with hyporesponsiveness to TLR ligands in patients with chronic HCV infection. The results showed that pro-inflammatory cyto-kine responses to TLR ligands were suppressed in PBMCs isolated from HCV-infected, but not HBV-infected, patients. The reduced cytokine responses to TLR ligands seen in HCV-infected patients correlated with platelet counts and serum prothrombin time levels. In contrast, there was no correlation between TLR-induced cytokine responses and serum levels of core antigen. Thus, hyporesponsiveness to TLR ligands in HCV-infected patients is correlated with liver dysfunction. In conclusion, both host factors and viral factors may be involved in the generation of hyporesponsiveness to TLR ligands in patients with chronic HCV infection.
• Relationship Between Serum Angiopoietin-2 Level and Perfusion CT Parameters in Severe Acute Pancreatitis

  Tsubasa Watanabe; Yoshihisa Tsuji; Yuzo Kodama; Hiroyoshi Isoda; Hiroshi Yamamoto; Tsutomu Chiba

  AMERICAN JOURNAL OF GASTROENTEROLOGY NATURE PUBLISHING GROUP 106 (10) 1859 - 1861 0002-9270 2011/10 [Refereed]
  
• Autoimmune pancreatitis exhibiting multiple mass lesions

  Masahiro Shiokawa; Yuzo Kodama; Yukiko Hiramatsu; Akira Kurita; Yugo Sawai; Norimitsu Uza; Tomohiro Watanabe; Tsutomu Chiba

  Case Reports in Gastroenterology 5 (3) 528 - 533 1662-0631 2011/09 [Refereed]
   

  Our case is a first report of autoimmune pancreatitis with multiple masses within the pancreas which was pathologically diagnosed by endoscopic ultrasound-guided fine needle aspiration and treated by steroid. The masses disappeared by steroid therapy. Our case is informative to know that autoimmune pancreatitis sometimes exhibits multiple masses within the pancreas and to diagnose it without unnecessary surgery. Copyright © 2011 S. Karger AG.
• NOD2, an intracellular innate immune sensor involved in host defense and Crohn's disease

  W. Strober; T. Watanabe

  Mucosal Immunology Springer Science and Business Media LLC 4 (5) 484 - 495 1933-0219 2011/09 [Refereed][Invited]
   

  Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular sensor for small peptides derived from the bacterial cell wall component, peptidoglycan. Recent studies have uncovered unexpected functions of NOD2 in innate immune responses such as induction of type I interferon and facilitation of autophagy moreover, they have disclosed extensive cross-talk between NOD2 and Toll-like receptors, which has an indispensable role both in host defense against microbial infection and in the development of autoimmunity. Of particular interest, polymorphisms of CARD15 encoding NOD2 are associated with Crohn's disease and other autoimmune states such as graft vs. host disease. In this review, we summarize recent findings regarding normal functions of NOD2 and discuss the mechanisms by which NOD2 polymorphisms associated with Crohn's disease lead to intestinal inflammation. © 2011 Society for Mucosal Immunology.
• Treatment of Leg Ischemia With Biodegradable Gelatin Hydrogel Microspheres Incorporating Granulocyte Colony-stimulating Factor

  Itta Kawamura; Genzou Takemura; Akiko Tsujimoto; Takatomo Watanabe; Hiromitsu Kanamori; Masayasu Esaki; Hiroyuki Kobayashi; Toshiaki Takeyama; Tomonori Kawaguchi; Kazuko Goto; Rumi Maruyama; Takako Fujiwara; Hisayoshi Fujiwara; Yasuhiko Tabata; Shinya Minatoguchi

  JOURNAL OF CARDIOVASCULAR PHARMACOLOGY LIPPINCOTT WILLIAMS & WILKINS 57 (4) 416 - 423 0160-2446 2011/04 [Refereed]
   

  Granulocyte colony-stimulating factor (G-CSF) is a potent angiogenic factor. We hypothesized that G-CSF-immersed gelatin hydrogel microspheres (G-CSF-GHMs) injected into the ischemic legs might continuously release a small amount of G-CSF to locally stimulate angiogenesis without unfavorable systemic effects. Just after ligation of the right femoral artery of BALB/c mice, recombinant human G-CSF (100-mu g/kg)-immersed GHM was injected into the right hindlimb muscles; the controls included a saline-injected group, an intramuscularly injected G-CSF group, a subcutaneously injected G-CSG group, and an empty GHM-injected group. Eight weeks later, improvement of blood perfusion to the ischemic limb was significantly augmented in the G-CSF-GHM group compared with any of the control groups. Despite there being no increase in the serum concentration of G-CSF, in peripheral granulocytes, or in circulating endothelial progenitor cells, not only capillary but also arteriolar density was significantly increased in this group. Next, we started treatment with G-CSF-GHM 4 weeks after ligation to examine whether the treatment is effective if performed during the chronic stage of ischemia. The late treatment was also found to effectively improve blood flow in the ischemic leg. In conclusion, G-CSF-GHM administration is suggested to be a promising and readily usable approach to treating peripheral artery disease, applicable even during the chronic stage.
• Hemobilia: Another complication associated with anti-thrombotic therapy

  Yukiko Hiramatsu; Tomohiro Watanabe; Masahiro Shiokawa; Akira Kurita; Minoru Matsuura; Norimitsu Uza; Yuzo Kodama; Tsutomu Chiba

  Clinical Journal of Gastroenterology 4 (1) 49 - 51 1865-7257 2011/02 [Refereed]
   

  It is generally accepted that anti-thrombotic therapy increases the risk of gastrointestinal bleeding, and concurrent therapy with a proton-pump inhibitor is the standard treatment for patients receiving aspirin. Therefore, much attention has been paid to the prevention of gastrointestinal bleeding in such patients; however, it should be noted that patients on anti-thrombotic therapy always carry a risk of hemorrhage from any organ, including the gastrointestinal tract. Here, we present a case with formation of a common bile duct stone caused by hemobilia associated with anti-thrombotic therapy. This case suggests that we need to be aware of the possibility of intrabiliary hemorrhage as well as gastrointestinal bleeding in patients receiving anti-thrombotic therapy. Patients with such complications show a variety of symptoms including liver abscess, cholangitis, pancreatitis, and duodenal bleeding. © 2010 Springer.
• Activation of type I IFN signaling by NOD1 mediates mucosal host defense againstHelicobacter pyloriinfection

  Tomohiro Watanabe; Naoki Asano; Atsushi Kitani; Ivan J. Fuss; Tsutomu Chiba; Warren Strober

  Gut Microbes Informa UK Limited 2 (1) 61 - 65 1949-0976 2011/01 [Refereed]
  
• NOD1を介するHelicobacter pylori感染免疫防御機構の解明

  渡邉 智裕

  日本ヘリコバクター学会誌 12 24 - 25 2011 [Invited]
  
• 腸管における自然免疫システムの破綻とIBDの発症

  渡邉智裕; 千葉勉

  Intestine 15 435 - 442 2011 [Invited]
  
• 遺伝子多型解析は異なる疾患の関連性の理解に貢献するか。クローン病、サルコイドーシス、抗酸菌感染症におけるNOD2多型

  渡邉智裕; 千葉勉

  分子消化器病 8 252 - 258 2011 [Invited]
  
• NOD2を介するシグナル伝達経路

  渡邉智裕; 千葉勉

  分子消化器病 8 369 - 374 2011 [Invited]
  
• Card15 Polymorphisms in the Immunopathogenesis of Crohn's Disease and Mycobacterial Infectious Diseases

  Tomohiro Watanabe; Tsutomu Chiba

  Gastroenterology Elsevier BV 139 (6) 2212 - 2214 0016-5085 2010/12 [Refereed]
  
• Hepatitis C Virus Core Protein Induces Homotolerance and Cross-Tolerance to Toll-Like Receptor Ligands by Activation of Toll-Like Receptor 2

  Hobyung Chung; Tomohiro Watanabe; Masatoshi Kudo; Tsutomu Chiba

  JOURNAL OF INFECTIOUS DISEASES OXFORD UNIV PRESS INC 202 (6) 853 - 861 0022-1899 2010/09 [Refereed]
   

  Background. Hepatitis C virus (HCV) activates host innate immune responses mediated by retinoic acid inducing gene-I (RIG-I) and Toll-like receptors (TLRs). Although the nonstructural protein 3/4A (NS3/4A) of HCV disrupts interferon responses by inhibiting RIG-I signaling, the effects of TLR activation by HCV-associated proteins on host innate immune responses are poorly understood. Methods. Proinflammatory cytokine responses to various TLR ligands in human antigen-presenting cells (APCs) were examined either with or without prestimulation by HCV core protein. Results. TLR2 activation by the HCV core protein leads to a decrease in interleukin 6 (IL-6) production by human APCs after subsequent stimulation with TLR2 (homotolerance) ligands and TLR4 (cross-tolerance) ligands. This hyporesponsiveness induced by preexposure to the HCV core protein was partially mediated by the negative regulation of nuclear factor-kappa B activation by the induction of IRAK-M. TLR ligand-induced IL-6 production was significantly reduced in peripheral blood monocytes isolated from HCV-infected patients, compared with those of healthy control subjects. Alloantigen presentation by monocytes isolated from HCV-infected patients results in impaired production of interleukin 17 by naive CD4(+) T cells in the presence of TLR ligands. Conclusions. Chronic stimulation of APCs with HCV core protein is associated with hyporesponsiveness in TLR-mediated innate immunity.
• Enhanced cytokine responses to Toll-like and NOD-like receptor ligands in primary biliary cirrhosis-CREST overlap syndrome

  Manabu Fukuhara; Tomohiro Watanabe; Taro Ueo; Hiroshi Ida; Yuzo Kodama; Tsutomu Chiba

  RHEUMATOLOGY OXFORD UNIV PRESS 49 (8) 1602 - 1604 1462-0324 2010/08 [Refereed]
  
• NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway

  Tomohiro Watanabe; Naoki Asano; Stefan Fichtner-Feigl; Peter L. Gorelick; Yoshihisa Tsuji; Yuko Matsumoto; Tsutomu Chiba; Ivan J. Fuss; Atsushi Kitani; Warren Strober

  Journal of Clinical Investigation American Society for Clinical Investigation 120 (5) 1645 - 1662 0021-9738 2010/05 [Refereed]
   

  Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular epithelial cell protein known to play a role in host defense at mucosal surfaces. Here we show that a ligand specific for NOD1, a peptide derived from peptidoglycan, initiates an unexpected signaling pathway in human epithelial cell lines that results in the production of type I IFN. Detailed analysis revealed the components of the signaling pathway. NOD1 binding to its ligand triggered activation of the serine-threonine kinase RICK, which was then able to bind TNF receptor-associated factor 3 (TRAF3). This in turn led to activation of TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) and the subsequent activation of IFN regulatory factor 7 (IRF7). IRF7 induced IFN-β production, which led to activation of a heterotrimeric transcription factor complex known as IFN-stimulated gene factor 3 (ISGF3) and the subsequent production of CXCL10 and additional type I IFN. In vivo studies showed that mice lacking the receptor for IFN-β or subjected to gene silencing of the ISGF3 component Stat1 exhibited decreased CXCL10 responses and increased susceptibility to Helicobacter pylori infection, phenotypes observed in NOD1-deficient mice. These studies thus establish that NOD1 can activate the ISGF3 signaling pathway that is usually associated with protection against viral infection to provide mice with robust type I IFN-mediated protection from H. pylori and possibly other mucosal infections.
• Defective Interleukin-10 Signaling in Human Inflammatory Bowel Disease

  Tomohiro Watanabe; Tsutomu Chiba

  Gastroenterology Elsevier BV 138 (5) 2016 - 2018 0016-5085 2010/05 [Refereed]
  
• Possible involvement of T helper type 2 responses to Toll-like receptor ligands in IgG4-related sclerosing disease

  Reiko Akitake; Tomohiro Watanabe; Chikage Zaima; Norimitsu Uza; Hiroshi Ida; Shinsuke Tada; Naoshi Nishida; Tsutomu Chiba

  GUT B M J PUBLISHING GROUP 59 (4) 542 - 545 0017-5749 2010/04 [Refereed]
   

  We report a case of immunoglobulin G4 (IgG4)-related sclerosing disease involving the pancreas, liver and salivary glands. Massive infiltration of IgG4-expressing plasma cells was seen in the liver and submandibular lymph nodes. Interestingly, accumulation of IgG4-expressing plasma cells was also seen in the colon and terminal ileum. Peripheral blood mononuclear cells (PBMCs) isolated from this patient exhibited enhanced production of IgG4 and interleukin-10 upon stimulation with Toll-like receptor (TLR) ligands as compared with those from a healthy control. In contrast, production of tumour necrosis factor alpha and interferon gamma by PBMCs from this patient was markedly reduced. Since colonic mucosa is always exposed to TLR ligands derived from commensal organisms, the results of immunological studies suggest that enhanced T helper type 2 responses to intestinal microflora may underlie the immunopathogenesis in this patient with IgG4-related sclerosing disease.
• Identification and characterization of IgG4-associated autoimmune hepatitis

  Hobyung Chung; Tomohiro Watanabe; Masatoshi Kudo; Osamu Maenishi; Yoshio Wakatsuki; Tsutomu Chiba

  LIVER INTERNATIONAL WILEY-BLACKWELL PUBLISHING, INC 30 (2) 222 - 231 1478-3223 2010/02 [Refereed]
   

  Background Autoimmune hepatitis (AIH) and autoimmune pancreatitis (AIP) share clinical and pathological features such as high serum levels of immunoglobulin (Ig) G and autoantibodies, and lymphoplasmacytic infiltration, suggesting the presence of common immunological abnormalities. However, little is known about the possible involvement of IgG4, a hallmark of AIP, in AIH. Aims In this study, we examined whether the IgG4 response contributes to the histopathological and clinical findings in AIH. Methods Liver sections from 26 patients with AIH, 10 patients with primary biliary cirrhosis (PBC), three patients with primary sclerosing cholangitis (PSC) and 20 chronic hepatitis patients with hepatitis C virus (HCV) infection were immunostained for IgG4. We investigated the relationship among the histopathology, the responses to steroid therapy and the IgG4 staining. Results Nine of the 26 liver specimens from patients with AIH showed positive staining for IgG4 whereas none of the 10 samples from patients with PBC, the three samples from patients with PSC or the 20 samples from patients with HCV hepatitis were positive. Patients with IgG4-positive AIH also showed increased serum levels of IgG. The numbers of T cells, B cells and plasma cells were significantly increased in the livers of patients with IgG4-positive AIH as compared with those patients with IgG4-negative AIH. Patients with IgG4-positive AIH also showed a marked response to prednisolone therapy. Conclusions AIH may be classified into either an IgG4-associated type or an IgG4 non-associated type with the former showing a marked response to prednisolone treatment.
• Age and immunoglobulin G4-associated autoimmune hepatitis: author's response

  Hobyung Chung; Tomohiro Watanabe; Masatoshi Kudo; Tsutomu Chiba

  LIVER INTERNATIONAL WILEY-BLACKWELL PUBLISHING, INC 30 (2) 333 - 333 1478-3223 2010/02 [Refereed]
  
• -651C/T promoter polymorphism in the CD14 gene is associated with severity of acute pancreatitis in Japan

  Atsushi Masamune; Kiyoshi Kume; Kazuhiro Kikuta; Takashi Watanabe; Morihisa Hirota; Kennichi Satoh; Atsushi Kanno; Noriaki Suzuki; Yoichi Kakuta; Tooru Shimosegawa

  JOURNAL OF GASTROENTEROLOGY SPRINGER TOKYO 45 (2) 225 - 233 0944-1174 2010/02 [Refereed]
   

  This study aimed to clarify the association of the promoter variants in the CD14 gene with pancreatic diseases in Japan. Three hundred forty-six unrelated patients with acute pancreatitis (AP) (107 with severe and 239 with mild), 263 patients with chronic pancreatitis (CP), 264 patients with pancreatic neoplasm, and 319 healthy controls were genotyped for the single nucleotide polymorphisms at positions -260 and -651 from the AUG start codon in the CD14 gene by polymerase chain reaction-restriction enzyme digestion. The allele and genotype frequencies of the -260C/T and -651C/T polymorphisms did not differ between controls and patients with AP. In subgroup analyses, patients with severe AP had more -651C allele than controls [P = 0.005; odds ratio (OR) 1.71; 95% confidence interval (CI) = 1.18-2.49] or patients with mild AP (P = 0.001; OR 1.95; 95% CI = 1.33-2.85). Genotype -651CC was more common (P = 0.001 vs. controls and P = 0.001 vs. mild AP), and -651CT was less (P = 0.009 vs. controls and P = 0.007 vs. mild AP) in patients with severe AP than in healthy controls or patients with mild AP. The frequencies of pseudocyst development and requirement of surgery were higher in AP patients with -651CC than in those without this genotype. The -260C/T polymorphism was not associated with the severity of AP. The allele and genotype frequencies of both polymorphisms did not differ between controls and patients with CP or pancreatic neoplasm. -651C/T promoter polymorphism in the CD14 gene was associated with severity of AP in Japan.
• Identification and functional characterization of paxillin as a target of protein tyrosine phosphatase receptor T

  Yiqing Zhao; Xiaodong Zhang; Kishore Guda; Earl Lawrence; Qun Sun; Toshio Watanabe; Yoichiro Iwakura; Masahide Asano; Lanlan Wei; Zhirong Yang; Weiping Zheng; Dawn Dawson; Joseph Willis; Sanford D. Markowitz; Masanobu Satake; Zhenghe Wang

  PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA NATL ACAD SCIENCES 107 (6) 2592 - 2597 0027-8424 2010/02 [Refereed]
   

  Protein tyrosine phosphatase receptor-type T (PTPRT) is the most frequently mutated tyrosine phosphatase in human cancers. However, the cell signaling pathways regulated by PTPRT largely remain to be elucidated. Here, we show that paxillin is a direct substrate of PTPRT and that PTPRT specifically regulates paxillin phosphorylation at tyrosine residue 88 (Y88) in colorectal cancer (CRC) cells. We engineered CRC cells homozygous for a paxillin Y88F knock-in mutant and found that these cells exhibit significantly reduced cell migration and impaired anchorage-independent growth, fail to form xenograft tumors in nude mice, and have decreased phosphorylation of p130CAS, SHP2, and AKT. PTPRT knockout mice that we generated exhibit increased levels of colonic paxillin phosphorylation at residue Y88 and are highly susceptible to carcinogen azoxymethane-induced colon tumor, providing critical in vivo evidence that PTPRT normally functions as a tumor suppressor. Moreover, similarly increased paxillin pY88 is also found as a common feature of human colon cancers. These studies reveal an important signaling pathway that plays a critical role in colorectal tumorigenesis.
• Spontaneous Rupture of Liver Plasmacytoma Mimicking Hepatocellular Carcinoma

  Kosuke Ueda; Hiroyuki Matsui; Tomohiro Watanabe; Junya Seki; Tatsuo Ichinohe; Yoshihisa Tsuji; Kayoko Matsumura; Yugo Sawai; Hiroshi Ida; Yoshihide Ueda; Tsutomu Chiba

  INTERNAL MEDICINE JAPAN SOC INTERNAL MEDICINE 49 (7) 653 - 657 0918-2918 2010 [Refereed]
   

  Extramedullary plasmacytoma of the liver is rare. Here, we report a case presenting with rupture of extramedullary plasmacytoma of the liver. She had a past history of multiple myeloma with IgA. type. Her serum was positive for hepatitis C virus infection and exhibited elevated levels of serum protein induced by vitamin K absence or antagonist-II. She was initially diagnosed as rupture of hepatocellular carcinoma (HCC) and then treated with transarterial chemoembolization (TACE) since bloody ascites and formation of hematoma were seen around hyper-vascular liver tumors on computed tomography. However, the clinical course of this case after TACE was atypical for HCC rupture, as shown by the development of a huge intra-abdominal abscess extending from the liver tumor. Immuno-histochemical analysis of the tumor biopsy specimen revealed massive infiltration of plasma cells expressing IgA and. chain. To our knowledge, this is the first case of rupture of extramedullary liver plasmacytoma.
• NOD1を介するHelicobacter pyloriに対する感染免疫防御はI型IFN経路とISGF3経路の活性化に依存する

  渡邉智裕; 千葉勉

  分子消化器病 7 405 - 409 2010 [Invited]
  
• NOD2はIBDの発症にどのようにかかわるのか

  渡邉智裕; 千葉勉

  分子消化器病 7 227 - 235 2010 [Invited]
  
• 自然免疫は急性膵炎の発症にどのようにかかわるのか

  辻喜久; 渡邉智裕

  分子消化器病 7 248 - 256 2010 [Invited]
  
• NOD1欠損マウスモデルからみたHelicobacter pylori感染免疫防御機構

  渡邉智裕; 千葉勉

  Helicobacter Research 14 475 - 480 2010 [Invited]
  
• 消化器領域における炎症性サイトカイン測定の方法と意義

  渡邉智裕; 千葉勉

  分子消化器病 7 55 - 60 2010 [Invited]
  
• NOD1-Mediated Mucosal Host Defense againstHelicobacter pylori

  Tomohiro Watanabe; Naoki Asano; Atsushi Kitani; Ivan J. Fuss; Tsutomu Chiba; Warren Strober

  International Journal of Inflammation Hindawi Limited 2010 1 - 6 2010 [Refereed]
   

  Infection of the stomach withHelicobacter pyloriis an important risk factor for gastritis, peptic ulcer, and gastric carcinoma. Although it has been well established that persistent colonization byH. pyloriis associated with adaptive Th1 responses, the innate immune responses leading to these Th1 responses are poorly defined. Recent studies have shown that the activation of nucleotide-binding oligomerization domain 1 (NOD1) in gastric epithelial cells plays an important role in innate immune responses againstH. pylori. The detection ofH. pylori-derived ligands by cytosolic NOD1 induces several host defense factors, including antimicrobial peptides, cytokines, and chemokines. In this paper, we review the molecular mechanisms by which NOD1 contributes to mucosal host defense againstH. pyloriinfection of the stomach.
• Attenuation of proteolysis-mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers

  Kyoko Ikeuchi; Hiroyuki Marusawa; Mikio Fujiwara; Yuko Matsumoto; Yoko Endo; Tomohiro Watanabe; Akio Iwai; Yoshiharu Sakai; Ryosuke Takahashi; Tsutomu Chiba

  INTERNATIONAL JOURNAL OF CANCER WILEY-LISS 125 (9) 2029 - 2035 0020-7136 2009/11 [Refereed]
   

  Parkin has a critical role in the ubiquitin-proteasome system as an E3-ligase targeting several substrates. Our recent finding that Parkin-deficient mice are susceptible to tumorigenesis provided evidence that Parkin is a tumor suppressor gene. Dysfunction of the Parkin gene is frequently observed in various human cancers, but the mechanism underlying the cell cycle disruption induced by Parkin dysfunction that leads to carcinogenesis is not known. Here, we demonstrated that Parkin expression in colonic epithelial cells is regulated in a cell cycle-associated manner. Epidermal growth factor (EGF) stimulation upregulated Parkin gene expression in human colon cells. Inhibition of the phosphoinositide 3-kinase [PI(3)K]-Akt-dependent pathways suppressed growth factor-induced Parkin expression. The expression of alternatively spliced Parkin isoforms with various deletions spanning exons 3-6 was detected in 18 of 43 (42%) human colorectal cancer tissues. Wildtype Parkin induced the degradation of cyclin E protein, but the alternatively spliced Parkin identified in colon cancers showed defective proteolysis of cyclin E. These findings indicate that Parkin expression is induced by growth factor stimulation and is involved in the cell cycle regulation of colon cells. Tumor-specific expression of alternatively spliced Parkin isoforms might contribute to enhanced cell proliferation through the attenuation of proteolysis-mediated cyclin E regulation in human colorectal cancers. (C) 2009 UICC
• Roles of Pancreatic Stellate Cells in Pancreatic Inflammation and Fibrosis

  Atsushi Masamune; Takashi Watanabe; Kazuhiro Kikuta; Tooru Shimosegawa

  CLINICAL GASTROENTEROLOGY AND HEPATOLOGY ELSEVIER SCIENCE INC 7 (11) S48 - S54 1542-3565 2009/11 [Refereed]
   

  Over a decade, there is accumulating evidence that activated pancreatic stellate cells (PSCs) play a pivotal role in the development of pancreatic fibrosis. In response to pancreatic injury or inflammation, quiescent PSCs are transformed (activated) to myofibroblast-like cells, which express alpha-smooth muscle actin. Activated PSCs proliferate, migrate, produce extracellular matrix components, such as type I collagen, and express cytokines and chemokines. Recent studies have suggested novel roles of PSCs in local immune functions and angiogenesis in the pancreas. If the pancreatic inflammation and injury are sustained or repeated, PSC activation is perpetuated, leading to the development of pancreatic fibrosis. In this context, pancreatic fibrosis can be defined as pathologic changes of extracellular matrix composition in both quantity and quality, resulting from perpetuated activation of PSCs. Because PSCs are very similar to hepatic stellate cells, PSC research should develop in directions more relevant to the pathophysiology of the pancreas, for example, issues related to trypsin, non-oxidative alcohol metabolites, and pancreatic cancer Indeed, in addition to their roles in chronic pancreatitis, it has been increasingly recognized that PSCs contribute to the progression of pancreatic cancer. Very recently, contribution of bone marrow-derived cells to PSCs was reported. Further elucidation of the roles of PSCs in pancreatic fibrosis should promote development of rational approaches for the treatment of chronic pancreatitis and pancreatic cancer.
• Colonic Polyposis Associated With Autoimmune Pancreatitis

  Hiroyuki Matsui; Tomohiro Watanabe; Kenji Ueno; Satoru Ueno; Yoshihisa Tsuji; Kayoko Matsumura; Masato Nakatsuji; Yoshihide Ueda; Tsutomu Chiba

  PANCREAS LIPPINCOTT WILLIAMS & WILKINS 38 (7) 840 - 842 0885-3177 2009/10 [Refereed]
  
• Isoflavones regulate innate immunity and inhibit experimental colitis

  Masakazu Morimoto; Tomohiro Watanabe; Masashi Yamori; Minoru Takebe; Yoshio Wakatsuki

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY WILEY-BLACKWELL PUBLISHING, INC 24 (6) 1123 - 1129 0815-9319 2009/06 [Refereed]
   

  Dysregulated immune responses in the gut to luminal antigens can cause inflammatory bowel diseases (IBD). The roles played by dietary antigens in the pathogenesis or prevention of IBD are poorly understood. Soybean isoflavones are digested in large amounts and have many biological activities. The aim of this study was to determine whether isoflavones in aglycon and bioavailable forms have any effect on gut immunity and protect the host from tissue damage in a mouse model of colitis. We administered daidzein-rich isoflavone aglycones (DRIA) to mice for 1 week and then treated them with 2% dextran sodium sulfate (DSS) in drinking water for 4 days to induce colitis. The effect of DRIA was evaluated by examining the histopathology of the colon, body weight changes, and functional analysis of mesenteric lymph node cells (MLN). DRIA inhibited interleukin (IL)-6 and IL-8 production by Toll-like receptor (TLR)2, and TLR4-stimulated monocytes in a dose-dependent manner. The mice administered DRIA had less inflammation and tissue damage in the colon than the control mice. This protective effect of DRIA was associated with a decrease in interferon-gamma, IL-6, and IL-12p40 secretion, and an increase in IL-10secretion and low cell-activation status of antigen-presenting cells (APC) in MLN. Ingested DRIA can downregulate the functions of APC and inhibit DSS colitis.
• Massive jejunal bleeding due to Heyde syndrome successfully treated with double balloon endoscopy.

  Sakiko Ohta; Tomohiro Watanabe; Shuko Morita; Satoru Ueno; Yoshihisa Tsuji; Hiroshi Nakase; Tsutomu Chiba

  Clinical journal of gastroenterology 2 (3) 187 - 189 1865-7265 2009/06 [Refereed]
   

  There is a well-documented relationship between aortic valve stenosis and recurrent gastrointestinal bleeding from angiodysplasia in elderly patients, called Heyde syndrome. We report a case of Heyde syndrome with massive jejunal bleeding. Capsule endoscopy showed bleeding from jejunal angiodysplasia. Spurting bleeding from jejunal angiodysplasia was identified and treated by double balloon endoscopy. No gastrointestinal bleeding was seen after the endoscopic treatment and aortic valve replacement was performed. This case suggests that capsule endoscopy and double balloon endoscopy were very useful for the diagnosis and treatment of small intestinal bleeding due to Heyde syndrome.
• Simultaneous Occurrence of Inflammatory Bowel Disease and Myelodysplastic Syndrome due to Chromosomal Abnormalities in Bone Marrow Cells

  Fumiyasu Nakamura; Tomohiro Watanabe; Kimiko Hori; Yoshiaki Ohara; Kouhei Yamashita; Yoshihisa Tsuji; Yoshihide Ueda; Sakae Mikami; Hiroshi Nakase; Tsutomu Chiba

  DIGESTION KARGER 79 (4) 215 - 219 0012-2823 2009 [Refereed]
   

  Background/Aims: Although chromosomal abnormalities in bone marrow (BM) cells, such as trisomy 8, are risk factors for the development of inflammatory bowel diseases (IBD) as well as myelodysplastic syndrome (MDS), the mechanisms of how these cytogenetic abnormalities cause intestinal inflammation are poorly understood. Methods and Results: A 55-year-old man with a 3-month history of watery diarrhea, fever and abdominal pain was admitted. Blood examinations revealed pancytopenia. Pathological analysis and endoscopic images of the entire colon led to the diagnosis of IBD of unclassified type. BM examination showed that the pancytopenia was due to MDS and that his BM cells had dual chromosomal abnormalities: 47, XY, +1, der(1;7)(q10;p10), +8. Immunological studies using peripheral blood monocytes from this patient revealed that the dual chromosomal abnormalities of BM cells led to the development of colitogenic monocytes producing a large amount of pro-inflammatory cytokines and showing resistance to apoptosis upon stimulation with microbial antigens. Conclusion: An abnormal karyotype of BM cells is not only responsible for the development of MDS, but also for IBD in this case. Copyright (C) 2009 S. Karger AG, Basel
• Helicobacter pylori感染による胃粘膜傷害機序についての新知見

  渡邉智裕; 千葉勉

  Helicobacter Research 13 195 - 200 2009 [Invited]
  
• Autophagyとクローン病

  渡邉智裕; 千葉勉

  IBD Research 3 216 - 221 2009 [Invited]
  
• Negative regulation of Toll-like receptor signaling by activation of NOD2

  渡邉智裕; 千葉勉

  Clinical immunology & allergology 科学評論社 52 (4) 370 - 376 1881-1930 2009 [Invited]
  
• 自然免疫システムの活性化を用いた食物アレルギーの新規治療法 の開発

  渡邉 智裕

  アレルギア 38 65 - 67 2009 [Invited]
  
• IgG4-related autoimmune pancreatitis involving the colonic mucosa

  Kenji Ueno; Tomohiro Watanabe; Yukiko Kawata; Tomoyuki Gotoh; Yoshihisa Tsuji; Hiroshi Ida; Shinsuke Tada; Shujiro Yazumi; Tsutomu Chiba

  EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY LIPPINCOTT WILLIAMS & WILKINS 20 (11) 1118 - 1121 0954-691X 2008/11 [Refereed]
   

  We report a case of autoimmune pancreatitis involving the colonic mucosa. Although serum level of IgG4 was normal, computed tomography and endoscopic retrograde cholangiopancreatography showed diffuse enlargement of the pancreas and irregular narrowing of the pancreatic ducts, respectively. Colonoscopy revealed a polypoidal lesion in the ascending colon. A lymphoplasmacytic infiltration was seen both in the pancreas and in the polypoidal lesion of the colon. Furthermore, immunohistochemical analysis showed abundant IgG4-positive plasma cells in these lesions. This is the first case report of a simultaneous occurrence of autoimmune pancreatitis and a colonic polypoidal lesion, both of which are characterized with increased IgG4 responses. Eur J Gastroenterol Hepatol 20:1118-1121 (C) 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.
• The molecular basis of NOD2 susceptibility mutations in Crohn's disease

  W. Strober; A. Kitani; I. Fuss; N. Asano; T. Watanabe

  MUCOSAL IMMUNOLOGY NATURE PUBLISHING GROUP 1 (Suppl 1) S5 - S9 1933-0219 2008/11 [Refereed][Invited]
   

  Nucleotide oligomerization domain (NOD) 2 is a member of the NOD-like receptor family of proteins that initiate inflammatory responses when exposed to ligands derived from bacterial components that gain access to the intracellular milieu. It is thus somewhat paradoxical that polymorphisms in the gene that encode NOD2 (CARD15) that lead to impaired NOD2 function, are susceptibility factors in Crohn's disease, a condition marked by excessive inflammatory responses to normal bacterial flora. In an initial series of studies conducted in our laboratory to better define NOD2 function and to resolve this paradox we showed that NOD2 activation by its ligand, muramyl dipeptide (MDP) ordinarily downregulates responses to Toll-like receptor (TLR) stimulation, and thus cells lacking NOD2 mount increased responses to such stimulation. This fits with the fact that mice bearing an NOD2 transgene, and thus having cells with increased NOD2 function display decreased responses to TLR stimulation and are resistant to experimental colitis induction. In further studies, we showed that prestimulation of cells with NOD2 ligand renders them unresponsive to TLR stimulation, because such prestimulation results in the elaboration of inhibitory factor (IRF4), an inhibitor of TLR-induced inflammatory pathways. Furthermore, administration of MDP to normal mice induces IRF4 and prevents experimental colitis. These studies strongly suggest that NOD2 polymorphisms are associated with Crohn's disease because they lead to a decrease in the negative regulation of TLR responses occurring in the normal gut, and thus a pathologic increase in responses to the normal flora. The finding that MDP administration prevents experimental colitis opens the door to the possibility that such treatment might quell Crohn's disease relapses in patients without NOD2 abnormalities.
• Helicobacter pylori immunology and vaccines

  Tamara Vorobjova; Tomohiro Watanabe; Tsutomu Chiba

  Helicobacter Wiley 13 (1) 18 - 22 1083-4389 2008/10 [Refereed]
   

  Helicobacter pylori infection causes chronic gastritis, peptic ulcer, and gastric cancer. Colonization of H. pylori in the stomach activates Toll-like and Nod-like receptors to induce not only innate immunity but also adaptive Th1 responses against this organism. Adaptive Th1 response is not sufficient to clear this organism and, as a result, the infection persists. Insufficient adaptive immunity can be explained by poor activation of Toll-like receptors, suppressive effects of bacterial factors, and induction of regulatory T-cell responses. Significant progress in the understanding of innate and adaptive immunity against H. pylori was made during the past year. Recent findings in the fields of vaccines for H. pylori are also reviewed. © 2008 The Authors.
• Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic cancer

  Atsushi Masamune; Kazuhiro Kikuta; Takashi Watanabe; Kennichi Satoh; Morihisa Hirota; Tooru Shimosegawa

  AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY AMER PHYSIOLOGICAL SOC 295 (4) G709 - G717 0193-1857 2008/10 [Refereed]
   

  Pancreatic cancer is characterized by excessive desmoplastic reaction and by a hypoxic microenvironment within the solid tumor mass. Chronic pancreatitis is also characterized by fibrosis and hypoxia. Fibroblasts in the area of fibrosis in these pathological settings are now recognized as activated pancreatic stellate cells (PSCs). Recent studies have suggested that a hypoxic environment concomitantly exists not only in pancreatic cancer cells but also in surrounding PSCs. This study aimed to clarify whether hypoxia affected the cell functions in PSCs. Human PSCs were isolated and cultured under normoxia (21% O-2) or hypoxia (1% O-2). We examined the effects of hypoxia and conditioned media of hypoxia-treated PSCs on cell functions in PSCs and in human umbilical vein endothelial cells. Hypoxia induced migration, type I collagen expression, and vascular endothelial growth factor (VEGF) production in PSCs. Conditioned media of hypoxia-treated PSCs induced migration of PSCs, which was inhibited by anti-VEGF antibody but not by antibody against hepatocyte growth factor. Conditioned media of hypoxia-treated PSCs induced endothelial cell proliferation, migration, and angiogenesis in vitro and in vivo. PSCs expressed several angiogenesis-regulating molecules including VEGF receptors, angiopoietin-1, and Tie-2. In conclusion, hypoxia induced profibrogenic and proangiogenic responses in PSCs. In addition to their established profibrogenic roles, PSCs might play proangiogenic roles during the development of pancreatic fibrosis, where they are subjected to hypoxia.
• Molecular mechanisms of portal vein tolerance

  Tomohiro Watanabe; Masatoshi Kudo; Tsutomu Chiba; Yoshio Wakatsuki

  HEPATOLOGY RESEARCH BLACKWELL PUBLISHING 38 (5) 441 - 449 1386-6346 2008/05 [Refereed]
   

  The liver has been considered as a tolerogenic organ in the sense that favors the induction of peripheral tolerance. The administration of antigens (Ags) via the portal vein causes tolerance, which is termed portal vein tolerance and can explain the occurrence of tolerogenic responses in the liver. Here we discuss the fundamental mechanisms accounting for portal vein tolerance. Antigen-presenting cells (APCs) in the liver, especially dendritic cells and sinusoidal endothelial cells, have limited the ability to produce pro-inflammatory cytokines upon stimulation with endotoxin, an effect that could be due to the continuous exposure to bacterial Ags derived from intestinal microflora. Ag presentation by liver APCs results in T cell tolerance through clonal deletion and selection of regulatory T cells. Thus, APCs with immunosuppressive functions are associated with the achievement of portal vein tolerance via the induction of clonal deletion and generation of regulatory T cells.
• Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis

  Tomohiro Watanabe; Naoki Asano; Peter Murray; Keiko Ozato; Atsushi Kitani; Ivan J. Fuss; Warren Strober

  GASTROENTEROLOGY W B SAUNDERS CO-ELSEVIER INC 134 (4) A16 - A16 0016-5085 2008/04 [Refereed]
  
• Notch1 signaling and regulatory T cell function

  Naoki Asano; Tomohiro Watanabe; Atsushi Kitani; Ivan J. Fuss; Warren Strober

  JOURNAL OF IMMUNOLOGY AMER ASSOC IMMUNOLOGISTS 180 (5) 2796 - 2804 0022-1767 2008/03 [Refereed]
   

  Previous studies have shown that the Notch1 and TGF-beta signaling pathways are mutually re-enforcing. Given recent evidence that regulatory T cell (Treg) effector function is mediated by TGF-beta signaling, we investigated whether Notch1 signaling also participated in Treg effector function. Initial studies showed that Notch1 ligands, particularly Jagged1, are present on Tregs and that, indeed, blockade of Notch1 signaling with an anti-jagged1 or a blocking anti-Notch1 Ab inhibits Treg suppressor function in vitro. We then showed that a signaling component generated by Notch1 activation (Notch1 intracellular domain) of dendritic cells physically interacts with a signaling component generated by TGF-beta signaling (pSmad3). Furthermore, this interaction has functional downstream effects because over-expression of Notch1 intracellular domain facilitates pSmad3 translocation to the nucleus and enhances pSmad3 transcriptional activity of a Smad-sensitive promoter linked to a luciferase reporter. Finally, we showed that blockade of TGF-beta signaling and Notch signaling did not have additive inhibitory effects on Treg suppressor function. These results are consistent with the conclusion that Notch1 signaling facilitates TGF-beta-mediated effector function of Tregs.
• Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis

  Tomohiro Watanabe; Naolki Asano; Peter J. Murray; Keiko Ozato; Prafullakurnar Tailor; Ivan J. Fuss; Atsushi Kitani; Warren Strober

  JOURNAL OF CLINICAL INVESTIGATION AMER SOC CLINICAL INVESTIGATION INC 118 (2) 545 - 559 0021-9738 2008/02 [Refereed]
   

  The mechanisms underlying the susceptibility of individuals with caspase recruitment domain 15 (CARD15) mutations and corresponding abnormalities of nucleotide-binding oligomerization domain 2 (NOD2) protein to Crohn disease are still poorly understood. One possibility is based on previous studies showing that muramyl dipeptide (MDP) activation of NOD2 negatively regulates TLR2 responses and that absence of such regulation leads to heightened Th1 responses. We now report that administration of MDP protects mice from the development of experimental colitis by downregulating multiple TLR responses, not just TLR2. The basis of these in vivo findings was suggested by in vitro studies of DCs, in which we showed that prestimulation of cells with MDP reduces cytokine responses to multiple TLR ligands and this reduction is dependent on enhanced IFN regulatory factor 4 (IRF4) activity. Further studies of mouse models of colitis showed that this inhibitory role of IRF4 does in fact apply to MDP-mediated protection from colitis, since neither IRF4-deficient mice nor mice treated with siRNA specific for IRF4 were protected. These findings indicate that MDP activation of NOD2 regulates innate responses to intestinal microflora by downregulating multiple TLR responses and suggest that the absence of such regulation leads to increased susceptibility to Crohn disease.
• Small Bowel Anisakiasis with Self-limiting Clinical Course

  Tomohiro Watanabe; Sakiko Ohta; Satoru Iwamoto; Yoshihisa Tsuji; Shuko Morita; Isao Doi; Yasunori Ueda; Tsutomu Chiba

  INTERNAL MEDICINE JAPAN SOC INTERNAL MEDICINE 47 (24) 2191 - 2192 0918-2918 2008 [Refereed]
  
• NADPH oxidase plays a crucial role in the activation of pancreatic stellate cells

  Atsushi Masamune; Takashi Watanabe; Kazuhiro Kikuta; Kennichi Satoh; Tooru Shimosegawa

  AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY AMER PHYSIOLOGICAL SOC 294 (1) G99 - G108 0193-1857 2008/01 [Refereed]
   

  Activated pancreatic stellate cells (PSCs) play an important role in pancreatic fibrosis and inflammation, where oxidative stress is implicated in the pathogenesis. NADPH oxidase might be a source of reactive oxygen species (ROS) in the injured pancreas. This study aimed to clarify the expression and regulation of cell functions by NADPH oxidase in PSCs. PSCs were isolated from rat and human pancreas tissues. Expression of NADPH oxidase was assessed by reverse transcription-PCR and immunostaining. Intracellular ROS production was assessed using 2', 7'-dichlorofluorescin diacetate. The effects of diphenylene iodonium (DPI) and apocynin, inhibitors of NADPH oxidase, on key parameters of PSC activation were evaluated in vitro. In vivo, DPI (at 1 mg . kg body wt(-1).day(-1)) was administered in drinking water to 10-wk-old male Wistar Bonn/Kobori rats for 10 wk and to rats with chronic pancreatitis induced by dibutyltin dichloride (DBTC). PSCs expressed key components of NADPH oxidase (p22(phox), p47(phox), NOX1, gp91(phox)/ NOX2, NOX4, and NOX activator 1). PDGF-BB, IL-1 beta, and angiotensin II induced ROS production, which was abolished by DPI and apocynin. DPI inhibited PDGF-induced proliferation, IL-1 beta- induced chemokine production, and expression of alpha-smooth muscle actin and collagen. DPI inhibited transformation of freshly isolated cells to a myofibroblast-like phenotype. In addition, DPI inhibited the development of pancreatic fibrosis in Wistar Bonn/Kobori rats and in rats with DBTC-induced chronic pancreatitis. In conclusion, PSCs express NADPH oxidase to generate ROS, which mediates key cell functions and activation of PSCs. NADPH oxidase might be a potential target for the treatment of pancreatic fibrosis.
• Pancreatic stellate cells express Toll-like receptors

  Atsushi Masamune; Kazuhiro Kikuta; Takashi Watanabe; Kennichi Satoh; Akihiko Satoh; Tooru Shimosegawa

  JOURNAL OF GASTROENTEROLOGY SPRINGER TOKYO 43 (5) 352 - 362 0944-1174 2008 [Refereed]
   

  Background Toll-like receptors (TLRs) are proteins involved in recognition of foreign pathogen-associated molecular patterns (PAMPs) and activation of innate immunity. This study aimed to clarify whether pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, expressed TLRs and responded to PAMPs. Methods. PSCs were isolated from rat pancreas tissue, and expression of TLRs was examined. PSCs were treated with lipoteichoic acid (a ligand for TLR2), polyinosinic-polycytidylic acid (a ligand for TLR3), lipopolysaccharide (a ligand for TLR4), or flagellin (a ligand for TLR5). The effects of the TLR ligands on key cell functions and activation of signaling pathways were examined. The ability of PSCs to perform endocytosis and phagocytosis was also examined. Results. PSCs expressed TLR2, 3, 4, and 5, as well as the associated molecules CD14 and MD2. All of the TLR ligands activated nuclear factor-kappa B, and three classes of mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase). TLR ligands induced expression of monocyte chemoattractant protein 1, cytokine-induced neutrophil chemoattractant 1 (a rat homolog of interleukin-8), and inducible nitric oxide synthase, but not proliferation or type I collagen production. PSCs could perform fluid-phase and receptor-mediated endocytosis, as well as phagocytosis of Escherichia coli. Conclusions. PSCs expressed a variety of TLRs and responded to TLR ligands, leading to the activation of signaling pathways and proinflammatory responses. PSCs could process exogenous antigens by endocytosis and phagocytosis. PSCs might play a role in the immune functions of the pancreas through the recognition of PAMPs.
• NOD2 Transgenic Mice Exhibit Enhanced MDP-Mediated Down-Regulation of TLR2 Responses and Resistance to Colitis Induction

  Zhiqiong Yang; Ivan J. Fuss; Tomohiro Watanabe; Naoki Asano; Michael P. Davey; James T. Rosenbaum; Warren Strober; Atsushi Kitani

  Gastroenterology Elsevier BV 133 (5) 1510 - 1521 0016-5085 2007/11 [Refereed]
  
• Periportal and sinusoidal liver dendritic cells suppressing T helper type 1-mediated hepatitis

  Tomohiro Watanabe; Hiroaki Katsukura; Tsutomu Chiba; Toru Kita; Yoshio Wakatsuki

  GUT B M J PUBLISHING GROUP 56 (10) 1445 - 1451 0017-5749 2007/10 [Refereed]
   

  Background: Recently, we found that portal vein tolerance is associated with generation of Th2 cells and apoptosis of Th1 cells in the liver, which is regulated by antigen (Ag)-presenting dendritic cells (DCs) in the periportal area and sinusoids. Aim: In this study, we tested whether the periportal and sinusoidal DCs, which were loaded with an Ag in vivo, can inhibit liver injury caused by Th1 cells activated by the Ag administered systemically. Methods: Ag-specific hepatitis model was created by adoptively transferring ovalbumin (OVA)-specific CD4(+) T cells to BALB/c mice and venous injection of OVA-containing liposomes. Liver CD11c(+) cells obtained from mice fed OVA were then transferred into these mice. Results: The transfer of liver CD11c(+) cells from OVA-fed mice completely inhibited hepatic injury, which was associated with apoptosis of OVA-specific CD4(+) T cells and emergence of Th2 cells in the liver. Transfer of CD11c(+) cells and subcutaneous OVA challenge led to enhancement of OVA-specific IgE Ab as well as Th2 cytokine responses in the recipient mice. Conclusions: Periportal and sinusoidal DCs loaded with an Ag in the portal vein can induce Th2 response in the liver and prevent hepatic injury caused by Th1 cells.
• Induction of IL-13 triggers TGF-beta(1)-dependent tissue fibrosis in chronic 2,4,6-trinitrobenzene sulfonic acid colitis

  Stefan Fichtner-Feigl; Ivan J. Fuss; Cheryl A. Young; Tomohiro Watanabe; Edward K. Geissler; Hans Juergen Schlitt; Atsushi Kitani; Warren Strober

  JOURNAL OF IMMUNOLOGY AMER ASSOC IMMUNOLOGISTS 178 (9) 5859 - 5870 0022-1767 2007/05 [Refereed]
   

  To investigate the immunopathogenesis of inflammation-associated fibrosis, we analyzed the chronic colitis and late-developing fibrosis occurring in BALB/c mice administered weekly doses of intrarectal 2,4,6-trinitrobenzene sulfonic acid. We showed first in this model that an initial Th1 response involving IL-12p70 and IFN-gamma subsides after 3 wk to be supplanted by an IL-23/IL-25 response beginning after 4-5 wk. This evolution is followed by gradually increasing production of IL-17 and cytokines ordinarily seen in a Th2 response, particularly IL-13, which reaches a plateau at 8-9 wk. In vitro stimulation studies suggest that this IL-13 production is dependent on IL-23 and IL-25, but not on IL-12p70. We then show that IL-13 production results in the induction of an IL-13R formerly thought to function only as a decoy receptor, IL-13R alpha(2), and this receptor is critical to the production of TGF-beta(1), and the onset of fibrosis. Thus, if IL-13 signaling through this receptor is blocked by administration of soluble IL-13R alpha(2)-Fc, or by administration of IL-13R alpha 2-specific small interfering RNA, TGF-beta(1) is not produced and fibrosis does not occur. These studies show that in chronic 2,4,6-trinitrobenzene sulfonic acid colitis, fibrosis is dependent on the development of an IL-13 response that acts through a novel cell surface-expressed IL-13R to induce TGF-beta(1). A similar mechanism may obtain in certain forms of human inflammatory bowel disease.
• NOD2/CARD15異常からみたIBD発症の分子機構

  渡邉智裕; 千葉勉

  IBD Research 1 178 - 183 2007 [Invited]
  
• 胃粘膜上皮細胞における自然免疫反応とその解析法

  渡邉智裕; 千葉勉

  分子消化器病 5 178 - 183 2007 [Invited]
  
• The ever-expanding immunological universe: Impact on mucosal immunity and inflammation

  Warren Strober; Atsushi Kitani; Tomohiro Watanabe

  INFLAMMATORY BOWEL DISEASES LIPPINCOTT WILLIAMS & WILKINS 12 S4 - S5 1078-0998 2006/10 [Invited]
  
• Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis

  Tomohiro Watanabe; Atsushi Kitani; Peter J. Murray; Yoshio Wakatsuki; Ivan J. Fuss; Warren Strober

  IMMUNITY CELL PRESS 25 (3) 473 - 485 1074-7613 2006/09 [Refereed]
   

  In this study, we determined conditions leading to the development of colitis in mice with nucleotide binding oligomerization domain 2 (NOD2) deficiency, a susceptibility factor in Crohn's disease. We found that NOD2-deficient antigen-presenting cells (APCs) produced increased amounts of interleukin (IL)-12 in the presence of ovalbumin (OVA) peptide and peptidoglycan or recombinant E. coli that express OVA peptide (ECOVA). Furthermore, these APCs elicited heightened interferon-gamma (IFN-gamma) responses from cocultured OVA-specific CD4(+) T cells. We then demonstrated that NOD2-deficient mice adoptively transferred OVA-specific CD4(+) T cells and that administered intrarectal ECOVA developed colitis associated with the expansion of OVA-specific CD4(+) T cells producing IFN-gamma. Importantly, this colitis was highly dependent on Toll-like receptor 2 (TLR2) function since it was suppressed in NOD2 and TLR2 double-deficient mice. Thus, NOD2-deficient mice become susceptible to colitis as a result of increased TLR2 responses when they have the capacity to respond to an antigen expressed by mucosal bacteria.
• Cecal necrosis due to ischemic colitis mimicking an abscess on sonography

  T Watanabe; S Tomita; H Shirane; Y Okabe; A Orino; A Todo; T Chiba; M Kudo

  JOURNAL OF ULTRASOUND IN MEDICINE AMER INST ULTRASOUND MEDICINE 25 (3) 393 - 396 0278-4297 2006/03 [Refereed]
   

  Ischemic colitis is a vascular disorder of the colon that causes rectal bleeding and abdominal pain in elderly patients.(1,2) It is classified into gangrenous and nongangrenous forms. Nongangrenous colonic ischemia usually requires only medical treatment and is associated with a good prognosis. In contrast, urgent surgical intervention is required for the treatment of gangrenous colonic ischemia, which is associated with high mortality.(3) Thus, in patients with ischemic colitis, it is especially important to determine whether colonic ischemia is the gangrenous or nongangrenous type. Endoscopic assessment of the colon is the most sensitive and reliable method of evaluating the ischemic colon mucosa(4); however, it is not always possible to perform a colonoscopic examination in patients with gangrenous ischemic colitis because of the severe general condition of these patients. Therefore, a noninvasive and rapid examination procedure is necessary for the diagnosis of gangrenous ischemic colitis. In this regard, a sonographic examination may be useful because it can be easily performed even in patients with shock status. In fact, several studies have reported that bowel wall thickening and decreased arterial flow in the affected colon are characteristic findings of patients with nongangrenous ischemic colitis(5-8); however, few articles have addressed the sonographic findings of gangrenous colonic ischemia. In this report, we describe the case of a patient with cecal necrosis due to ischemic colitis and discuss its unique sonographic findings.
• Signalling pathways and molecular interactions of NOD1 and NOD2

  Warren Strober; Peter J. Murray; Atsushi Kitani; Tomohiro Watanabe

  Nature Reviews Immunology Springer Science and Business Media LLC 6 (1) 9 - 20 1474-1733 2006/01 [Refereed][Invited]
  
• Crohn's disease - NOD2 regulation of Toll-like receptor responses and the pathogenesis of Crohn's disease

  T Watanabe; A Kitani; W Strober

  GUT B M J PUBLISHING GROUP 54 (11) 1515 - 1518 0017-5749 2005/11 [Refereed][Invited]
   

  NOD2 signalling can both positively and negatively regulate Toll-like receptor (TLR) responses. Previous studies have shown that lack of NOD2 signalling ( in NOD2 knockout mice) leads to increased peptidoglycan induction of interleukin (IL)-12 via TLR2. Studies in this issue of Gut show that lack of NOD2 signalling ( in patients with NOD2 mutations) leads to decreased CpG induction of tumour necrosis factor and IL-8 via TLR9. The first type of abnormality suggests that NOD2 mutations act by enhancing effector T cell function and the second that NOD2 mutations act by impairing regulatory T cell function. We weigh these possibilities.
• CD4+CD25+ T cells regulate colonic localization of CD4 T cells reactive to a microbial antigen

  Tomohiro Watanabe; Masashi Yamori; Toru Kita; Tsutomu Chiba; Yoshio Wakatsuki

  Inflammatory Bowel Diseases Oxford University Press (OUP) 11 (6) 541 - 550 1078-0998 2005/06 [Refereed]
   

  Background: In patients with inflammatory bowel diseases, T-cell activation driven by microflora has been implicated as a mechanism causing clonal expansion and infiltration of CD4+ T cells in colonic lamina propria (LP). We explored a regulatory mechanism preventing infiltration of CD4 + T cells specific to a microbe-associated antigen in the gut. Methods: SCID mice were reconstituted with CD4+ T cells specific to ovalbumin (OVA) and were orally administered with Escherichia coli engineered to produce OVA. Results: OVA-specific CD4+ T cells (KJ1-26+) were recruited to colonic LP in an Ag-dependent manner, which was inhibited by adoptive transfer of naturally occurring CD4+CD25+ T (Treg) cells. KJ1-26+ T cells and Treg cells are localized preferentially to the colonic follicles that contain dendritic cells. In mice given Treg cells, LP CD4+ T cells showed a decrease in proliferative and interferon γ response and an increase in transforming growth factor β1 response to OVA stimulation. Treg cells inhibited both antigenic activation of effector CD4+ T cells and class II/CD80/CD86 up-regulation of dendritic cells. Conclusion: Treg cells suppress recruitment of CD4+ T cells specific to a microbe-associated antigen to LP, which was associated with colocalization of effector CD4+ T cells and Treg cells in colonic follicles. Copyright © 2005 by Lippincott Williams & Wilkins.
• NOD2 is a negative regulator of Toll-like receptor 2–mediated T helper type 1 responses

  Tomohiro Watanabe; Atsushi Kitani; Peter J Murray; Warren Strober

  Nature Immunology Springer Science and Business Media LLC 5 (8) 800 - 808 1529-2908 2004/08 [Refereed]
  
• Antigenic activation of Th1 cells in the gastric mucosa enhances dysregulated apoptosis and turnover of the epithelial cells

  Masashi Yamori; Masaru Yoshida; Tomohiro Watanabe; Yasuhiko Shirai; Tadahiko Iizuka; Toru Kita; Yoshio Wakatsuki

  Biochemical and Biophysical Research Communications Elsevier BV 316 (4) 1015 - 1021 0006-291X 2004/04 [Refereed]
   

  Colonization of Helicobacter pylori in the stomach leads to chronic gastritis with massive infiltration by Th1 cells. To assess a role played by those T cells in the remodeling of gastric epithelium, we activated gastric T cells utilizing mice with CD4 T cells bearing transgenic TCR with or without deficiency in either IL-4 or IFN-γ or IL-12. Mice developed gastritis upon injection of an antigen into gastric mucosa. While neutrophil infiltration occurred even with a control antigen, infiltration by transgenic T cells was dependent on the specific antigen. The numbers of epithelial cells undergoing apoptosis and regeneration were increased in the mice with infiltrating T cells producing IFN-γ and the alignment of those cells in the glands was markedly dysregulated. In contrast, mice deficient in Th1 response showed no increase in cell division and apoptosis of epithelial cells. Thus, Th1 type T cells infiltrating into gastric mucosa play an independent role in controlling turnover of epithelial cells. © 2004 Elsevier Inc. All rights reserved.
• Portal vein tolerenace and development of regulatory CD4 T cells in the liver

  Watanabe T; Chiba T; Wakatsuki Y

  Mucosal Immunology Update 12 5 - 7 2004
• A liver tolerates a portal antigen by generating CD11c(+) cells, which select Fas ligand(+) Th2 cells via apoptosis

  T Watanabe; H Katsukura; Y Shirai; M Yamori; T Nishi; T Chiba; T Kita; Y Wakatsuki

  HEPATOLOGY W B SAUNDERS CO 38 (2) 403 - 412 0270-9139 2003/08 [Refereed]
   

  Administration of an antigen (Ag) per oral route leads to apoptosis of Ag-specific CD4(+) T cells and to development of Th2 cells expressing Fas ligand (FaSL) in the liver. We determined whether presentation of an ingested Ag in the liver alone was enough to select these FasL(+)Th2 cells and explored how this selection was achieved in the liver. Ovalbumin (OVA) administered orally was colocalized with class II+ cells in the periportal and parenchymal area of the liver. On coculture with naive OVA-specific CD4(+) T cells, hepatic CD11c(+) cells from mice fed OVA generated Ag-specific Th2 cells. This was achieved by apoptosis of CD4(+) T cells, decrease of interleukin 12 (IL-12) secretion, and increase of IL-18 secretion by the CD11c(+) cells. Addition of IL-12 to this coculture prevented apoptosis of the CD4(+) T cells, which was associated with up-modulation of IL-2 receptor beta chain expression. Administration of IL-12 to mice fed OVA prevented apoptosis of OVA-specific CD4(+) T cells in the liver. Moreover, adoptive transfer of hepatic CD11c(+) cells from mice fed OVA together with OVA-specific CD4(+) T cells led to development of Th2 cells as well as apoptosis of the transferred CD4(+) T cells in the lymph nodes of the recipient mice on immunization with OVA. In conclusion, presentation of an ingested Ag by hepatic CD11c(+) cells selects Th2 cells resistant to apoptosis in the liver, which is mediated in part by down-regulation of IL-12 secretion by the former cells.
• Scintigraphic study of regenerative nodules due to fulminant hepatic failure

  Tomohiro Watanabe; Masahiko Kondo; Masahiro Hirasa; Hirofumi Shirane; Yoshihiro Okabe; Yasuyoshi Ibuki; Shusuke Tomita; Akio Orino; Akio Todo; Yoshio Wakatsuki; Tsutomu Chiba; Masatoshi Kudo

  Journal of Gastroenterology Springer Science and Business Media LLC 38 (7) 695 - 699 0944-1174 2003/07 [Refereed]
   

  We report the case of a 25-year-old woman with fulminant hepatic failure (FHF). Liver scintigraphy using 99mTc-galactosyl human serum albumin (GSA) and 99mTc-phytate produced interesting findings regenerative nodules appeared as nodules of increased accumulation of 99mTc-GSA, whereas these nodules were expressed as defects of accumulation of 99mTc-phytate. These scintigraphic findings suggested that the functions of hepatocytes in regenerative nodules were maintained, whereas those of Kupffer cells were impaired. Although 99mTc-GSA scintigraphy indicated hepatic functional reserve enough to survive, she died despite intensive therapy including plasma exchange. Based on this case, it is recommended that not only 99mTc-GSA scintigraphy but also 99mTc-phytate scintigraphy is required to evaluate the prognosis of patients with FHF.
• Helper CD4+ T cells for IgE response to a dietary antigen develop in the liver

  Tomohiro Watanabe; Hiroaki Katsukura; Yasuhiko Shirai; Masashi Yamori; Tsutomu Chiba; Toru Kita; Yoshio Wakatsuki

  Journal of Allergy and Clinical Immunology Mosby Inc. 111 (6) 1375 - 1385 0091-6749 2003/06 [Refereed]
   

  Background: Although T-cell responses to food antigens are normally inhibited either by deletion, active suppression, or both of antigen-specific T cells, T helper cells for IgE response to a food antigen still develop by unknown mechanisms in a genetically susceptible host. Objective: We determined the site at which those IgE helper T cells develop. Methods: We administered ovalbumin (OVA) orally to DO11.10 mice and studied CD4+ T cells in Peyer's patches, the spleen, and the liver. Helper activity for IgE response was assessed by adoptively transferring those CD4+ T cells to naive BALB/c mice, followed by systemic immunization with OVA. Results: OVA-specific CD4+ T cells were deleted by cell death in the liver and Peyer's patches of DO11.10 mice fed OVA. OVA-specific CD4+ T cells that survived apoptosis in the liver expressed Fas ligand and secreted IL-4, IL-10, and transforming growth factor β1. CD4+ T cells producing IFN-γ were deleted in the liver by repeated feeding of OVA. On transfer of CD4+ T cells to naive mice and systemic immunization with OVA, a marked increase in OVA-specific IgE response developed only in the mice that received hepatic CD4+ T cells from OVA-fed mice, the effect of which was not observed in the recipients of hepatic CD4+ T cells deficient in IL-4. In addition, significant suppression of delayed-type hypersensitivity and IgG1/IgG2a responses to OVA was observed in the recipients of hepatic CD4+ T cells, and this suppression required Fas/Fas ligand interaction. Conclusion: Together, these results suggested that a food antigen might negatively select helper T cells for IgE response to the antigen by preferential deletion of TH1 cells in the liver.
• Involvement of myeloid dendritic cells in the development of gastric secondary lymphoid follicles in Helicobacter pylori-infected neonatally thymectomized BALB/c mice.

  Toshiki Nishi; Kazuichi Okazaki; Kimio Kawasaki; Toshiro Fukui; Hiroyuki Tamaki; Minoru Matsuura; Masanori Asada; Tomohiro Watanabe; Kazushige Uchida; Norihiko Watanabe; Hiroshi Nakase; Masaya Ohana; Hiroshi Hiai; Tsutomu Chiba

  Infection and immunity American Society for Microbiology 71 (4) 2153 - 62 0019-9567 2003/04 [Refereed]
   

  We previously described an animal model of Helicobacter pylori-induced follicular gastritis in neonatally thymectomized (nTx) mice. However, it is still not clear whether antigen-presenting dendritic cells (DCs) in the stomach have a role in the development of secondary follicles in H. pylori-infected nTx mice. We investigated the distribution of DC subsets using this model and examined their roles. To identify lymphoid and myeloid DCs, sections were stained with anti-CD11c (pan-DC marker) in combination with anti-CD8alpha (lymphoid DC marker) or anti-CD11b (myeloid DC marker) and were examined with a confocal microscope. Expression of macrophage inflammatory protein 3alpha (MIP-3alpha), which chemoattracts immature DCs, was analyzed by real-time PCR and immunohistochemistry. Follicular dendritic cells (FDCs) were stained with anti-SKY28 antibodies. In noninfected nTx mice, a few myeloid and lymphoid DCs were observed in the bottom portion of the lamina propria, whereas in H. pylori-infected nTx mice, there was an increased influx of myeloid DCs throughout the lamina propria. FDC staining was also observed in the stomachs of members of the infected group. MIP-3alpha gene expression was upregulated in the infected nTx group, and the immunohistochemistry analysis revealed MIP-3alpha-positive epithelial cells. These data suggest that H. pylori infection upregulates MIP-3alpha gene expression in gastric epithelial cells and induces an influx of myeloid DCs in the lamina propria of the gastric mucosa in nTx mice. Myeloid DCs and FDCs might contribute to the development of gastric secondary lymphoid follicles in H. pylori-infected nTx mice.
• Differential localization of colitogenic Th1 and Th2 cells monospecific to a microflora-associated antigen in mice

  Masaru Yoshida; Yasuhiko Shirai; Tomohiro Watanabe; Masashi Yamori; Yoichiro Iwakura; Tsutomu Chiba; Toru Kita; Yoshio Wakatsuki

  Gastroenterology W.B. Saunders 123 (6) 1949 - 1961 0016-5085 2002/12 [Refereed]
   

  Background & Aims: Clonal expansion of T cells is associated with inflammatory bowel diseases, which indicates antigenic activation of the T cells. We investigated whether the introduction of CD4 T cells specific to a microflora would initiate colitis and assessed the cytokine requirements for colitogenic CD4 T cells. Methods: Severe combined immunodeficiency disease (SCID) mice were reconstituted with CD4 T cells, which were either deficient in interleukin (IL)-4/interferon (IFN)-γ production or differentiated in vitro to T-helper (Th) 1/Th 2 and bearing a transgenic T-cell receptor (TCR) specific to ovalbumin (OVA), and then inoculated with an Escherichia coli-producing OVA (ECOVA). Clinical and histologic manifestations of colitis were assessed. Results: Mice with ECOVA colonization and OVA-specific CD4 T cells developed colitis with histologic features of focal infiltration by mononuclear cells, destruction of crypts, and loss of goblet cells. Further, infiltration was initiated in pre-existing lymph follicles. Th1- and IL-4 deficient T cells were diffusely localized in the lamina propria and submucosa, whereas Th2- and IFN-γ-deficient T cells were localized preferentially in lymph follicles. Conclusions: A microbe-associated antigen, non-crossreactive to colonic tissue, can drive antigen-specific CD4 T cells to cause colitis in SCID mice. Although the presence of IFN-γ and IL-4 in the effector CD4 T cells was not an absolute requirement for the development of colitis, they seemed to regulate it in part by modulating migration of the effector T cells.
• Administration of an antigen at a high dose generates regulatory CD4+ T cells expressing CD95 ligand and secreting IL-4 in the liver

  Tomohiro Watanabe; Masaru Yoshida; Yasuhiko Shirai; Masashi Yamori; Hideo Yagita; Toshiyuki Itoh; Tsutomu Chiba; Toru Kita; Yoshio Wakatsuki

  Journal of Immunology American Association of Immunologists 168 (5) 2188 - 2199 0022-1767 2002/03 [Refereed]
   

  Ags administered orally at a high dose are absorbed in immunogenic forms and perfuse the liver, which raises a question regarding the relevance of hepatic lymphocyte activation to the systemic hyporesponsiveness against the ingested Ag. Oral administration of 100 mg of OVA to the mice led to massive cell death of OVA-specific (KJ1-26+) CD4+ T cells by Fas-Fas ligand (FasL)-mediated apoptosis in the liver, which was associated with the emergence of hepatic KJ1-26+CD4+ T cells expressing FasL. Hepatic CD4+ T cells in OVA-fed mice secreted large amounts of IL-4, IL-10, and TGF-β1 upon restimulation in vitro and inhibited T cell proliferation. Adoptive transfer of these hepatic CD4+ T cells to naive mice and subsequent antigenic challenge led to suppression of T cell proliferation as well as IgG Ab responses to OVA this effect was mostly abrogated by a blocking Ab to FasL. i.p. administration of an Ag at a high dose also generated hepatic CD4+FasL+ T cells with similar cytokine profile as T cells activated by oral administration of Ags at a high dose. Finally, we did not see an increase in FasL+ cells in the hepatic CD4+Vβ8+ T cell subset of MRL/lpr/lpr mice given staphylococcal enterotoxin B, indicating the requirement for Fas-mediated signals. These hepatic CD4+FasL+ regulatory cells may explain the tolerogenic property of the liver and play roles in systemic hyporesponsiveness induced by an Ag administered at a high dose.
• 消化器と免疫寛容

  渡邉智裕; 若月芳雄

  最新医学 57 997 - 1003 2002 [Invited]
  
• 抗原感作により肝臓内に誘導される免疫調節性CD4+Fas ligand+ T細胞

  渡邉智裕; 若月芳雄

  臨床免疫 38 242 - 248 2002 [Invited]
  
• Rectal immunization with antigen-containing microspheres induces stronger Th2 responses than oral immunization: A new method for vaccination

  Hiroshi Nakase; Kazuichi Okazaki; Yasuhiko Tabata; Kazushige Uchida; Suguru Uose; Masaya Ohana; Toshiki Nishi; Tomohiro Watanabe; Minoru Matsuura; Hiroshi Hisatsune; Kazuyoshi Matsumura; Toshiyuki Itoh; Chiharu Kawanami; Tsutomu Chiba

  Vaccine Elsevier BV 20 (3-4) 377 - 384 0264-410X 2001/11 [Refereed]
   

  The rectum as an effective site for induction of systemic and local immunity has received little attention. Rectal immunization with microspheres-containing ovalbumin (MS-OVA) was tested for its ability to elicit systemic and mucosal immune responses. Rectal immunization with MS-OVA enhanced both Th2 dominant OVA-specific IgG levels in the serum and OVA-specific IgA levels in fecal extracts more prominently than did oral immunization. Cytokine analysis of CD4+ T cells indicated a predominant induction of Th2-type responses compared to Th1-type responses following rectal immunization compared to oral immunization. These results demonstrate that rectal immunization with microspheres could be an effective new vaccination method. © 2001 Elsevier Science Ltd. All rights reserved.
• CD4 T cells monospecific to ovalbumin produced by Escherichia coli can induce colitis upon transfer to BALB/c and SCID mice

  Masaru Yoshida; Tomohiro Watanabe; Takashi Usui; Yoichi Matsunaga; Yasuhiko Shirai; Masashi Yamori; Toshiyuki Itoh; Sonoko Habu; Tsutomu Chiba; Toru Kita; Yoshio Wakatsuki

  International Immunology Oxford University Press 13 (12) 1561 - 1570 0953-8178 2001 [Refereed]
   

  Although some animal models suggest an involvement of CD4 T cells reactive to luminal microrbial antigen(s) for the pathogenesis of inflammatory bowel diseases (IBD), direct linkage between microflora-driven clonal expansion of CD4 T cells and the development of colitis has not been well studied. Here, BALB/c and SCID mice were given CD4 T cells purified from Rag-2-/- mice crossed to transgenic mice expressing TCR specific to ovalbumin (OVA) then administered with antibiotic-resistant Escherichia coli producing OVA (ECOVA) or LacZ (ECLacZ) via the rectum. The ECOVA-inoculated BALB/c and SCID mice developed a subacute colitis with microscopic features of distortion of crypt architecture, loss of goblet cells, and focal infiltration by mononuclear cells in the lamina propria (LP) and submucosa. Expanding OVA-specific CD4 T cells were detected in colonic follicles of mice with ECOVA. Early in colitis, OVA-specific CD4 T cells producing IFN-γ predominate in the LP of the colon, which was followed by an emergence of OVA-specific CD4 T cells producing IL-4 and IL-10 at a later time point. Co-transfer of an IL-10-secreting OVA-specific CD4 T cell line prevented colitis. Thus, an expansion of CD4 T cells monospecific to OVA, an antigen non-cross-reactive to colonic tissue, can mediate both induction and inhibition of the colitis which was associated with hyperplasia of lymph follicles.
• Effects of Helicobacter pylori infection on Zollinger-Ellison syndrome

  T Watanabe; Y Matsushima; H Nakase; M Iwano; R Hosotani; M Imamura; Y Kinoshita; T Chiba

  JOURNAL OF GASTROENTEROLOGY SPRINGER-VERLAG 35 (10) 735 - 741 0944-1174 2000/10 [Refereed]
   

  Both Zollinger-Ellison syndrome (ZES) and Helicobacterpylori infection are major etiologic factors for peptic ulcer. The aim of this study was to investigate the effect of H. pylori infection on ZES with special reference to acid secretion. Sixteen patients with ZES were selected (median age, 59 years; range, 39-66 years; M/F, 9/7), and H. pylori status, ulcer location, gastric acid secretion, serum pepsinogen (PG) I and II concentrations, and PG I/II ratio were determined. The seroprevalence of H. pylori infection was 50%, whereas active H. pylori infection was seen in only 25% of the patients. Thirteen patients had duodenal ulcer (DU), 1 had gastric ulcer (GU), and 2 had both GU and DU. DU was seen in both H. pylori-positive and H. pylori-negative patients, whereas GU was found only in H. pylori-positive patients. Both basal and maximal acid outputs were significantly lower in H. pylori-positive patients than in H. pylori-negative patients (P < 0.05). Moreover, both serum PG I and the PG I/II ratio were significantly lower in H, pylori-positive patients than in H. pylori-negative patients. These results indicate that ZES is an independent risk factor for DU, but H. pylori infection may play some role in the development of GU in ZES. In patients with ZES, N. pylori infection may reduce both hypersecretion from parietal cells and PG I secretion from chief cells, and hyperacidity of the stomach in ZES may have eradicated H. pylori in some patients.
• Massive rectal bleeding due to ileal tuberculosis

  Tomohiro Watanabe; Masatoshi Kudo; Makoto Kayaba; Hirofumi Shirane; Shusuke Tomita; Akio Orino; Akio Todo; Tsutomu Chiba

  Journal of Gastroenterology Springer Science and Business Media LLC 34 (4) 525 - 529 0944-1174 1999/08 [Refereed]
   

  A patient with massive rectal bleeding due to ileal tuberculosis is reported. Technetium-99m labelled red blood cell scintigraphy indicated hemorrhage from the ileum, and laparotomy was then carried out. A 70-cm segment of ileum containing ulcers and erosions was resected, and epitheloid granuloma with Langhans-type giant cell was found in the resected specimen. Massive rectal bleeding is considered a rare presenting symptom of intestinal tuberculosis. Intestinal tuberculosis, including small intestinal tuberculosis, although uncommon, should be taken into consideration as a cause of rectal bleeding.
• Cronkhite-Canada syndrome associated with triple gastric cancers: A case report

  T. Watanabe; M. Kudo; H. Shirane; H. Kashida; S. Tomita; A. Orino; A. Todo; T. Chiba

  Gastrointestinal Endoscopy Mosby Inc. 50 (5) 688 - 691 0016-5107 1999 [Refereed]
  
• Detection of Helicobacter pylori gene by means of immunomagnetic separation-based polymerase chain reaction in feces

  T Watanabe; S Tomita; M Kudo; M Kurokawa; A Orino; A Todo; T Chiba

  SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY SCANDINAVIAN UNIVERSITY PRESS 33 (11) 1140 - 1143 0036-5521 1998/11 [Refereed]
   

  Background: Detection of Helicobacter pylori is usually performed by culture, polymerase chain reaction (PCR), histology, or urease test on gastric biopsy samples. Although methods based on feces are noninvasive, their sensitivity has been relatively low. In this study, to improve its sensitivity, immunomagnetic separation (LMS) was used as a pre-PCR step for direct detection of H. pylori in feces. Methods: Fresh fecal samples were taken from 72 patients attending for endoscopy. Of these, 57 patients had a positive H. pylori status according to the results of culture, histology, and PCR on gastric biopsy samples. Anti-H. pylori antibody-sensitized immunomagnetic beads were used to concentrate the bacteria. PCR was then performed to detect the H. pylori urease A-encoding gene. Results: Of the 57 H. pylori-positive patients, 35 (61.4%) had positive fecal samples by IMS-based PCR method. None of the 15 H. pylori-negative patients had positive fecal samples. The sensitivity of this method was 61.4%, and the specificity 100.0%. Conclusions: This study confirms that non-invasive diagnosis of H. pylori infection could be made from feces by using IMS-based PCR.
• MRCPが診断に有用であった膵胆管合流異常の4例

  木本 直哉; 岡部 純弘; 織野 彬雄; 西本 正興; 鄭 浩柄; 上嶋 一臣; 渡邊 智裕; 福永 豊和; 樫田 博史; 平佐 昌弘

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 40 (Suppl.2) 1660 - 1660 0387-1207 1998/10
• 急性炎症性腸炎の血流〜カラードプラ法を用いて 虚血性腸炎,薬剤性腸炎と細菌性腸炎との比較

  木本 直哉; 岩崎 信広; 富田 周介; 上嶋 一臣; 渡邊 智裕; 福永 豊和; 岡部 純弘; 樫田 博史; 平佐 昌弘; 伊吹 康良

  超音波医学 (公社)日本超音波医学会 25 (8) 913 - 913 1346-1176 1998/08
• 陥凹型腫瘍 陥凹型を中心とした大腸早期癌の診断

  樫田 博史; 柴田 俊一; 上嶋 一臣; 木本 直哉; 渡邊 智裕; 福永 豊和; 平佐 昌弘; 伊吹 康良; 冨田 周介; 織野 彬雄

  早期大腸癌 (株)日本メディカルセンター 2 (3) 365 - 365 1343-2443 1998/05
• Mapping of Nakano cataract gene nct on mouse chromosome 16

  H Hiai; S Kato; Y Horiuchi; R Shimada; T Tsuruyama; T Watanabe; A Matsuzawa

  GENOMICS ACADEMIC PRESS INC 50 (1) 119 - 120 0888-7543 1998/05 [Refereed]
  
• 出血性大腸炎O157腸炎の超音波像

  渡邉智裕; 冨田周介; 藤堂彰男; 箕輪和士; 岩崎信広; 曽我登志子; 田村周二; 栃尾人司; 森本義人; 黒川学

  検査と技術 26 (1) 81 - 83 0301-2611 1998 [Invited]
  
• カラ−ドプラ法による慢性肝疾患に見られる小結節の良悪性診断−流入する定常性血流シグナルについて−

  杤尾人司; 冨田周介; 工藤正俊; 岡部純弘; 岩崎信広; 蓑輪和士; 曽我登志子; 田村周二; 森本義人; 渡邉智裕; 福永豊和; 近藤雅彦; 樫田博史; 平佐昌弘; 伊吹康良; 織野彬雄; 藤堂彰男

  Clinical Information 9 1 - 13 1997 [Refereed]
  
• パワードプラ法の臨床応用─肝腫瘤の血流動態からみた質的診断─

  杤尾人司; 樫田博史; 冨田周介; 岩崎信広; 簑輪和士; 田村周二; 曽我登志子; 森本義人; 渡辺智裕; 福永豊和; 岡部純弘; 平佐昌弘; 伊吹康良; 工藤正俊; 織野彬雄; 藤堂彰男

  臨床成人病 27 1075 - 1082 1997 [Refereed]
  
• 脂肪肝に伴う胆嚢床のSpared Areaと肝内胆嚢流出血流との関連: カラードプラ法による検討

  杤尾人司; 岡部純弘; 冨田周介; 工藤正俊; 樫田博史; 岩崎信広; 蓑輪和士; 田村周二; 曽我登志子; 森本義人; 渡邉智裕; 福永豊和; 平佐昌弘; 伊吹康良; 織野彬雄; 藤堂彰男

  ＪMed Ultrasonics 24 1651 - 1661 1997 [Refereed]
  
• 慢性肝疾患にみられる小結節性病変に対するカラードプラ診断: 流入する定常性血流の意義を中心に

  杤尾人司; 冨田周介; 工藤正俊; 岡部純弘; 樫田博史; 岩崎信広; 蓑輪和士; 曽我登志子; 田村周二; 森本義人; 渡邉智裕; 福永豊和; 平佐昌弘; 伊吹康良; 織野彬雄; 藤堂彰男

  超音波医学 24 1025 - 1033 1997 [Refereed]
  
• カラ−ドプラ法にて特徴的な血流動態を観察し得た右胃静脈と考えられる還流異常に伴う肝内過形成結節の１例

  杤尾人司; 岡部純弘; 冨田周介; 織野彬雄; 岩崎信広; 蓑輪和士; 曽我登志子; 田村周二; 森本義人; 渡邉智裕; 福永豊和; 近藤雅彦; 樫田博史; 平佐昌弘; 伊吹康良; 工藤正俊; 藤堂彰男

  J Med Ultrasonics 787 - 794 1997 [Refereed]
  
• Ultrasonographic Imaging of Intestinal Malignant Lymphoma

  TOCHIO Hitoshi; TOMITA Syusuke; OKABE Yoshihiro; ORINO Akio; IWASAKI Nobuhiro; HAMADA Kazumi; MINOWA Kazushi; HAMADA Michiko; SOGA Toshiko; TAMURA Syuji; MORIMOTO Yoshito; WATANABE Tomohiro; FUKUNAGA Toyokazu; KONDOH Masahiko; KASHIDA Hiroshi; HIRASA Masahiro; IBUKI Yasuyosi; KUDOH Masatoshi; TODO Akio

  J Med Ultrasonics 24 (1) 21 - 28 0287-0592 1997 [Refereed]
  
• Reg gene expression is increased in rat gastric enterochromaffin-like cells following water immersion stress

  M Asahara; S Mushiake; S Shimada; H Fukui; YA Kinoshita; C Kawanami; T Watanabe; S Tanaka; A Ichikawa; Y Uchiyama; Y Narushima; S Takasawa; H Okamoto; M Tohyama; T Chiba

  GASTROENTEROLOGY W B SAUNDERS CO 111 (1) 45 - 55 0016-5085 1996/07 [Refereed]
   

  Background & Aims: Reg gene has been isolated from regenerating rat pancreatic islets, and subsequent studies have shown a trophic effect of Reg protein on islet cells. However, little is known about the role of Reg protein in the stomach. The aim of this study was to clarify the localization of Reg messenger RNA (mRNA) and its product in the stomach and to examine changes in the level of their expression during regeneration of gastric mucosal cells. Methods: Gastric lesions were experimentally induced in Sprague-Dawley rats by water immersion stress. Northern blot analysis and in situ hybridization studies were performed to examine changes in mRNA levels. Immunohistochemical studies were performed to identify the cellular localization and to investigate the change in Reg protein level. Results: Reg mRNA and its product were distributed in the basal part of the oxyntic mucosa and were expressed mainly in enterochromaffin-like cells. Levels of both Reg mRNA and its product were markedly increased in the water immersion-induced gastric lesions. Conclusions: Reg mRNA and its product are expressed in gastric enterochromaffin-like cells, and their levels are increased during the healing process of water immersion-induced gastric lesions.
• 十二指腸潰瘍患者におけるHelicobacter pylori除菌療法について

  冨田周介; 渡邉智裕; 近藤雅彦; 福永豊和; 岡部純弘; 樫田博史; 平佐昌弘; 伊吹康良; 工藤正俊; 織野彬雄; 藤堂彰男; 三木寛二; 大西伸策; 黒川 学

  神戸市立病院紀要 35 19 - 23 1995 [Refereed]
  
• INDUCTION OF HISTIDINE-DECARBOXYLASE IN NON-MAST CELLS IN THE SPLEEN OF MICE BY INJECTION OF STAPHYLOCOCCAL ENTEROTOXIN-A

  K KAWAGUCHINAGATA; T WATANABE; A YAMATODANI; M INOUE; J FUJITA; H OKAMURA; T TAMURA; K SHOJI; H WADA; Y KITAMURA

  JOURNAL OF BIOCHEMISTRY JAPANESE BIOCHEMICAL SOC 102 (3) 551 - 557 0021-924X 1987/09 [Refereed]
  

Books etc

• ヤクルト・バイオサイエンス研究財団 年報 第30号

  渡邉智裕 (ContributorAkkermansia muciniphilaとBifidobacterium pseudolongumが慢性炎症性膵臓疾患の病態に果たす役割の解明と新規治療法の開発)ヤクルト・バイオサイエンス研究財団 2022/10
• Akkermansia muciniphilaとBifidobacterium pseudolongumが慢性炎症性膵臓疾患の病態に果たす役割の解明と新規治療法の開発

  渡邉 智裕 (Contributor)ヤクルトバイオサイエンス研究財団 年報 第29号 2021/10
• Akkermansia muciniphilaとBifidobacterium pseudolongumが慢性炎症性膵臓疾患の病態に果たす役割の解明と新規治療法の開発

  渡邉 智裕 (Contributor)ヤクルトバイオサイエンス研究財団 年報第28号 2020/11
• 展望 小林がん学術振興会

  渡邉 智裕 (Contributor自然免疫反応の制御を用いた膵臓癌の予防法の開発)2018/11
• Current Protocols in Immunology

  Kamata K; Watanabe T; Minaga K; Strober W; Kudo M (Joint workAutoimmune Pancreatitis Mouse Model)Wiley 2018/02
• 消化器内科診察 レジデントマニュアル

  渡邉 智裕 (Joint work)医学書院 2018
• 腸内細菌叢からみた膵臓疾患の発症機序の解明と新規治療法の開発

  渡邉 智裕 (Contributor)ヤクルトバイオサイエンス研究財団 年報 第26号 2018
• ESMO HandBook Immuno-Oncology 2018

  Harding JJ; Watanabe T; El-Dika I; Nishida N; Abou-alfa GK; Kudo M (Joint work2.5 GI Malignancies, 2.5.3 HCC)2018
• 腸内細菌叢からみた膵炎の発症機序の解明と新規治療法の開発

  渡邉 智裕 (Contributor)先進医薬研究振興財団 2017年度研究成果報告集 2018
• Current Topics in Microbiology and Immunology

  Watanabe T; Yamashita K; Kudo M (ContributorIgG4-Related Disease and Innate Immunity)Springer 2017
• 膵臓疾患と腸内細菌

  渡邉 智裕 (Contributor)内藤財団時報 2017
• IgG4関連全身硬化性疾患の診断法の確立と治療方法の開発に関する研究

  渡邉 智裕; 千葉勉 (Contributor)厚生労働科学研究委託費 難治性疾患実用化研究事業 平成26年度 委任業務成果報告書 2015
• IgG4関連疾患と自然免疫

  渡邉 智裕 (Contributor)IgG4関連疾患 実践的臨床から病因へ 2015
• Mucosal Immunology 4th Edition

  Watanabe T; Chiba T; Strober W (ContributorChapter 88 Immune mechanisms of pancreatitis)Academic Press 2015
• トップランナーに聞く。最先端の医療に挑む若手研究者への直撃インタビュー自然免疫反応と消化器疾患とのかかわり

  渡邉 智裕 (Contributor)最新医学 2013
• IgG4関連型自己免疫性膵臓炎におけるTLR/NLRの活性化の関与

  渡邉 智裕 (Contributor)細胞科学研究財団助成研究報告集 2012
• 自然免疫システムの制御によるクローン病の新規治療法の開発

  渡邉 智裕 (Contributor)ヤクルト・バイオサイエンス研究財団年報 2012
• 炎症性腸疾患の基礎研究の進歩と展望

  渡邉智裕; 千葉勉 (Contributor)炎症性腸疾患 病因解明と診断･治療の最新知見 2012
• 腸内細菌由来抗原の免疫制御機能を用いた炎症性腸疾患の新規治療法の開発

  渡邉 智裕 (Contributor)厚生労働科学研究費補助金 難治性疾患克服事業: 平成22年度 総括・分担研究報告書 2011
• IgG4関連硬化性疾患の発症に関わる自然免疫及び獲得免疫反応の解明療

  渡邉 智裕 (Contributor)膵臓病研究財団第18回研究報告書 2010
• 腸内細菌由来抗原Muramyl Dipeptide (MDP)による自然免疫システムの活性化を利用した炎症性腸疾患の新規治療法の開発

  渡邉 智裕 (Contributor)ヤクルト・バイオサイエンス研究財団年報 2009
• 経口からの抗原投与により活性化される肝内CD11c+樹状細胞を用いた実験肝炎の治療

  渡邉智裕; 若月芳雄; 千葉勉 (Contributor)消化器と免疫 2009
• NOD2の活性化を用いたクローン病の新たな免疫制御療法

  渡邉智裕; 千葉勉 (Contributor)消化器と免疫 2008
• 経口免疫寛容の誘導における肝内Tリンパ球の関与

  渡邉智裕; 若月芳雄; 吉田優; 伊藤俊之; 臼井崇; 白井泰彦; 松永洋一; 垣生園子; 千葉勉; 北徹 (Contributor)消化器と免疫 1999
• ヤクルト・バイオサイエンス研究財団 年報第30号

  渡邉智裕 (ContributorAkkermansia muciniphilaとBifidobacterium pseudolongumが慢性炎症性膵臓疾患の病態に果たす役割の解明と新規治療法の開発)
• 肝性脳症に対するInterventional radiology

  樫田博史; 渡邉智裕; 藤堂彰男 (Contributor)門脈圧亢進症

Conference Activities & Talks

• 益田 康弘, 原 茜, 栗本 真之, 大塚 康生, 正木 翔, 本庶 元, 鎌田 研, 三長 孝輔, 工藤 正俊, 渡邉 智裕  [Not invited]

  NOD2の活性化によるI型IFN経路の制御機構; を用いた潰瘍性大腸炎の個別化治療の可能性

  第110回日本消化器病学会総会  2024/05
• 芳香族炭化水素受容体の活性化によるIL-22を介したシグナル伝達. 経路は自己免疫性膵炎の新規治療ターゲットとなり得る  [Not invited]

  鎌田 研,三長 孝輔, 渡邉 智裕, 工藤 正俊

  第110回日本消化器病学会総会  2024/05
• 自己免疫性膵炎の発症に関わる腸内細菌の同定  [Not invited]

  三長 孝輔; 吉川 智恵; 原 茜; 鎌田 研; 工藤 正俊; 渡邉 智裕

  第110回日本消化器病学会総会  2024/05
• 消化管真菌叢はパーキンソン病感受性遺伝子LRRK2の活性化を介して、膵炎を重症化させる  [Not invited]

  大塚 康生; 三長 孝輔; 渡邉 智裕

  2023/11
• 高脂肪食による肥満は自己免疫性疾患の危険因子である  [Not invited]

  瀬海 郁衣; 三長 孝輔; 渡邉 智裕

  JDDW2023  2023/11
• NOD2の活性化によるI型IFN経路の制御機構が炎症性腸疾患の病態に果たす役割  [Not invited]

  益田康弘; 三長孝輔; 鎌田研; 大塚康生; 本庶元; 正木翔; 瀬海郁衣; 栗本真之; 大丸直哉; 原茜; 岡井夏輝; 新井康之; 山下公平; 工藤正俊; 渡邉智裕

  第60回日本消化器免疫学会総会  2023/10
• 芳香族炭化水素受容体の活性化はIL-22を介したシグナル伝達経路を通じて自己免疫性膵炎の発症を抑制する  [Not invited]

  鎌田研; 渡邉智裕; 工藤正俊

  第60回日本消化器免疫学会総会  2023/10
• 腸内真菌叢はパーキンソン病感受性蛋白LRRK2を介し、急性膵炎の重症化に関与する  [Not invited]

  大塚康生; 三長孝輔; 栗本真之; 瀬海郁衣; 原茜; 鎌田研; 渡邉智裕; 工藤正俊

  第60回日本消化器免疫学会総会  2023/10
• 新型コロナワクチン接種後にIgA血管炎を発症し、コロナ感染を契機に再燃を繰り返した一例  [Not invited]

  勝部洸平; 永井知行; 駒谷真; 有山武尊; 栗本真之; 岡井夏輝; 吉田早希; 半田康平; 正木翔; 河野匡志; 米田頼晃; 本庶元; 松井繁長; 渡邉智裕; 辻直子; 樫田博史; 工藤正俊

  日本消化器病学会近畿支部 第119回例会19  2023/09
• カボサンチニブ投与による腫瘍の著明な縮小、腫瘍マーカーの低下を認めたMET遺伝子増幅を伴う肝細胞癌の一例  [Not invited]

  八田寛朗; 萩原智; 上嶋一臣; 大丸直哉; 松原卓哉; 盛田真弘; 千品寛和; 田北雅弘; 南康範; 依田広; 渡邉智裕; 西田直生志; 工藤正俊

  日本消化器病学会近畿支部 第119回例会  2023/09
• IL-6免疫応答亢進を伴う潰瘍性大腸炎関連脊椎関節炎の一例  [Not invited]

  藤田峻輔; 本庶元; 高田隆太郎; 原茜; 益田康弘; 半田康平; 三長孝輔; 渡邉智裕; 工藤正俊; 辻成佳

  日本消化器病学会近畿支部 第118回例会  2023/01
• 空腸濾胞性リンパ腫から形質転換した腹部Double Expressor Lymphoma (DEL)の一例  [Not invited]

  高田隆太郎; 三長孝輔; 渡邉智裕; 工藤正俊

  日本消化器病学会近畿支部 第117回例会  2022/10
• COVID-19ワクチン接種後のI型インターフェロン反応を特徴とする潰瘍性大腸炎再発の一例

  益田康弘; 三長孝輔; 渡邉智裕; 工藤正俊

  日本消化器病学会近畿支部 第117回例会  2022/10
• 急激な経過を辿ったClostridium perfringens肝膿瘍・多臓器ガス壊疽の一例  [Not invited]

  原茜; 三長孝輔; 大塚康生; 渡邉智裕; 工藤正俊; 梶山博

  日本消化器病学会近畿支部 第117回例会  2022/10
• 腸内細菌に対する免疫反応とIgG4関連疾患  [Invited]

  渡邉智裕

  第30回日本シェーグレン学会学術集会  2022/09
• 非代償性肝硬変による直腸静脈瘤出血に対して内視鏡的組織接着剤注入術を施行した一例

  加藤弘樹; 松井繁長; 田北雅弘; 上中大地; 今村瑞貴; 原茜; 野村健司; 瀬海郁衣; 高田隆太郎; 河野匡司; 正木翔; 永井知行; 本庶元; 米田頼晃; 上嶋一臣; 渡邉智裕; 西田直生志; 辻直子; 樫田博史; 工藤正俊

  第108回日本消化器内視鏡学会近畿支部例会  2022/06
• クローン病疾患感受性遺伝子 NOD2 の欠損は T 細胞依存性腸炎の発症を抑制する

  高田隆太郎; 渡邉 智裕; 工藤 正俊

  第108回日本消化器病学会総会  2022/04
• 自己免疫性膵炎の発症に関わるサイトカイン・ケモカインネットワークの解明と新規バ イオマーカーの同定

  原 茜; 渡邉 智裕; 工藤 正俊

  第108回日本消化器病学会総会1  2022/04
• 腸管バリアの破壊に伴い，膵臓に定着する Staphylococcus sciuri が自己免疫性膵炎の発 症に果たす役割  [Not invited]

  吉川 智恵; 渡邉 智裕; 工藤 正俊

  第108回日本消化器病学会総会  2022/04
• 腸内細菌から紐解く膵臓・腸管臓器関連；自己免疫性炎からの考察  [Invited]

  渡邉智裕

  第 2章 腸内微生物叢研究の最前線シリーズ  2022/03
• 腸内細菌と臓器連関  [Invited]

  渡邉智裕

  富田林医師会学術講演会  2022/03
• 制御性T細胞に依存しない寛解を得たCollagenous Colitisの一例  [Not invited]

  瀬海 郁衣; 本庶 元; 今村 瑞貴; 松原 卓哉; 河野 匡志; 原 茜; 栗本 真之; 吉川 馨介; 益田 康弘; 大塚 康生; 高田 隆太郎; 吉川 智恵; 鎌田 研; 三長 孝輔; 松井 繁長; 木村 雅友; 渡邉 智裕; 工藤 正俊

  日本消化器病学会近畿支部 第116回例会  2022/02
• 腸内細菌に対する炎症性サイトカイン応答の増強を示すクローン病関連型脊椎関節炎の一例  [Not invited]

  福西香栄; 本庶元; 岡井夏輝; 河野匡司; 鎌田研; 三長孝輔; 米田頼晃; 辻成佳; 渡邉智裕; 工藤正俊

  日本消化器病学会近畿支部 第116回例会  2022/02
• 診断に難渋した小腸GISTの一例  [Not invited]

  福西香栄; 永井知行; 杉森啓伸; 岡井夏輝; 高田隆太郎; 河野匡志; 正木翔; 米田頼晃; 本庶元; 松井繁長; 渡邉智裕; 辻直子; 樫田博史; 工藤正俊

  第107回日本消化器内視鏡学会 近畿支部例会  2021/12
• 腸内細菌と臓器連関  [Invited]

  渡邉智裕

  第4回あわざ乾癬セミナー  2021/11
• 自己免疫性膵炎の発症に関わるサイトカイン・ケモカインネットワークの解明と新規バイオマーカーの同定  [Not invited]

  原茜; 吉川智恵; 三長孝輔; 鎌田研; 渡邉智裕; 工藤正俊

  第29回 若手膵臓病研究会  2021/11
• インフリキシマブが有効であった腸型Bechet病のサイトカイン反応の解析

  吉川馨介; 渡邉智裕; 瀬海郁衣; 高田隆太郎; 原茜; 栗本真之; 益田康弘; 大塚康夫; 吉川友恵; 正木翔; 鎌田研; 三長孝輔; 米田頼晃; 工藤正俊; 筑後孝章

  日本消化器病学会近畿支部 第115回例回  2021/09
• EUS-FNAにて術前診断できた食道schwannomaの1例

  福西香栄; 松井繁長; 杉森啓伸; 高田隆太郎; 正木翔; 河野匡志; 永井知行; 米田頼晃; 山崎友裕; 山雄健太郎; 竹中完; 本庶元; 渡邉智裕; 辻直子; 樫田博史; 工藤正俊; 白石治; 安田卓司

  日本消化器病学会近畿支部 第115回例回  2021/09
• TNF-alphaおよびIL-6の関与が考えられた好酸球性胃腸炎の1例

  瀬海郁衣; 吉川馨介; 高田隆太郎; 原茜; 吉川智恵; 鎌田研; 三長孝輔; 渡邉智裕; 工藤正俊

  日本消化器病学会近畿支部 第115回例回  2021/09
• 内視鏡的に保存的に回収できた胃石の一例  [Not invited]

  杉森啓伸; 本庶元; 原茜; 益田康弘; 吉田早希; 高田隆太郎; 河野匡志; 正木翔; 永井知行; 米田頼晃; 櫻井俊治; 松井繁長; 渡邉智裕; 辻直子; 樫田博史; 工藤正俊

  第106回日本消化器内視鏡学会 近畿支部例会  2021/09
• IgG4関連疾患の病態-腸内細菌・自然免疫反応を中心に  [Invited]

  渡邉智裕

  第１回IgG4-RD Web 研究会  2021/08
• 腸内細菌と臓器連関  [Invited]

  渡邉 智裕

  日本消化器病学会近畿支部 第66回教育講演会  2021/07
• 自己免疫性膵炎の発症に関わる腸内細菌叢の解析  [Not invited]

  鎌田 研; 渡邉 智裕; 原 茜; 瀬海 郁衣; 大塚 康夫; 三長 孝輔; 工藤 正俊

  第58回 日本消化器免疫学会総会  2021/07
• ステロイド治療前後の腸内微生物叢からみた自己免疫性膵炎の病態解明  [Not invited]

  鎌田研; 渡邉智裕; 工藤正俊

  第107回日本消化器病学会総会  2021/04
• 炎症性腸疾患の疾患感受性遺伝子とサイトカイン反応  [Invited]

  渡邉 智裕

  IBD Web Seminar-Expert Meeting-  2020/12
• 自己免疫性膵炎・IgG4関連疾患と腸内細菌  [Invited]

  渡邉 智裕

  第３回リウマチ関連疾患領域フォーラム  2020/12
• 疾患感受性遺伝子・炎症性サイトカインとIBD  [Invited]

  渡邉 智裕

  IBD Clinical Conference in 静岡東部  2020/11
• IRF7-I型IFN-IL-33経路がIgG4関連疾患の病態に果たす役割とバイオマーカーとしての有用性  [Not invited]

  三長孝輔; 渡邉智裕; 工藤正俊

  JDDW2020  2020/11
• ATG16L1はRICK/RIP2シグナル伝達経路を抑制する  [Not invited]

  本庶元; 渡邉智裕; 工藤正俊

  JDDW 2020  2020/11
• 形質細胞様樹状細胞の活性化に着⽬したIgG4 関連疾患のバイオマーカーの同定  [Not invited]

  三⻑孝輔; 原茜; 吉川智恵; 鎌田研; 渡邉智裕; 工藤正俊

  第28回 若手膵臓研究会  2020/11
• ステロイド治療前後の腸内微⽣物叢からみた⾃⼰免疫性膵炎の病態解明

  鎌田研; 渡邉智裕; 原茜; 瀬海郁衣; 大塚康生; 三⻑孝輔; 本庶元; 工藤正俊

  第28回 若手膵臓研究会  2020/11
• 転写因子IRF7の活性化からみた自己免疫性膵炎の病態解明  [Not invited]

  三長 孝輔; 渡邉 智裕; 工藤正俊

  第106回日本消化器病学会総会  2020/08
• 腸内細菌叢の変化がIgG4関連型自己免疫性膵炎の発症に及ぼす効果の検討  [Not invited]

  鎌田 研; 渡邉 智裕; 工藤 正俊

  第106回日本消化器病学会総会  2020/08
• 自己免疫性膵炎の発症に関わる腸内細菌叢の解析  [Not invited]

  鎌田 研; 渡邉 智裕; 工藤 正俊

  第57回 日本消化器免疫学会総会  2020/07
• ATG16L1はRICK/RIP2シグナル伝達経路を抑制する  [Not invited]

  本庶 元; 渡邉 智裕; 鎌田 研; 三長 孝輔; 工藤 正俊

  第57回 日本消化器免疫学会総会  2020/07
• 腸内環境と炎症性腸疾患〜脊椎関節炎にフォーカスを当てて  [Invited]

  渡邉 智裕

  SpAを考える会 2020  2020/01
• Freyの手術後7年目に膵空腸吻合部から出血をきたし、バルーン内視鏡で止血が得られた１例  [Not invited]

  家村 郁衣; 本庶 元; 松村 まり子; 高島 耕太; 正木 翔; 河野 匡志; 山田 光成; 米田 頼晃; 永井 知行; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 辻 直子; 樫田 博史; 工藤 正俊

  第103回日本消化器内視鏡学会近畿支部例会  2020/01
• LENVATINIB AS AN INITIAL TREATMENT IN PATIENTS WITH INTERMEDIATE-STAGE HEPATOCELLULAR CARCINOMA BEYOND UP-TO-SEVEN CRITERIA AND CHILD-PUGH A LIVER FUNCTION: A MULTICENTER PROPENSITY-SCORE MATCHED STUDY  [Not invited]

  Kazuomi Ueshima; Stephen L. Chan; Tomohiro Minami; Hirokazu Chishina; Tomoko Aoki; Masahiro Takita; Satoru Hagiwara; Yasunori Minami; Hiroshi Ida; Mamoru Takenaka; Toshiharu Sakurai; Tomohiro Watanabe; Masahiro Morita; Chikara Ogawa; Yoshiyuki Wada; Masafumi Ikeda; Hiroshi Ishii; Namiki Izumi; Naoshi Nishida

  American Society for the Study of Liver Disease (AASLD) 2019  2019/11
• MPACT OF BASELINE ALBI GRADE ON THE OUTCOMES OF HEPATOCELLULAR CARCINOMA PATIENTS TREATED WITH LENVATINIB: A MULTICENTER STUDY  [Not invited]

  Masatoshi Kudo; Kazuomi Ueshima; Naoshi Nishida; Satoru Hagiwara; Tomoko Aoki; Tomohiro Minami; Hirokazu Chishina; Masahiro Takita; Yasunori Minami; Hiroshi Ida; Mamoru Takenaka; Toshiharu Sakurai; Tomohiro Watanabe; Masahiro Morita; Chikara Ogawa; Atsushi Hiraoka

  American Society for the Study of Liver Disease (AASLD) 2019  2019/11
• PPI長期投与の有無からみた胃底腺ポリープの臨床病理学的検討  [Not invited]

  松村 まり子; 辻 直子; 梅原 康湖; 正木 翔; 岡元 寿樹; 山田 光成; 永井 知行; 米田 頼晃; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 樫田 博史; 工藤 正俊

  JDDW 2019  2019/11
• Intestinal microenvironment and autoimmune pancreatitis  [Invited]

  Tomohiro Watanabe

  American Pancreatic Association (APA) Annual Meeting 2019  2019/11
• DLBCLに発症したリンパ管拡張症に対してステロイド投与、食事両方が奏功した１症例  [Not invited]

  大塚 康生; 米田 頼晃; 正木 翔; 吉川 馨介; 高島 耕太; 橋本 有人; 山田 光成; 本庶 元; 永井 知行; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 辻 直子; 樫田 博史; 工藤 正俊; 筑後 孝章

  日本消化器病学会近畿支部 第111回例会  2019/10
• 血清IFN-alpha/IL-33が治療効果判定に有用と考えられた自己免疫性膵炎/IgG4関連疾患の１例  [Not invited]

  原 茜; 三長 孝輔; 岡本 彩那; 石川 嶺; 山崎 友裕; 中井 敦史; 大本 俊介; 鎌田 研; 山雄 健太郎; 竹中 完; 渡邉 智裕; 工藤 正俊; 安川 覚

  日本消化器病学会近畿支部 第111回例会  2019/10
• 消化器疾患とサイトカイン  [Invited]

  渡邉 智裕

  堺市医師会内科医会消化器談話会 講演会  2019/09
• SpAとIBDの病態における腸管免疫の関与  [Invited]

  渡邉 智裕

  日本脊椎関節炎学会 第29回学術集会  2019/09
• 転写因子 IRF7 の活性化からみた IgG4 関連疾患の病態解明  [Not invited]

  三長 孝輔; 渡邉 智裕; 新井 康之; 塩川 雅広; 吉川 智恵; 鎌田 研; 山下 浩平; 工藤 正俊

  第56回日本消化器免疫学会  2019/08
• RICK/RIP2 is a NOD2-independent nodal point of gut inflammation  [Invited]

  Tomohiro Watanabe

  International Congress of Mucosal Immunology  2019/07
• CMV腸炎を合併した紫斑のない成人IgA血管炎の一例  [Not invited]

  松村 まり子; 米田 頼晃; 大塚 康生; 河野 辰哉; 高島 耕太; 正木 翔; 岡元 寿樹; 山田 光成; 永井 知行; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 辻 直子; 樫田 博史; 工藤 正俊; 榎木 英介

  第102回日本消化器病内視鏡学会近畿支部例会  2019/07
• Computer-Aided Diagnosis Based on Convolutional Neural Network System using AI for Colorectal Polyp Classification  [Not invited]

  Yoriaki Komeda; Hisashi Handa; Ryoma Matsui; Tomohiro Watanabe; Toshiharu Sakurai; Hiroshi Kashida; Masatoshi Kudo

  DDW2019  2019/05
• 好酸球性食道炎の臨床的意義の特徴  [Not invited]

  正木翔; 松井繁長; 大塚康生; 松村まり子; 高島耕太; 河野辰哉; 岡元寿樹; 河野匡志; 山田光成; 米田頼晃; 櫻井俊治; 渡邉智裕; 辻直子; 樫田博史; 工藤正俊

  第97回日本消化器内視鏡学会総会  2019/05
• 腸内細菌叢からみた膵酵素補充療法の慢性膵炎に対する炎症抑制機序の解明  [Not invited]

  三長 孝輔; 渡邉 智裕; 工藤 正俊

  第105回日本消化器病学会総会  2019/05
• Computer-Aided Diagnosis (CAD) Based on Convolutional Neural Network (CNN) System using AI (Artificial Intelligence) for Colorectal Polyp Classification  [Not invited]

  Yoriaki Komeda; Hisashi Handa; Ryoma Matsui; Tomohiro Watanabe; Toshiharu Sakurai; Hiroshi Kashida; Masatoshi Kudo

  ESGE2019  2019/04
• TNF-alphaと腸管免疫  [Invited]

  渡邉 智裕

  第28回南大阪膠原病カンファレンス  2019/02
• 抗TNF製剤の寛解維持効果を基礎から考察する  [Invited]

  渡邉 智裕

  第33回大阪クローン病治療研究会  2019/02
• Cap polyposisにおける腸内細菌叢の解析  [Not invited]

  岡元 寿樹; 渡邉 智裕; 工藤 正俊

  JDDW 2018  2018/11
• 乾癬の併存疾患〜炎症性腸疾患のサイトカイン反応〜  [Invited]

  渡邉 智裕

  第48回 日本免疫皮膚アレルギー学会総会 モーニングセミナー  2018/11
• 若年性ポリポーシスより胃切除をした２症例  [Not invited]

  Tomohiro Watanabe

  第101回 日本消化器内視鏡学会近畿支部例会  2018/11
• 表在型食道内分泌癌の一例  [Not invited]

  高島耕太; 松井繁長; 岡元寿樹; 山田光成; 正木翔; 河野匡志; 米田頼晃; 永井知行; 櫻井俊治; 渡邉智裕; 辻直子; 樫田博史; 工藤正俊

  第101回 日本消化器内視鏡学会近畿支部例会  2018/11
• 腸内細菌叢からみたIgG4関連疾患の発症機序の解明  [Not invited]

  鎌田 研; 渡邉 智裕; 工藤 正俊

  JDDW2018  2018/11
• 腸内細菌叢からみたIgG4関連疾患の発症機序の解明  [Not invited]

  鎌田 研; 渡邉 智裕; 工藤 正俊

  第26回 若手膵臓研究会  2018/10
• 膵酵素補充療法が慢性膵炎の発症に及ぼす効果の解明  [Not invited]

  三長孝輔; 渡邉 智裕; 工藤正俊

  第26回 若手膵臓研究会  2018/10
• 偽性腸閉塞に対し、胃瘻造設が有効であった一例  [Not invited]

  田中秀和; 永井知行; 櫻井俊治; 河野辰哉; 高島耕太; 正木翔; 岡元寿樹; 河野匡志; 山田光成; 米田頼晃; 渡邉智裕; 松井繁長; 辻直子; 樫田博史; 工藤正俊

  第109回日本消化器病学会近畿支部例会  2018/09
• 炎症性腸疾患におけるTNF-alphaの役割  [Invited]

  渡邉 智裕

  第22回 日本脊椎関節炎学会ランチョンセミナー  2018/09
• 腸内細菌に対する自然免疫反応が膵臓の慢性炎症に果たす役割  [Invited]

  渡邉 智裕

  第1回宮城消化器学術講演会  2018/08
• タビガトランによる薬剤性食道潰瘍の検討  [Not invited]

  益田康弘; 松井繁長; 河野匡志; 岡元寿樹; 山田光成; 米田頼晃; 永井知行; 櫻井俊治; 渡邉 智裕; 樫田博史; 工藤正俊

  第100回日本消化器内視鏡学会近畿支部例会  2018/05
• パンクレリパーゼ摂取による腸管内および便の腸内細菌叢に対する影響の検討  [Not invited]

  永井知行; 西山拓輝; 櫻井俊治; 渡邉智裕; 緒方博之; 工藤正俊

  第104回日本消化器病学会総会  2018/04
• mFOLFOX6+Cetuximab併用により画像的にComplete Responseが得られた切除不能肝転移を伴う S状結腸癌の１例  [Not invited]

  大塚康生; 永井知行; 櫻井俊治; 福永明洋; 半田康平; 高田隆太郎; 岡元寿樹; 木下淳; 河野匡志; 山田光成; 米田頼晃; 松井繁長; 渡邉智裕; 汐見幹夫; 樫田博史; 工藤正俊

  第108回日本消化器病学会近畿支部例会  2018/03
• 超音波内視鏡下吸引細胞診（EUS-FNA）にて診断に至ったスキルス胃癌の１例  [Not invited]

  高田隆太郎; 米田頼晃; 櫻井俊治; 福永明洋; 半田康平; 木下淳; 河野匡志; 岡元寿樹; 山田光成; 永井知行; 松井繁長; 渡邉智裕; 樫田博史

  第108回日本消化器病学会近畿支部例会  2018/03
• セツキシマブを含む抗がん剤にて肺胞出血を来した一例  [Not invited]

  福永明洋; 岡元寿樹; 櫻井俊治; 半田康平; 高田隆太郎; 木下淳; 石川嶺; 河野匡志; 山田光成; 永井知行; 米田頼晃; 松井繁長; 渡邉智裕; 汐見幹夫; 樫田博史; 工藤正俊

  第108回日本消化器病学会近畿支部例会  2018/03
• 乾癬の併存疾患〜炎症性腸疾患のサイトカイン反応〜  [Invited]

  渡邉 智裕

  第４回 南大阪PsA治療の医療連携の会  2018/02
• 空腸穿通魚骨を小腸内視鏡にて除去し得た一例  [Not invited]

  福永朋洋; 永井知行; 櫻井俊治; 岡元寿樹; 岡本彩那; 河野匡志; 山田光成; 米田頼晃; 松井繁長; 渡邉智裕; 樫田博史; 工藤正俊

  第99回日本消化器内視鏡学会近畿支部例会  2017/11
• 大網裂孔ヘルニアによるレイウスの1例  [Not invited]

  吉川馨介; 木下 淳; 櫻井俊治; 高島耕太; 河野辰哉; 石川 嶺; 岡本彩那; 河野匡志; 岡元寿樹; 山田光成; 永井知行; 米田頼晃; 松井繁長; 渡邉智裕; 樫田博史; 工藤正俊

  第99回日本消化器内視鏡学会近畿支部例会  2017/11
• 止血に難渋した十二指腸静脈瘤出血の1例,  [Not invited]

  中野省吾; 松井繁長; 高島耕太; 河野辰哉; 石川 嶺; 岡元寿樹; 山田光成; 河野匡志; 木下 淳; 米田頼晃; 永井知行; 朝隈 豊; 櫻井俊治; 渡邉智裕; 樫田博史; 工藤正俊

  第99回日本消化器内視鏡学会近畿支部例会  2017/11
• 乾癬の併存疾患〜炎症性腸疾患のサイトカイン反応〜  [Invited]

  渡邉 智裕

  第81回 日本皮膚科学会東京支部学術大会ランチョンセミナー  2017/11
• Bleeding after endoscopic resection for early gastric lesions in patients on antithrombotic therapy  [Not invited]

  Tomohiro Watanabe

  UEGW2017  2017/10
• 抗血栓薬内服での大腸ESDにおける検討  [Not invited]

  岡元寿樹; 米田頼晃; 樫田博史; 岡本彩那; 河野匡志; 永井知行; 櫻井俊治; 松井繁長; 渡邉智裕; 工藤正俊

  JDDW2017  2017/10
• 抗血栓薬服用に対する胃病変のESD/EMRの安全性の評価検討  [Not invited]

  永井知行; 松井繁長; 岡本彩那; 岡元寿樹; 河野匡志; 山田光成; 米田頼晃; 櫻井俊治; 渡邉智裕; 樫田博史; 工藤正俊

  JDDW2017  2017/10
• カテーテルアブレーション後に急性胃拡張を来した2例  [Not invited]

  久家 沙希那; 永井; 知行; 木下淳; 石川嶺; 岡元寿樹; 河野匡志; 山田光成; 米田頼晃; 櫻井俊治; 松井繁長; 渡邉智裕; 樫田博史; 工藤正俊

  第107回日本消化器病学会近畿支部例会  2017/09
• 炎症性サイトカインから見るクローン病治療  [Invited]

  渡邉 智裕

  ヒュミラインターネットライブセミナー  2017/09
• IBD治療における抗体療法を基礎・臨床の両面から考える  [Invited]

  渡邉 智裕

  第54回 日本消化器免疫学会イブニングセミナー  2017/09
• I型IFNとIL-33が慢性膵炎と自己免疫性膵炎の発症に果たす役割  [Not invited]

  渡邉智裕; 工藤正俊

  第48回日本膵臓学会大会  2017/07
• 膵炎の発症に関わる免疫反応  [Invited]

  渡邉 智裕

  第126回NIH金曜会セミナー  2017/07
• IL-33 plays a pathogenic role in chronic and autoimmune pancreatitis  [Invited]

  Tomohiro Watanabe

  International Congress of Mucosal Immunology  2017/07
• 大腸早期印環細胞癌の一例  [Not invited]

  高島耕大; 樫田博史; 朝隈 豊; 岡本彩那; 岡元寿樹; 河野匡志; 山田光成; 足立哲平; 米田頼晃; 櫻井俊治; 松井繁長; 渡邉智裕; 工藤正俊

  第98回日本消化器内視鏡学会近畿支部例会  2017/06
• ESDを施行した胃底腺型胃癌の検討  [Not invited]

  河野辰哉; 松井繁長; 岡本彩那; 岡元寿樹; 河野匡志; 足立哲平; 米田頼晃; 永井知行; 朝隈 豊; 櫻井俊治; 渡邉智裕; 樫田博史; 工藤正俊

  第98回日本消化器内視鏡学会近畿支部例会  2017/06
• Follow-up examination of the recurrence after endoscopic treatment of colorectal tumors  [Not invited]

  Komeda Y; Kashida H; Sakurai T; Asakuma Y; Nagai T; Matsui S; Watanabe T; Kudo M

  DDW 2017  2017/05
• 広範囲食道表在癌ESD後の狭窄に対する治療成績の検討  [Not invited]

  岡元寿樹; 松井繁長; 樫田博史; 河野匡志; 山田光成; 足立哲平; 永井知行; 朝隈 豊; 米田頼晃; 櫻井俊治; 渡邉智裕; 樫田博史; 工藤正俊

  第93回日本消化器内視鏡学会総会  2017/05
• IgG4関連疾患の病因と自然免疫  [Invited]

  渡邉 智裕

  第61回日本リウマチ学会総会  2017/04
• Plasmacytoid dendritic cells producing both IFN-alpha and IL-33 mediate chronic fibro-inflammatory responses in IgG4-related disease  [Not invited]

  Watanabe T; Kudo M

  3rd International Symposium on IgG4-RD & Fibrosis  2017/02
• 大腸腫瘍内視鏡治療後の局所再発に対するサーベイランスについて  [Not invited]

  米田頼晃; 樫田博史; 橋本有人; 岡元寿樹; 河野匡志; 山田光成; 足立哲平峯; 宏昌; 永井知行; 朝隈 豊; 櫻井俊治; 松井繁長; 渡邉智裕; 工藤正俊

  第１３回日本消化管学会総会学術集会  2017/02
• 腸管症型T細胞リンパ腫の一例  [Not invited]

  岡本彩那; 樫田博史; 米田頼晃; 岡元寿樹; 河野匡志; 足立哲平; 永井知行; 朝隈 豊; 櫻井俊治; 松井繁長; 渡邉智裕; 工藤正俊

  第106回日本消化器病学会近畿支部例会  2017/02
• 形質細胞様樹状細胞が産生するIL-33がIgG4関連疾患の病態に果たす役割  [Not invited]

  渡邉智裕; 工藤正俊

  24th JDDW  2016/11
• Single balloon enteroscopy in the elderly  [Not invited]

  Tomohiro Watanabe

  APDW2016  2016/11
• 透析患者の胃粘膜組織からリン酸ランタン沈着を証明できた一例  [Not invited]

  橋本有人; 松井繁長; 岡元寿樹; 河野匡志; 田中梨絵; 山田光成; 足立哲平; 峯宏昌; 永井知行; 米田頼晃; 朝隈豊; 櫻井俊治; 渡邉智裕; 樫田博史; 工藤正俊

  第105回日本消化器病学会近畿支部例会  2016/09
• 自己免疫性膵炎の発症に関わる腸内細菌叢の解析  [Not invited]

  渡邉智裕; 工藤正俊

  53回日本消化器免疫学会総会  2016/07
• 腸内細菌により活性化されるNOD1が膵炎の発症に果たす役割  [Not invited]

  渡邉智裕; 千葉勉

  23th JDDW  2015/10
• NOD2 Downregulates Colonic Inflammation Through IRF-4 Mediated Inhibition of K63 Directed Polyubiquitination of RICK and TRAF6 Molecules  [Invited]

  Tomohiro Watanabe

  DDW2015  2015
• 消化器の炎症に関わる自然免疫反応  [Invited]

  渡邉 智裕

  岡山大学第二内科 最新医学セミナー  2015
• Immune mechanisms of pancreatitis  [Invited]

  Tomohiro Watanabe

  1st Kyoto University UC San Diego Joint Symposium (Kyoto)  2015
• Sensing of commensal organisms by the intracellular sensor NOD1 mediates experimental pancreatitis  [Invited]

  Tomohiro Watanabe

  GI Research Academy (Tokyo)  2015
• Neutrophil extracellular trapsによるPlasmacytoid dendritic cellの活性化とIgG4関連疾患  [Not invited]

  新井康之; 渡邉智裕; 山下浩平; 髙折晃史; 千葉勉

  51回日本消化器免疫学会総会  2014/07
• Plasmacytoid dendritic cells activated by neutrophil extracellular traps contribute to the pathogenesis of IgG4-related disease  [Not invited]

  Arai Y; Yamashita K; Watanabe T; Takaori A; Chiba T

  2nd International Symposiumon IgG4-related disease & Associated Conditions  2014/02
• Sensing of commensal organisms by the intracellular sensor NOD1 mediates experimental pancreatitis  [Invited]

  Tomohiro Watanabe

  JSGE-APAGE Joint Conference Asian-Pacific Topic Conference  2014
• Activation of Toll-like receptors and NOD-like receptors in monocytes and basophils is involved in the immunopathogenesis of IgG4-related disease  [Invited]

  Tomohiro Watanabe

  2nd International Symposium on IgG4-RD & Associated Conditions  2014
• IgG4産生に関わる自然免疫反応の解明  [Invited]

  渡邉 智裕

  金沢医科大学血液免疫内科  2011
• Activation of Toll-like receptors and NOD-like receptors is involved in enhanced IgG4 responses in autoimmune pancreatitis  [Invited]

  Tomohiro Watanabe

  The International Pancreatic Research Forum  2011
• 急性膵炎の重症化に関わる自然免疫担当分子の同定とその分子機序の解明  [Not invited]

  辻喜久; 渡邉智裕; 千葉勉

  18th JDDW  2010/10
• 消化管粘膜に存在するIgG4陽性形質細胞のIgG4関連硬化性疾患における役割  [Not invited]

  渡邉智裕; 千葉勉

  96回日本消化器病学会総会  2010/04
• Infliximabが奏功した壊疽性膿皮症を合併したステロイド抵抗性潰瘍性大腸炎の一例  [Not invited]

  平松有紀子; 松浦稔; 宇座徳光; 塩川雅広; 渡邉智裕; 仲瀬裕志; 千葉勉

  日本消化器病学会近畿支部例会  2010
• NOD1を介するHelicobacter pylori感染免疫防御機構の解明  [Invited]

  渡邉 智裕

  16回日本ヘリコバクター学会学術集会  2010
• NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway  [Invited]

  Tomohiro Watanabe

  US-Japan GI & Liver Meeting in 21st Century (Tokyo)  2010
• NOD1を介する Helicobacter pylori感染免疫防御機構の解析  [Not invited]

  渡邉智裕; 千葉勉

  17th JDDW  2009/10
• 経口からの抗原投与により活性化される肝内CD11c+樹状細胞を用いた実験肝炎の治療  [Not invited]

  渡邉智裕; 若月芳雄; 千葉勉

  46回日本消化器免疫学会総会  2009/07
• CREST症候群合併原発性胆汁性肝硬変の免疫学的解析  [Not invited]

  福原学; 渡邉智裕; 上尾太郎; 依田広; 児玉裕三; 千葉勉

  日本消化器病学会近畿支部例会  2009
• Muramyl dipeptide activation of NOD2 negatively regulates TLR9-induced Th1 chemokine production  [Not invited]

  Tomohiro Watanabe

  14th International Congress of Mucosal Immunogy (Boston)  2009
• NOD1 mediates mucosal host defense utilizing a novel mechanims involving the IFN-stimulated gene factor 3 signaling pathway  [Not invited]

  Watanabe T; Chiba T

  Kyoto University Global COE International Symposium / Retreat 2009  2009
• Muramyl dipeptide activation of NOD2 inhibits multiple Toll-like receptors pathways vi ainduction of IRF4  [Not invited]

  Watanabe T; Asano N; Chiba T; Strober W

  38回日本免疫学会総会  2008/12
• NOD2の活性化を用いたクローン病の新たな免疫制御療法  [Not invited]

  渡邉智裕; 千葉勉

  45回日本消化器免疫学会総会  2008/07
• HCV Core抗原、NS3蛋白によるTLR2を介するCross Tolerance の誘導  [Not invited]

  鄭浩柄; 渡邉智裕; 工藤正俊

  95回日本消化器病学会総会  2008/05
• IgG4関連自己免疫性肝炎の臨床的特徴像及び治療反応性に関する検討  [Not invited]

  鄭浩柄; 渡邉智裕; 工藤正俊

  94回日本消化器病学会総会  2008/05
• ダブルバルーン小腸内視鏡にて診断・止血し得たHeyde症候群の小腸出血の一例  [Not invited]

  太田彩貴子; 森田周子; 岩本諭; 上野晢; 渡邉智裕; 仲瀬裕志

  日本消化器内視鏡学会近畿地方会  2008
• 自己免疫性膵炎に併発したIgG4陽性大腸ポリープの一例  [Not invited]

  川田有希子; 上野憲司; 後藤知之; 辻喜久; 依田広; 多田真輔; 八隅秀二郎; 渡邉智裕; 千葉勉

  日本消化器病学会近畿支部例会  2008
• Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis  [Invited]

  Watanabe T; Asano N; Murray P; Ozato K; Kitani A; Fuss IJ; Strober W

  DDW2008  2008
• Muramyl dipeptide activation of NOD2 protects mice from experimental colitis  [Invited]

  Tomohiro Watanabe

  US-Japan GI & Liver Meeting in 21st Century  2008
• NOD2の活性化による腸管免疫の制御機構  [Not invited]

  渡邉智裕; 千葉勉

  13th JDDW  2007/10
• A liver tolerates to a portal antigen by generating CD11c+ cells wich select regulatory Cd4+ T cells via apoptosis  [Not invited]

  Watanabe T; Yamori M; ChibaT; Wakatsuki Y

  12th International Congress of Mucosal Immunogy (Orlando)  2005/07
• CD4+CD25+ T cells regulate colonic localization of CD4 T cells reactive to a microbial antigen "  [Not invited]

  Tomohiro Watanabe

  12th International Congress of Mucosal Immunogy (Orlando)  2005
• NOD2 deficiency leads to enhanced peptidoglycan-induced IL-12 secretion  [Invited]

  Tomohiro Watanabe

  Experimental Biology  2005
• H. pylori感染胃における宿主免疫反応は胃粘膜上皮のリモデリングを制御する  [Not invited]

  家森正志; 吉田優; 渡邉智裕; 白井泰彦; 洪壽; 千葉勉; 北徹; 飯塚忠彦; 若月芳雄

  第34回日本免疫学会総会  2004
• 抗原特異的SCID細胞移入潰瘍性大腸炎モデルを用いたCD4+CD25+細胞の腸炎抑止機構の解明  [Not invited]

  若月芳雄; 渡邉智裕; 家森正志; 白井泰彦; 吉田優; 千葉勉

  第33回日本免疫学会総会  2003
• 感染胃粘膜上皮のリモデリングにおける宿主の免疫遺伝学的背景の果たす役割  [Not invited]

  家森正志; 吉田優; 白井泰彦; 渡邉智裕; 勝倉浩昭; 岸野小葉; 飯塚忠彦; 千葉勉; 北徹; 若月芳雄

  第33回日本免疫学会総会  2003
• Deficient Th1 response to a gastritogenic antigen suppresses cell turnover and augments apoptosis of gastric epithelium  [Not invited]

  Tomohiro Watanabe

  DDW2003  2003
• CD4+CD25+ regulatory T cells inhibit antigen-specific colitis by altering the localization of colitogenic CD4+ T cells  [Not invited]

  Tomohiro Watanabe

  DDW 2003  2003
• 肝内CD4T細胞の選択に関わる抗原提示細胞の機能解析  [Not invited]

  渡邉智裕; 勝倉浩昭; 家森正志; 白井泰彦; 千葉勉; 北徹; 若月芳雄

  第32回日本免疫学会総会  2002
• The chemokine response in the stomach is regulated by the host immune status  [Not invited]

  Tomohiro Watanabe

  DDW2002  2002
• Differential localization of colitogenic CD4 T cell subsets monospecific to a micro flora-associated antigen in a SCID-transfer model  [Not invited]

  Tomohiro Watanabe

  DDW2002  2002
• Development of immunoregulatory CD4+ T cells expressing CD95 ligand and secreting IL-4 in the liver  [Not invited]

  Tomohiro Watanabe

  DDW2002  2002
• 胃炎組織のリモデリングにおける宿主免疫応答の果たす役割  [Not invited]

  家森正志; 吉田優; 渡邉智裕; 白井泰彦; 勝倉浩昭; 飯塚忠彦; 千葉勉; 北徹; 若月芳雄

  第32回日本免疫学会総会  2002
• 抗原の経口投与による抗原特異的肝炎の発症抑制 (ワークショップ）  [Not invited]

  勝倉浩昭; 渡邉智裕; 家森正志; 白井泰彦; 北徹; 若月芳雄

  第32回日本免疫学会総会  2002
• 抗原非特異的なT細胞免疫応答によってもHeliobacter pylori菌量制御に影響する  [Not invited]

  白井泰彦; 若月芳雄; 吉田優; 渡邉智裕; 家森正志; 飯塚忠彦; 北徹

  第31回日本免疫学会総会  2001
• 経口免疫は胃粘膜におけるT細胞のサイトカイン産生能を制御する  [Not invited]

  家森正志; 若月芳雄; 吉田優; 渡邉智裕; 白井泰彦; 垣生園子; 千葉勉; 飯塚忠彦; 北徹

  第31回日本免疫学会総会  2001
• A role played by salivary glands in the induction and maintenance of oral immunization to Helicobacter pylori in the stomach  [Not invited]

  Tomohiro Watanabe

  DDW2001  2001
• Peripheral tolerance mediated by CD4 T cells expressing CD95 ligand and screting IL-4 in the liver  [Not invited]

  Wakatsuki Y; Watanabe T; Chiba T; katsukura H; Kita T

  11th International Congress of Mucosal Immunogy  2001
• SCID腸炎モデルにおける管腔内微生物性抗原特異的CD4T細胞の産生するサイトカインと組織病理の比較検討  [Not invited]

  若月芳雄; 吉田優; 渡邉智裕; 白井泰彦; 家森正志; 千葉勉; 北徹

  第31回日本免疫学会総会  2001
• 経口シグナルによる全身性免疫制御と肝臓の果たす役割について  [Not invited]

  渡邉智裕; 千葉勉; 若月芳雄

  9th JDDW  2001
• 抗原刺激とFas/FasL系を介して、肝内に誘導される免疫調節性T細胞の同定  [Not invited]

  渡邉智裕; 吉田優; 白井泰彦; 家森正志; 八木田秀雄; 千葉勉; 北徹; 若月芳雄

  第31回日本免疫学会総会 （東京）  2001
• 経口免疫応答の唾液腺による調節機構について  [Not invited]

  白井泰彦; 若月芳雄; 楠元貴司; 吉田優; 渡邉智裕; 家森正志; 中川淳; 飯塚忠彦; 北徹

  第30回日本免疫学会総会  2000
• 抗原特異的実験大腸炎における経口免疫寛容誘導療法の検討  [Not invited]

  吉田優; 若月芳雄; 渡邉智裕; 白井泰彦; 家森正志; 垣生園子; 千葉勉; 北徹

  第30回日本免疫学会総会  2000
• High dose-antigen feeding induces CD4 T cells with suppressor activity in the liver  [Not invited]

  Tomohiro Watanabe

  Immunology 2000  2000
• 大量の経口抗原投与後における肝内Tリンパ球の機能  [Not invited]

  渡邉智裕; 若月芳雄; 吉田優; 白井泰彦; 家森正志; 中川淳; 千葉勉; 北徹

  30回日本免疫学会総会  2000
• Involvement of intrahepatic lymphocyte in the induction of oral tolerance  [Not invited]

  Tomohiro Watanabe

  10th International Congress of Mucosal Immunology  1999
• 当院における Stage II, 単発 HCCに対する治療−LpTAE+PEIT の有用性について−  [Not invited]

  福永豊和; 上嶋一臣; 木本直哉; 渡邉智裕; 岡部純弘; 樫田博史; 平佐昌弘; 伊吹康良; 冨田周介; 織野彬雄; 藤堂彰男; 工藤正俊

  第2回肝動脈塞栓療法研究会  1997/11
• 小腸内視鏡生検により診断し得た空腸リンパ腫の一例  [Not invited]

  木本直哉; 上嶋一臣; 渡邉智裕; 福永豊和; 岡部純弘; 樫田博史; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第59回日本消化器内視鏡学会近畿地方会  1997/10
• 腹部リンパ節腫大を伴い診断に難渋した十二指腸狭窄の一例  [Not invited]

  上嶋一臣; 織野彬雄; 木本直哉; 渡邉智裕; 福永豊和; 岡部純弘; 樫田博史; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 藤堂彰男

  第59回日本消化器内視鏡学会近畿地方会  1997/09
• 内視鏡による大腸早期癌の診断について  [Not invited]

  樫田博史; 上嶋一臣; 木本直哉; 渡邉智裕; 福永豊和; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第59回日本消化器内視鏡学会近畿地方会  1997/09
• 胃十二指腸動脈瘤の上腸間膜静脈穿破による急性門脈圧亢進症の一例  [Not invited]

  鄭 浩柄; 工藤正俊; 冨田周介; 渡邉智裕; 福永豊和; 岡部純弘; 樫田博史; 藤堂彰男

  第4回日本門脈圧亢進症食道静脈瘤学会  1997/09
• 超音波パワードプラ法3次元表示による肝腫瘍血流の描出について  [Not invited]

  福永豊和; 冨田周介; 工藤正俊; 木本直哉; 上嶋一臣; 渡邉智裕; 岡部純弘; 樫田博史; 平佐昌弘; 伊吹康良; 織野彬雄; 藤堂彰男

  日本超音波医学会第14回関西地方会  1997/08
• 高分化型肝癌および過形成結節における結節内門脈血流の評価:パワ−および造影ドプラによる検討  [Not invited]

  山村真佐子; 工藤正俊; 冨田周介; 杤尾人司; 森本義人; 岡部純弘; 渡邉智裕; 福永豊和; 近藤雅彦; 藤堂彰男

  第33回日本肝癌研究会  1997/06
• 胃十二指腸動脈瘤の上腸間膜静脈穿破による急性門脈圧亢進症の一例  [Not invited]

  鄭浩柄; 工藤正俊; 冨田周介; 渡邉智裕; 近藤雅彦; 福永豊和; 岡部純弘; 樫田博史; 藤堂彰男; 杤尾人司

  第69回日本超音波医学会  1997/05
• CO2動注US angiographyによる嚢胞性膵腫瘍の臨床診断  [Not invited]

  岡部純弘; 渡邉智裕; 近藤雅彦; 福永豊和; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第28回日本膵臓学会大会  1997/04
• 感染経路を特定できた腸管出血性大腸菌O157腸炎の一例 −免疫磁気ビ−ズを用いたPCR法による当院の検査体制を通して−  [Not invited]

  平佐昌弘; 渡邉智裕; 冨田周介; 福永豊和; 近藤雅彦; 岡部純弘; 樫田博史; 伊吹康良; 工藤正俊; 織野彬雄; 藤堂彰男; 黒川 学

  第83回日本消化器病学会総会  1997/04
• 免疫磁気ビ−ズを用いたPCR 法による病原性大腸菌O157の便からの検出  [Not invited]

  渡邉智裕; 冨田周介; 黒川 学; 近藤雅彦; 福永豊和; 岡部純弘; 樫田博史; 平佐昌弘; 伊吹康良; 工藤正俊; 織野彬雄; 藤堂彰男

  第83回日本消化器病学会総会  1997/04
• 胃粘膜傷害の指標としてのIL-8 mRNA量測定  [Not invited]

  黒川 学; 冨田周介; 渡邉智裕; 近藤雅彦; 福永豊和; 平佐昌弘; 伊吹康良; 工藤正俊; 織野彬雄; 藤堂彰男

  第83回日本消化器病学会総会  1997/04
• B-RTOにて軽快したportosystemic shuntによる肝性脳症の1例  [Not invited]

  渡邉智裕; 樫田博史; 近藤雅彦; 福永豊和; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第7回B-RTO勉強会  1997/04
• 腹部超音波にて発見されたS状結腸間膜腫瘍  [Not invited]

  山村真佐子; 近藤雅彦; 岩崎信広; 田村周二; 森本義人; 渡邊智裕; 福永豊和; 岡部純弘; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  日本超音波医学会第13回関西地方会  1997/02
• MRCPが有用であった膵胆管合流異常の１例  [Not invited]

  岡部純弘; 渡邉智裕; 近藤雅彦; 福永豊和; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男; 臼杵則朗

  第66回日本消化器病学会近畿支部例会  1997/02
• 集学的治療が有用であった肝門部腫瘍の１症例  [Not invited]

  福永豊和; 岡部純弘; 渡邉智裕; 近藤雅彦; 樫田博史; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第66回日本消化器病学会近畿支部例会  1997/02
• アメーバ性肝膿瘍にデヒドロエメチンが奏功した１例  [Not invited]

  桐谷景一; 渡邉智裕; 近藤雅彦; 福永豊和; 岡部純弘; 樫田博史; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第66回日本消化器病学会近畿支部例会  1997/02
• 特異な肝シンチ像を呈した亜急性肝炎の１剖検例  [Not invited]

  渡邉智裕; 近藤雅彦; 福永豊和; 岡部純弘; 樫田博史; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第66回日本消化器病学会近畿支部例会  1997/02
• 麻疹の皮膚病変と同時に、消化器症状と特異的な胃病変をみとめた１症例  [Not invited]

  平佐昌弘; 工藤正俊; 渡邉智裕; 福永豊和; 近藤雅彦; 岡部純弘; 樫田博史; 伊吹康良; 冨田周介; 織野彬雄; 藤堂彰男

  第58回日本消化器内視鏡学会近畿地方会  1997/02
• 選択的IgA欠損症に見られた大腸ポリーシスの一例  [Not invited]

  樫田博史; 渡邉智裕; 近藤雅彦; 福永豊和; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第58回日本消化器内視鏡学会近畿地方会  1997/02
• 胃十二指腸動脈瘤の上腸間膜静脈穿破による急性門脈圧亢進症の一例  [Not invited]

  鄭 浩柄; 工藤正俊; 冨田周介; 渡邉智裕; 近藤雅彦; 福永豊和; 岡部純弘; 藤堂彰男; 臼杵則朗; 杤尾人司

  第3回肝血流動態イメ−ジ研究会  1997/02
• 肝血管筋脂肪腫の3例  [Not invited]

  福永豊和; 岡部純弘; 工藤正俊; 渡邉智裕; 近藤雅彦; 樫田博史; 平佐昌弘; 伊吹康良; 冨田周介; 藤堂彰男

  第68回日本超音波医学会  1996/11
• 肝内結節性病変の動脈性血流動態の評価−肝動脈CTとUS angiographyの比較検討−  [Not invited]

  近藤雅彦; 岡部純弘; 工藤正俊; 渡邉智裕; 福永豊和; 冨田周介

  第68回日本超音波医学会  1996/11
• 嚢胞性膵腫瘍におけるUS angiograpyの意義  [Not invited]

  岡部純弘; 冨田周介; 工藤正俊; 渡邉智裕; 福永豊和; 近藤雅彦; 田村周二; 岩崎信広; 濱田充生; 蓑輪和士; 杤尾人司; 曽我登志子; 森本義人; 藤堂彰男

  第1回日本腹部造影エコ−・ドプラ診断研究会  1996/10
• 肝内結節性病変の動脈性血流動態の評価−肝動脈CTとUS angiographyの比較検討−  [Not invited]

  近藤雅彦; 岡部純弘; 工藤正俊; 渡邉智裕; 福永豊和; 冨田周介

  第1回日本腹部造影エコ−・ドプラ診断研究会  1996/10
• 当院で経験した結腸脂肪腫の5例  [Not invited]

  永豊和; 渡邉智裕; 近藤雅彦; 寺井裕二; 山本健二; 岡部純弘; 樫田博史; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第57回日本消化器内視鏡学会近畿地方会  1996/10
• 選択的膵管造影および内視鏡的膵生検が有用であった粘液産生膵癌の1例  [Not invited]

  岡部純弘; 渡邉智裕; 近藤雅彦; 福永豊和; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第57回日本消化器内視鏡学会近畿地方会  1996/10
• 粘液産生膵腫瘍の臨床診断−体腔内超音波検査法を中心として−  [Not invited]

  岡部純弘; 渡邉智裕; 福永豊和; 近藤雅彦; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第45回近畿膵疾患談話会,  1996/09
• 膵石症に対する非観血的治療法の検討  [Not invited]

  岡部純弘; 伊吹康良; 織野彬雄; 渡邉智裕; 近藤雅彦; 福永豊和; 平佐昌弘; 工藤正俊; 冨田周介; 藤堂彰男

  第38回 日本消化器病学会  1996/09
• 胃悪性リンパ腫とH.Pylori感染（特にlow-grade MALTリンパ腫との関連について)  [Not invited]

  平佐昌弘; 冨田周介; 渡邉智裕; 福永豊和; 近藤雅彦; 寺井裕二; 山本健二; 岡部純弘; 樫田博史; 伊吹康良; 工藤正俊; 織野彬雄; 藤堂彰男

  第38回 日本消化器病学会  1996/09
• PCR法を用いた便によるHelicobacter pylori感染の診断  [Not invited]

  渡邉智裕; 冨田周介; 近藤雅彦; 福永豊和; 寺井裕二; 山本健二; 岡部純弘; 樫田博史; 平佐昌弘; 伊吹康良; 工藤正俊; 織野彬雄; 藤堂彰男

  第38回 日本消化器病学会  1996/09
• 体腔内超音波検査法による粘液産生膵腫瘍の臨床診断  [Not invited]

  岡部純弘; 渡邉智裕; 福永豊和; 近藤雅彦; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第52回日本消化器内視鏡学会総会  1996/09
• 出血性胃潰瘍とヘリコバクタ−ピロリ感染およびCagA遺伝子との関連  [Not invited]

  冨田周介; 渡邉智裕; 福永豊和; 近藤雅彦; 樫田博史; 平佐昌弘; 伊吹康良; 工藤正俊; 織野彬雄; 藤堂彰男

  第52回日本消化器内視鏡学会総会  1996/09
• 潰瘍性大腸炎に合併した下行結腸癌の1例  [Not invited]

  寺井裕二; 渡邊智裕; 福永豊和; 近藤雅彦; 山本健二; 岡部純弘; 樫田博史; 平佐昌弘; 伊吹康良; 工藤正俊; 冨田周介; 織野彬雄; 藤堂彰男

  第65回 日本消化器病学会近畿支部例会  1996/09
• 大動脈炎症候群、脳梗塞を合併した潰瘍性大腸炎の1例  [Not invited]

  櫻井俊治; 冨田周介; 渡邉智裕; 福永豊和; 近藤雅彦; 寺井裕二; 山本健二; 樫田博史; 岡部純弘; 平佐昌弘; 伊吹康良; 工藤正俊; 織野彬雄; 藤堂彰男

  第65回 日本消化器病学会近畿支部例会  1996/06
• 62.肋軟骨肉腫の1例  [Not invited]

  渡辺 智裕; 羽白 高; 渡辺 勇夫; 松本 久子; 西村 裕志; 長谷川 幹; 岡崎 美樹; 片上 信之; 石原 享介; 梅田 文一; 西内 素; 庄村 東洋; 内田 博也

  第62回日本肺癌学会関西支部会  1995/10
• 心電図上, 前下行枝領域の急性心筋梗塞に類似した心筋炎の1例  [Not invited]

  渡辺 智裕; 吉川 純一; 吉田 清; 赤阪 隆史; 赤土 正洋; 穂積 健之; 高木 力; 本多 康浩; 大倉 宏之; 山室 淳

  日本循環器学会第78回近畿地方会  1995/06

MISC

• 非代償性肝硬変による直腸静脈瘤出血に対して内視鏡的組織接着剤注入術を施行した1例

  加藤 弘樹; 松井 繁長; 田北 雅弘; 上中 大地; 今村 瑞貴; 原 茜; 野村 健司; 瀬海 郁衣; 高田 隆太郎; 河野 匡志; 正木 翔; 永井 知行; 本庶 元; 米田 頼晃; 上嶋 一臣; 渡邉 智裕; 西田 直生志; 辻 直子; 樫田 博史; 工藤 正俊  日本消化器内視鏡学会近畿支部例会プログラム・抄録集  108回-  89  -89  2022/06
• インフリキシマブが有効であった腸型Bechet病のサイトカイン反応の解析

  吉川馨介; 渡邉智裕; 瀬海郁江; 高田隆太郎; 原茜; 栗本真之; 益田康弘; 大塚康夫; 吉川友恵; 正木翔; 鎌田研; 三長孝輔; 米田頼晃; 筑後孝章; 工藤正俊  日本消化器病学会近畿支部例会プログラム・抄録集  115th-  2021
• 潰瘍性大腸炎に合併したcolitis associated cancerおよびdyspasia症例の特徴

  米田頼晃; 櫻井俊治; 樫田博史; 正木翔; 河野匡志; 永井知行; 本庶元; 松井繁長; 渡邉智裕; 辻直子; 工藤正俊  大腸癌研究会プログラム・抄録集  94th-  2021
• Initial lenvatinib therapy with no prior TACE in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and Child-Pugh A liver function: A proof-of-concept study

  Masatoshi Kudo; Kazuomi Ueshima; Stephen Lam Chan; Tomoko Aoki; Satoru Hagiwara; Yasunori Minami; Hiroshi Ida; Mamoru Takenaka; Tomohiro Watanabe; Masahiro Morita; Chikara Ogawa; Yoshiyuki Wada; Masafumi Ikeda; Hiroshi Ishii; Namiki Izumi; Atsushi Hiraoka; Hiroshi Aikata; Naoshi Nishida  JOURNAL OF CLINICAL ONCOLOGY  38-  (4)  2020/02
• 膵癌早期診断のための3D CT解析による膵実質萎縮の検討

  山雄健太郎; 竹中完; 石川嶺; 沼本勲; 鶴崎正勝; 渡邉智裕; 工藤正俊  日本消化器病学会雑誌(Web)  117-  2020
• 小腸内視鏡診療ガイドラインでのカプセル内視鏡検査の運用の実際

  米田頼晃; 樫田博史; 櫻井俊治; 松村まり子; 高島耕太; 正木翔; 河野匡志; 山田光成; 本庶元; 永井知行; 松井繁長; 辻直子; 渡邉智裕; 工藤正俊  Gastroenterological Endoscopy (Web)  62-  (Supplement2)  2020
• 拡大観察から見たPPI関連胃底腺ポリープの特徴

  友岡瑞貴; 辻直子; 高島耕太; 正木翔; 河野匡志; 永井知之; 米田頼晃; 本庶元; 櫻井俊治; 松井繁長; 渡邉智裕; 樫田博史; 工藤正俊  Gastroenterological Endoscopy (Web)  62-  (Supplement2)  2020
• 当院での直腸NENの治療成績からみた治療方法の検討

  永井知行; 樫田博史; 益田康弘; 友岡瑞貴; 高島耕太; 高田隆太郎; 正木翔; 河野匡志; 米田頼晃; 本庶元; 櫻井俊治; 松井繁長; 渡邉智裕; 辻直子; 工藤正俊  日本大腸肛門病学会雑誌(Web)  73-  (9)  2020
• PPI長期投与の有無からみた胃底腺ポリープの臨床病理学的検討

  松村 まり子; 辻 直子; 梅原 康湖; 正木 翔; 岡元 寿樹; 山田 光成; 永井 知行; 米田 頼晃; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 樫田 博史; 工藤 正俊  日本消化器病学会雑誌  116-  (臨増大会)  A755  -A755  2019/11
• 血清IFN-α/IL-33が治療効果判定に有用と考えられた自己免疫性膵炎/IgG4関連疾患の1例

  原 茜; 三長 孝輔; 岡本 彩那; 石川 嶺; 山崎 友裕; 中井 敦史; 大本 俊介; 鎌田 研; 山雄 健太郎; 竹中 完; 渡邉 智裕; 安川 覚; 工藤 正俊  日本消化器病学会近畿支部例会プログラム・抄録集  111回-  78  -78  2019/10
• DLBCLに発症したリンパ管拡張症に対してステロイド投与、食事療法が奏効した1症例

  大塚 康生; 米田 頼晃; 正木 翔; 筑後 孝章; 吉川 馨介; 高島 耕太; 橋本 有人; 山田 光成; 本庶 元; 永井 知行; 櫻井 俊治; 松井 繁長; 渡邉 智裕; 辻 直子; 樫田 博史; 工藤 正俊  日本消化器病学会近畿支部例会プログラム・抄録集  111回-  91  -91  2019/10
• 血清IFN-α/IL-33が治療効果判定に有用と考えられた自己免疫性膵炎/IgG4関連疾患の1例

  原 茜; 三長 孝輔; 岡本 彩那; 石川 嶺; 山崎 友裕; 中井 敦史; 大本 俊介; 鎌田 研; 山雄 健太郎; 竹中 完; 渡邉 智裕; 安川 覚; 工藤 正俊  日本消化器病学会近畿支部例会プログラム・抄録集  111回-  78  -78  2019/10
• 微小膵癌診断の新たなアプローチ法―3D CTによる膵実質萎縮評価から見えてきたもの―

  山雄健太郎; 竹中完; 吉川智恵; 石川嶺; 岡本彩那; 中井敦; 山崎友宏; 大本俊介; 鎌田研; 三長孝輔; 松本逸平; 竹山宜典; 鶴崎正勝; 渡邉智裕; 工藤正俊  膵臓(Web)  34-  (3)  A33‐A34(J‐STAGE)  2019/06
• 膵癌早期診断の最前線 微小膵癌診断の新たなアプローチ法 3D CTによる膵実質萎縮評価から見えてきたもの

  山雄 健太郎; 竹中 完; 吉川 智恵; 石川 嶺; 岡本 彩那; 中井 敦; 山崎 友宏; 大本 俊介; 鎌田 研; 三長 孝輔; 松本 逸平; 竹山 宜典; 鶴崎 正勝; 渡邉 智裕; 工藤 正俊  膵臓  34-  (3)  A33  -A34  2019/06
• 好酸球性食道炎の臨床的特徴の検討

  正木 翔; 松井 繁長; 工藤 正俊; 大塚 康生; 松村 まり子; 高島 耕太; 河野 辰哉; 岡元 寿樹; 河野 匡志; 山田 光成; 永井 知行; 米田 頼晃; 櫻井 俊治; 渡邉 智裕; 辻 直子; 樫田 博史  Gastroenterological Endoscopy  61-  (Suppl.1)  963  -963  2019/05
• 消化器領域における腸内細菌研究と臨床応用 腸内細菌叢からみた膵酵素補充療法の慢性膵炎に対する炎症抑制機序の解明

  三長 孝輔; 渡邉 智裕; 工藤 正俊  日本消化器病学会雑誌  116-  (臨増総会)  A163  -A163  2019/03
• VALUE OF ADDITIONAL ENDOSCOPIC ULTRASONOGRAPHY FOR SURVEILLANCE AFTER SURGICAL REMOVAL OF INTRADUCTAL PAPILLARY MUCINOUS NEOPLASMS

  鎌田研; 竹中完; 三長孝輔; 大本俊介; 宮田剛; 山雄健太郎; 今井元; 中井敦史; 田中秀和; 千葉康敬; 渡邉智裕; 櫻井俊治; 西田直生志; 筑後考章; 松本逸平; 竹山宜典; 北野雅之; 工藤正俊  Gastroenterological Endoscopy (Web)  61-  (4)  2019
• 好酸球性食道炎の臨床的特徴の検討

  正木翔; 松井繁長; 工藤正俊; 大塚康生; 松村まり子; 高島耕太; 河野辰哉; 岡元寿樹; 河野匡志; 山田光成; 永井知行; 米田頼晃; 櫻井俊治; 渡邉智裕; 辻直子; 樫田博史  Gastroenterological Endoscopy (Web)  61-  (Supplement1)  2019
• 報告 自己免疫性膵炎臨床診断基準2018 自己免疫性膵炎臨床診断基準2011改訂版

  竹山 宜典; 岡崎 和一; 新倉 則和; 池浦 司; 糸井 隆夫; 伊藤 鉄英; 乾 和郎; 井上 大; 入江 裕之; 入澤 篤志; 岩崎 栄典; 植木 敏晴; 上原 剛; 内田 一茂; 大原 弘隆; 神澤 輝実; 川 茂幸; 菅野 敦; 窪田 賢輔; 洪 繁; 児玉 裕三; 阪上 順一; 清水 京子; 全 陽; 多田 稔; 中沢 貴宏; 西野 隆義; 能登原 憲司; 浜野 英明; 平野 賢二; 廣岡 芳樹; 正宗 淳; 増田 充弘; 水野 伸匡; 吉田 仁; 井戸 章雄; 下瀬川 徹; 妹尾 浩; 滝川 一; 千葉 勉; 仲瀬 裕志; 伊佐山 浩通; 伊藤 哲也; 梅村 武司; 太田 正穂; 鎌田 研; 河邉 顕; 菅野 敦; 木村 理; 栗山 勝利; 小山 貴; 塩川 雅広; 田妻 進; 田中 篤; 玉木 長良; 露口 利夫; 内藤 格; 仲野 俊成; 濱田 晋; 藤永 康成; 村木 崇; 本谷 雅代; 渡邉 貴之; 渡邉 智裕; 日本膵臓学会; 厚生労働科学研究費補助金; 難治性疾患等政策研究事業; IgG; 関連疾患の診断基準並びに治療指針の確立を目指す研究; 班; 自己免疫性膵炎臨床診断基; 改訂合同委員会; 日本膵臓学会膵炎調査研究委員会  膵臓  33-  (6)  902  -913  2018/12
• パンクレリパーゼ摂取による腸管内および便の腸内細菌叢に対する影響の検討

  永井知行; 櫻井俊治; 工藤正俊; 西山拓輝; 岡崎能久; 東慶直; 渡邉智裕; 五斗進; 緒方博之  日本消化器病学会雑誌(Web)  115-  2018
• 臓器間ネットワークからみた肝胆膵の恒常性とその破綻 臓器間ネットワークの破綻による疾患 膵炎における腸管免疫機構破綻と重症化機序

  渡邉智裕; 三長孝輔; 鎌田研; 山雄健太郎; 竹中完; 工藤正俊  肝胆膵  75-  (5)  991‐996  2017/11
• 抗血栓薬服用者に対する胃病変のESD/EMRの安全性評価検討

  永井 知行; 松井 繁長; 岡本 彩那; 岡元 寿樹; 河野 匡志; 山田 光成; 米田 頼晃; 櫻井 俊治; 渡邉 智裕; 樫田 博史; 工藤 正俊  Gastroenterological Endoscopy  59-  (Suppl.2)  2130  -2130  2017/09
• 抗血栓薬服用者に対する胃病変のESD/EMRの安全性評価検討

  永井 知行; 松井 繁長; 岡本 彩那; 岡元 寿樹; 河野 匡志; 山田 光成; 米田 頼晃; 櫻井 俊治; 渡邉 智裕; 樫田 博史; 工藤 正俊  Gastroenterological Endoscopy  59-  (Suppl.2)  2130  -2130  2017/09
• 抗血栓薬内服での大腸ESDにおける検討

  岡元 寿樹; 米田 頼晃; 樫田 博史; 岡本 彩菜; 河野 匡志; 永井 知行; 櫻井 俊治; 松井 繁長; 渡邊 智裕; 工藤 正俊  日本消化器病学会雑誌  114-  (臨増大会)  A818  -A818  2017/09
• ケモカインCXCL16は壊死性膵炎の形成に重要である

  佐久間洋二朗; 児玉裕三; 宇座徳光; 辻喜久; 辻喜久; 塩川雅広; 渡邉智裕; 渡邉智裕; 仲瀬裕志; 仲瀬裕志; 千葉勉; 千葉勉; 妹尾浩  すい臓  32-  (3)  339  -339  2017/05
• ソナゾイド造影EUSを用いた膵癌肝転移検出に関する検討

  三長 孝輔; 竹中 完; 北野 雅之; 中井 敦史; 大本 俊介; 宮田 剛; 鎌田 研; 山雄 健太郎; 今井 元; 渡邉 智裕; 工藤 正俊  膵臓  32-  (3)  552  -552  2017/05
• 大腸腫瘍内視鏡治療後の局所再発に対するサーベイランスについて

  米田頼晃; 樫田博史; 橋本有人; 岡元寿樹; 河野匡志; 山田光成; 足立哲平; 峯宏昌; 永井知行; 朝隈豊; 櫻井俊治; 松井繁長; 渡邉智裕; 工藤正俊  日本消化管学会総会学術集会プログラム・抄録集  13th-  178  2017
• Single balloon enteroscopy in the elderly

  Mitsunari Yamada; Hiroshi Kashida; Yoriaki Komeda; Hiromasa Mine; Tomoyuki Nagai; Yutaka Asakuma; Toshiharu Sakurai; Shigenaga Matui; Tomohiro Watanabe; Masatoshi Kudo  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY  31-  132  -132  2016/11
• Chemokine CXCL16 Plays a Critical Role in the Development of Severe Acute Pancreatitis

  Yojiro Sakuma; Yuzo Kodama; Tomoaki Matsumori; Teruko Tomono; Nobuyuki Kakiuchi; Atsushi Mima; Yuki Yamauchi; Yoshihiro Nishikawa; Motoyuki Tsuda; Tatsuki Ueda; Katsutoshi Kuriyama; Takahisa Maruno; Yuji Ota; Masahiro Shiokawa; Yoshihisa Tsuji; Norimitsu Uza; Tomohiro Watanabe; Hiroshi Nakase; Hiroshi Seno; Tsutomu Chiba  GASTROENTEROLOGY  150-  (4)  S327  -S327  2016/04
• Attenuation of proteolysis-mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers (vol 125, pg 2029, 2009)

  K. Ikeuchi; H. Marusawa; M. Fujiwara; Y. Matsumoto; Y. Endo; T. Watanabe; A. Iwai; Y. Sakai; R. Takahashi; T. Chiba  INTERNATIONAL JOURNAL OF CANCER  138-  (1)  E3  -E3  2016/01
• microbiome(腸内細菌)と肝胆膵領域の新世紀 膵臓とmicrobiome 良性膵疾患と腸内細菌

  森田敏広; 児玉裕三; 大田悠司; 辻喜久; 渡邉智裕  肝胆膵  70-  (6)  2015
• Activation of Toll-like Receptors and NOD-like Receptors Is Involved in Enhanced IgG4 Responses in Autoimmune Pancreatitis

  渡邉 智裕; 山下 浩平; 藤川 砂織  細胞科学研究財団助成研究報告集  23-  47  -58  2012
• Somatic Mutations in PIK3CA and Activation of AKT in Intraductal Tubulopapillary Neoplasms of the Pancreas

  Hiroshi Yamaguchi; Yuko Kuboki; Takashi Hatori; Masakazu Yamamoto; Keiko Shiratori; Shunji Kawamura; Makio Kobayashi; Michio Shimizu; Shinichi Ban; Isamu Koyama; Morihiro Higashi; Nobuhiro Shin; Kazuyuki Ishida; Takanori Morikawa; Fuyuhiko Motoi; Michiaki Unno; Atsushi Kanno; Kennichi Satoh; Tooru Shimosegawa; Hideki Orikasa; Tomoo Watanabe; Kazuhiko Nishimura; Youji Harada; Toru Furukawa  AMERICAN JOURNAL OF SURGICAL PATHOLOGY  35-  (12)  1812  -1817  2011/12
• CD4 + CD25 + regulatory T cells inhibit antigen-specific colitis by altering the localization of colitogenic CD4 + T cells

  T Watanabe; M Yoshida; T Chiba; Y Wakatsuki  GASTROENTEROLOGY  124-  (4)  A491  -A491  2003/04
• Deficient Th1 response to a gastritogenic antigen suppresses cell turnover and augments apoptosis of gastric epithelium

  Y Wakatsuki; M Yamori; T Watanabe; Y Shirai; T Kita; T Chiba  GASTROENTEROLOGY  124-  (4)  A402  -A402  2003/04
• Rectal immunization with antigen-containing microspheres induces stronger Th2 responses than oral immunization: A new method for vaccination.

  M Matsuura; K Okazaki; H Nakase; Y Tabata; M Ohana; T Nishi; T Watanabe; H Tamaki; K Uchida; T Chiba  GASTROENTEROLOGY  122-  (4)  A152  -A152  2002/04
• The chemokine response in the stomach is regulated by the host immune status

  M Yamori; T Watanabe; Y Shirai; H Katsukura; T Iizuka; T Chiba; T Kita; Y Wakatsuki  GASTROENTEROLOGY  122-  (4)  A272  -A273  2002/04
• Differential localization of colitogenic CD4 T cell subsets monospecific to a micro flora-associated antigen in a SCID-transfer model

  Y Wakatsuki; M Yoshida; Y Shirai; T Watanabe; M Yamori; T Kita; T Chiba  GASTROENTEROLOGY  122-  (4)  A85  -A85  2002/04
• Development of immunoregulatory, CD4+T cells expressing CD95 ligand and secreting IL-4 in the liver

  T Watanabe; H Katsukura; M Yoshida; Y Shirai; M Yamori; T Kita; T Chiba; Y Wakatsuki  GASTROENTEROLOGY  122-  (4)  A152  -A152  2002/04
• 抗原刺激とFas/FasL系を介して,肝内に誘導される免疫調節性T細胞の同定

  渡辺 智裕; 吉田 優; 白井 泰彦; 家森 正志; 八木田 秀雄; 千葉 勉; 北 徹; 若月 芳雄  日本免疫学会総会・学術集会記録  31-  248  -248  2001/12
• A cellular immune response non-specific to H-pylori is still effective to prevent colonization in the stomach

  Y Wakatsuki; Y Shirai; M Yamori; M Yoshida; T Watanabe  GUT  49-  A23  -A23  2001/09
• Helicobacter pylori infection and acid secretion in patients with duodenal ulcer in Japan

  T Chiba; T Watanabe; T Ito  GUT  48-  (6)  871  -872  2001/06
• A role played by salivary glands in the induction and maintenance of oral immunization to Helicobacter pylori in the stomach

  Y Shirai; T Kusumoto; M Yamori; T Watanabe; A Nakagawa; T Iizuka; T Kita; Y Wakatsuki  GASTROENTEROLOGY  120-  (5)  A321  -A321  2001/04
• A novel colitis model induced by immune responses to an antigen expressed in luminal bacteria

  M Yoshida; T Watanabe; M Yamori; Y Shirai; A Nakagawa; T Kita; T Chiba; Y Wakatsuki  GASTROENTEROLOGY  120-  (5)  A519  -A519  2001/04
• A new phenotype of regulatory T cells is induced in the liver by high dose antigen feeding.

  T Watanabe; Y Wakatsuki; M Yoshida; T Itoh; Y Shirai; M Yamori; H Yagita; T Chiba; T Kita  GASTROENTEROLOGY  120-  (5)  A320  -A321  2001/04
• Correlation of primary and secondary immune responses in the stomach to the gastric pathology

  M Yamori; M Yoshida; T Watanabe; Y Shirai; A Nakagawa; T Chiba; T Kita; Y Wakatsuki  GASTROENTEROLOGY  120-  (5)  A320  -A320  2001/04
• High dose-antigen feeding induces CD4 T cells with suppressor activity in the liver.

  T Watanabe; Y Wakatsuki; M Yoshida; T Itoh; T Usui; T Chiba; T Kita  FASEB JOURNAL  14-  (6)  A1199  -A1199  2000/04
• 大量の経口抗原投与における肝内Tリンパ球の機能

  WATANABE TOMOHIRO; WAKATSUKI YOSHIO; YOSHIDA MASARU; ITO TOSHIYUKI; USUI TAKASHI; SHIRAI YASUHIKO; CHIBA TSUTOMU; KITA TOORU  消化器と免疫  (37)  51  -53  2000
• The load of Helicobacter pylori and the titer of antibodies do not correlate to the gastritis in lymphokine knockout mice.

  T Watanabe; M Yoshida; T Itoh; Y Shirai; T Chiba; T Kita; Y Wakatsuki  GASTROENTEROLOGY  116-  (4)  A350  -A350  1999/04
• Cytotoxicity of autoantibodies to gastric mucosa is augmented by Th1 cytokines in Helicobacterpylori-infected Balb c mice.

  T Itoh; M Yoshida; T Watanabe; T Usui; T Chiba; T Kita; Y Wakatsuki  GASTROENTEROLOGY  116-  (4)  A742  -A742  1999/04
• Antigen priming in the stomach lead to Th1 type cytokine response despite the absence of H-pylori

  M Yoshida; T Watanabe; T Itoh; T Shirai; T Chiba; T Kita; Y Wakatsuki  GASTROENTEROLOGY  116-  (4)  A849  -A849  1999/04
• A novel experimental colitis model induced by antigen specific T cells

  M Yoshida; T Watanabe; Y Wakatsuki  FASEB JOURNAL  13-  (5)  A666  -A666  1999/03
• Small depressed lesions of the colorectum

  H Kashida; N Kimoto; T Watanabe; T Fukunaga; M Hirasa; K Ibuki; S Tomita; A Orino; A Todo  GASTROINTESTINAL ENDOSCOPY  47-  (4)  AB98  -AB98  1998/04
• Association Between Focal Spared Area at the Gallbladder Bed in the Fatty Liver and Intrahepatic Efferent Blood Flow From the Gallbladder Wall : Evaluation With Color Doppler Imaging

  TOCHIO Hitoshi; OKABE Yoshihiro; TOMITA Syusuke; KUDO Masatoshi; KASHIDA Hiroshi; IWASAKI Nobuhiro; MINOWA Kazushi; TAMURA Syuji; SOGA Toshiko; MORIMOTO Yoshito; WATANABE Tomohiro; FUKUNAGA Toyokazu; HIRASA Masahiro; IBUKI Yasuyoshi; ORINO Akio; TODO Akio  Journal of medical ultrasonics = 超音波医学  24-  (10)  43  -53  1997/10
• Rerationships between Gallbladder Draining Vessel and Focal Spared Area with Fatty Liver : Evaluation by Color Doppler Imaging

  TOCHIO H.; MORIMOTO Y.; TOMITA S.; WATANABE Tomohiro; FUKUNAGA Toyokazu; OKABE Yoshihiro; KASHIDA Hiroshi; HIRASA Masahiro; IBUKI Yasuyosi; ORINO Akio  Journal of medical ultrasonics = 超音波医学  24-  (9)  243  -243  1997/09
• Color Doppler Diagnosis of Small Hepatic Nodules Associated With Chronic Liver Diseases : Meaning of Afferent Continuous Waveform Signals

  TOCHIO Hitoshi; TOMITA Syusuke; KUDO Masatoshi; OKABE Yoshihiro; KASHIDA Hiroshi; IWASAKI Nobuhiro; MINOWA Kazushi; SOGA Toshiko; TAMURA Syuji; MORIMOTO Yoshito; WATANABE Tomohiro; FUKUNAGA Toyokazu; HIRASA Masahiro; IBUKI Yasuyosi; ORINO Akio; TODO Akio  Journal of medical ultrasonics = 超音波医学  24-  (8)  21  -29  1997/08
• Hyperplastic Nodule of the Liver with Aberrant Right Gastric Vein Drainage : Observation by Color Doppler Imaging

  TOCHIO Hitoshi; OKABE Yoshihiro; TOMITA Syusuke; ORINO Akio; IWASAKI Nobuhiro; MINOWA Kazushi; SOGA Toshiko; TAMURA Syuji; MORIMOTO Yoshito; WATANABE Tomohiro; FUKUNAGA Toyokazu; KONDO Masahiko; KASHIDA Hiroshi; HIRASA Masahiro; IBUKI Yasuyoshi; KUDO Masatoshi; TODO Akio  Journal of medical ultrasonics = 超音波医学  24-  (5)  37  -44  1997/05
• A Case of Acute Portal Hypertension Following Rapidly Progressed Communication between Gastroduodenal Aneurysm and Superior Mesenteric Vein

  TEI H.; KUDO M.; TOMITA S.; WATANABE T.; KONDO M.; FUKUNAGA T.; OKABE Y.; KASHIDA H.; TODO A.; TOCHIO H.  Journal of medical ultrasonics = 超音波医学  24-  (3)  443  -443  1997/03
• US Image in Acute enterocolitis by Enterohemorrhagic Escherichia Coli : O-157

  MINOWA K.; IWASAKI N.; TOCHIO H.; TAMURA S.; SOGA T.; MORIMOTO Y.; WATANABE T.; HIRASA M.; KUDO M.; TOMITA S.  Journal of medical ultrasonics = 超音波医学  24-  (3)  372  -372  1997/03
• Diagnosis of Portal Blood Supplying Nodules Associated with Liver Cirrhosis by Power Doppler Imaging

  KUDO M.; TOMITA S.; TOCHIO H.; MINOWA K.; MORIMOTO Y.; WATANABE T.; KONDO M.; FUKUNAGA T.; OKABE Y.; TODO A.  Journal of medical ultrasonics = 超音波医学  24-  (3)  331  -331  1997/03
• Early diagnosis of Escherichia coli O157 infection.

  渡辺智裕; 冨田周介; 木本直哉; 上嶋一臣; 福永豊和; 岡部純弘; 樫田博史; 平佐昌弘; 黒川学  神戸市立病院紀要  (36)  1997

Industrial Property Rights

• 特許WO2008070564A1:Uses of muramyl dipeptide (MDP) for treating inflammation  

  Warren Strober, Peter Mannon, Tomohiro Watanabe, Ivan Fuss, Atsushi Kitani

Awards & Honors

• 2022 喫煙科学研究財団 研究助成
   

  受賞者: 渡邉智裕
• 2021 ヤクルトバイオサイエンス研究財団 特別研究助成
   

  受賞者: 渡邉 智裕
• 2020 先進医薬研究振興財団 血液医学研究助成
   

  受賞者: 渡邉 智裕
• 2020 ヤクルトバイオサイエンス研究財団 特別研究助成
   

  受賞者: 渡邉 智裕
• 2019 ヤクルトバイオサイエンス研究財団 特別研究助成
   

  受賞者: 渡邉 智裕
• 2019 喫煙科学研究財団 研究助成
   

  受賞者: 渡邉 智裕
• 2018 喫煙科学研究財団 研究助成
   

  受賞者: 渡邉 智裕
• 2017 ヤクルトバイオサイエンス研究財団 一般研究助成
   

  受賞者: 渡邉 智裕
• 2017 先進医薬研究振興財団 血液医学研究助成
   

  受賞者: 渡邉 智裕
• 2017 内藤記念科学振興財団 内藤記念科学奨励金・研究助成
   

  受賞者: 渡邉 智裕
• 2017 小林がん学術振興会 研究助成
   

  受賞者: 渡邉 智裕
• 2017 喫煙科学研究財団 研究助成
   

  受賞者: 渡邉 智裕
• 2017 武田科学振興財団 生命科学研究助成
   

  受賞者: 渡邉 智裕
• 2016 加藤記念難病研究助成基金 研究助成
   

  受賞者: 渡邉 智裕
• 2011 日本消化器病学会 学術研究助成金
   

  受賞者: 渡邉 智裕
• 2011 持田記念医学薬学振興財団 研究助成金
   

  受賞者: 渡邉 智裕
• 2010 膵臓病研究財団 膵臓病研究奨励賞
   

  受賞者: 渡邉 智裕
• 2010 アステラス病態代謝研究会 研究助成金
   

  受賞者: 渡邉 智裕
• 2010 武田科学振興財団 医学系研究継続助成
   

  受賞者: 渡邉 智裕
• 2010 ヤクルトバイオサイエンス研究財団 一般研究助成
   

  受賞者: 渡邉 智裕
• 2010 先進医薬振興財団 血液医学研究助成
   

  受賞者: 渡邉 智裕
• 2010 日本ヘリコバクター学会 上原 H. pylori 最優秀賞
   

  受賞者: 渡邉 智裕
• 2009 清水免疫学振興財団 研究助成
   

  受賞者: 渡邉 智裕
• 2009 細胞科学研究財団 研究助成
   

  受賞者: 渡邉 智裕
• 2009 ウイルス肝炎研究財団 研究奨励金
   

  受賞者: 渡邉 智裕
• 2009 加藤記念難病研究助成基金 研究助成
   

  受賞者: 渡邉 智裕
• 2009 アボットジャパン アレルギー学術奨励賞
   

  受賞者: 渡邉 智裕
• 2008 金原一郎記念医学医療振興財団 研究助成
   

  受賞者: 渡邉 智裕
• 2008 藤原記念財団 研究助成
   

  受賞者: 渡邉 智裕
• 2008 膵臓病研究財団 研究奨励金
   

  受賞者: 渡邉 智裕
• 2008 武田科学振興財団 医学系研究助成
   

  受賞者: 渡邉 智裕
• 2008 上原記念生命科学財団 研究助成金
   

  受賞者: 渡邉 智裕
• 2007 ヤクルトバイオサイエンス研究財団 一般研究助成
   

  受賞者: 渡邉 智裕
• 2007 アステラス病態代謝研究会 研究助成金
   

  受賞者: 渡邉 智裕
• 2007 住友財団 基礎科学研究助成
   

  受賞者: 渡邉 智裕
• 2007 持田記念医学薬学振興財団 研究助成金
   

  受賞者: 渡邉 智裕
• 2007 京都免疫ワークショップ 石坂公成 奨励賞
   

  受賞者: 渡邉 智裕
• 2006 清水免疫学振興財団 研究助成
   

  受賞者: 渡邉 智裕
• 2003 アステラス病態代謝研究会 海外留学補助金
   

  受賞者: 渡邉 智裕

Research Grants & Projects

• Mechanism of multi-organ involvements in IgG4-related disease from the view of microbiome profile

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2023/04 -2026/03 

  Author : 三長 孝輔; 渡邉 智裕
• 疾患感受性遺伝子の機能からみた炎症性腸疾患の新規治療法開発

  近畿大学学内助成金 21世紀研究開発奨励金

  Date (from‐to) : 2023/04 -2026/03 

  Author : 渡邉 智裕
• 腸内細菌に対する免疫反応の制御を用いた膵臓疾患の新規治療法開発

  近畿大学学内助成金：21世紀研究開発奨励金

  Date (from‐to) : 2022/04 -2025/03 

  Author : 渡邉智裕
• 青黛による芳香族炭化水素受容体の活性化を用いた慢性膵疾患の治療法の開発

  科学研究費補助金 基盤研究C：

  Date (from‐to) : 2022/04 -2025/03 

  Author : 鎌田 研 (研究代表者)、渡邉 智裕
• 喫煙習慣と疾患感受性遺伝子の相互作用がクローン病の発症に及ぼす効果の解明

  喫煙科学研究財団：一般研究助成

  Date (from‐to) : 2022/04 -2025/03 

  Author : 渡邉智裕
• 自己免疫性膵炎・IgG4関連疾患の発症に関わる腸管・膵臓免疫ネットワークの解明

  科学研究費補助金：基盤研究

  Date (from‐to) : 2022/04 -2025/03 

  Author : 渡邉 智裕
• 次世代シークエンス解析による新型コロナウイルス院内感染メカニズムの解明

  “オール近大”新型コロナウイルス感染症対策支援プロジェクト

  Date (from‐to) : 2021/09 -2022/08 

  Author : 渡邉 智裕
• 自然免疫担当分子RIP2を標的とする炎症性腸疾患の新規治療法の開発

  科学研究費補助金：基盤研究C

  Date (from‐to) : 2019 -2021 

  Author : 渡邉 智裕
• Akkermansia muciniphilaとBifidobacterium pseudolongumが慢性炎症性膵臓 疾患の病態に果たす役割の解明と新規治療法の開発

  ヤクルトバイオサイエンス研究財団：特別研究助成

  Date (from‐to) : 2019 -2021 

  Author : 渡邉 智裕
• 自然免疫反応からみた膵臓疾患の発症機序の解明と新規治療法の開発

  武田科学振興財団：生命科学研究助成

  Date (from‐to) : 2017 -2021 

  Author : 渡邉 智裕
• 腸管ー膵臓免疫ネットワークからみたIgG4関連疾患の発症機序の解明

  先進医薬研究振興財団：血液医学研究助成

  Date (from‐to) : 2019 -2019 

  Author : 渡邉 智裕
• 腸内細菌に対する免疫反応からみた喫煙関連膵臓疾患の発症機序の解明

  喫煙科学研究財団：

  Date (from‐to) : 2017 -2019 

  Author : 渡邉 智裕
• IgG4関連疾患の新規バイオマー カーと治療ターゲット開発に 関する研究 (研究代表者 三森 経世）

  日本医療研究開発機構：難治性疾患実用化研究事業

  Date (from‐to) : 2017 -2019 

  Author : 渡邉 智裕
• 腸内細菌叢からみた膵臓疾患の発症機序の解明と 新規治療法の開発

  ヤクルトバイオサイエンス研究財団：

  Date (from‐to) : 2017 -2017 

  Author : 渡邉智裕
• 腸内細菌叢からみた膵臓疾患の発症機序の解明と新規治療法の開発

  内藤記念科学振興財団：内藤記念科学奨励金・研究助成

  Date (from‐to) : 2017 -2017 

  Author : 渡邉 智裕
• 自然免疫反応の制御を用いた膵臓癌の予防法の開発

  小林がん学術振興会：研究助成

  Date (from‐to) : 2017 -2017 

  Author : 渡邉 智裕
• 腸内細菌叢からみた膵炎の発症機序の解明と新規治療法の 開発

  先進医薬研究振興財団：

  Date (from‐to) : 2016 -2016
• 腸内細菌叢からみたIgG4関連疾患の発症機序の解明と新規治療法の開発

  科学研究費補助金 萌芽研究：

  Date (from‐to) : 2015 -2016 

  Author : 渡邉 智裕
• IgG4関連疾患の病因病態解明と新規治療法確立に関する研究 (研究代表者 三森 経世）

  厚生労働科学研究委託費：難治性疾患実用化研究事業

  Date (from‐to) : 2014 -2016 

  Author : 渡邉 智裕
• 腸内細菌叢からみたIgG4関連疾患の発症機序の解明と新規治療法の開発

  加藤記念難病研究助成基金：

  Date (from‐to) : 2015 -2015 

  Author : 渡邉 智裕
• 自然免疫システムの制御を用いた膵炎の新規治療法の開発

  科学研究費補助金 基盤研究B：

  Date (from‐to) : 2013 -2015 

  Author : 渡邉 智裕
• NOD-like receptorの活性化からみた消化器疾患の発症機序の解明

  科学技術振興機構：京都大学「次世代免疫制御を目指す創薬医学融合拠点」

  Date (from‐to) : 2011 -2015 

  Author : 渡邉 智裕
• 炎症からの消化器発癌におけるゲノム・エピゲノム異常の統合的解析と生成機構の解明 (研究代表者 千葉 勉）

  科学研究費補助金：基盤研究S

  Date (from‐to) : 2012 -2014 

  Author : 渡邉 智裕
• 炎症を背景とした消化器発癌過程におけるゲノム不安定性の生成機構の解明 (研究代表者 千葉 勉）

  科学研究費補助金：基盤研究S

  Date (from‐to) : 2009 -2012 

  Author : 渡邉 智裕
• Nod-like receptorの活性化からみたHelicobacter pylori感染免疫防御機構の解明

  日本消化器病学会 学術研究助成金：

  Date (from‐to) : 2011 -2011 

  Author : 渡邉 智裕
• 自然免疫シグナルの活性化からみた炎症性腸疾患の発症機序の解明と新規治療法の開発

  持田記念医学薬学振興財団：

  Date (from‐to) : 2011 -2011 

  Author : 渡邉 智裕
• 腸内細菌由来抗原の免疫制御機能を用いたクローン病の新規治療法の開発

  科学研究費補助金 基盤研究C：

  Date (from‐to) : 2009 -2011 

  Author : 渡邉 智裕
• Nod-like receptorの活性化からみた消化器疾患発症機序の 解析

  細胞科学研究財団：

  Date (from‐to) : 2010 -2010 

  Author : 渡邉 智裕
• IgG4関連硬化性疾患の発症に関わる自然免疫及び獲得免疫反応の解明

  膵臓病研究財団：

  Date (from‐to) : 2010 -2010 

  Author : 渡邉 智裕
• 自然免疫システムの制御を用いた炎症性腸疾患の新規治療法の開発

  病態代謝研究会：

  Date (from‐to) : 2010 -2010 

  Author : 渡邉 智裕
• 自然免疫システムの活性化によるクローン病の新規治療法の開発 (継続助成)

  武田科学振興財団：

  Date (from‐to) : 2010 -2010 

  Author : 渡邉 智裕
• 自然免疫システムの制御による炎症性腸疾患の新規治療法の開発

  先進医薬振興財団：

  Date (from‐to) : 2010 -2010 

  Author : 渡邉 智裕
• 自然免疫シグナルの制御によるクローン病の新規治療法の開発

  ヤクルトバイオサイエンス研究財団：

  Date (from‐to) : 2010 -2010 

  Author : 渡邉 智裕
• H.pylori感染胃炎の病態形成・疾患予後に関わる宿主側因子の研究 (研究代表者 若月 芳雄）

  科学研究費補助金：基盤研究C

  Date (from‐to) : 2008 -2010 

  Author : 渡邉 智裕
• 自然免疫システムの活性化を用いた食物アレルギーの新規治療法開発

  アボットジャパン アレルギー学術奨励賞：

  Date (from‐to) : 2009 -2009 

  Author : 渡邉智裕
• Nod-like receptor の活性化からみた消化器疾患発症機序の解析

  清水免疫学振興財団：

  Date (from‐to) : 2009 -2009 

  Author : 渡邉 智裕
• 炎症性腸疾患の新規治療法の開発

  上原記念生命科学財団：

  Date (from‐to) : 2009 -2009 

  Author : 渡邉 智裕
• NOD1及びNOD2を介するHCV宿主免疫防御機構の解明

  ウイルス肝炎研究 財団：

  Date (from‐to) : 2009 -2009 

  Author : 渡邉 智裕
• 急性膵炎による多臓器不全の免疫学的解析と新規治療法の開発

  加藤記念難病研究 助成基金：

  Date (from‐to) : 2009 -2009 

  Author : 渡邉 智裕
• クローン病感受性蛋白質NOD2の活性化による腸管免疫制御機構の解析

  金原一郎記念医学医療振興財団：

  Date (from‐to) : 2008 -2008 

  Author : 渡邉 智裕
• 自然免疫システムの活性化を用いた炎症性腸疾患の新規治療法の開発

  藤原記念財団：

  Date (from‐to) : 2008 -2008 

  Author : 渡邉 智裕
• 自然免疫システムの活性化を用いた急性膵炎の新規治療法の開発

  膵臓病研究財団：

  Date (from‐to) : 2008 -2008 

  Author : 渡邉 智裕
• 自然免疫システムの活性化によるクローン病の新規治療法の開発

  武田科学振興財団：

  Date (from‐to) : 2008 -2008 

  Author : 渡邉 智裕
• 細菌性抗原受容体NOD2の活性化による腸管免疫制御機構の解析

  科学研究費補助金 基盤研究C：

  Date (from‐to) : 2007 -2008 

  Author : 渡邉 智裕
• 腸内細菌由来抗原Muramyl Dipeptide (MDP)による自然免疫システムの活性化を利用した炎症性腸疾患の新規治療法の開発

  ヤクルトバイオサイエンス研究財団：

  Date (from‐to) : 2007 -2007 

  Author : 渡邉 智裕
• クローン病感受性蛋白質NOD2の活性化による腸管免疫制御機構の解析

  病態代謝研究会：

  Date (from‐to) : 2007 -2007 

  Author : 渡邉 智裕
• 自然免疫システムの活性化を用いた炎症性腸疾患新規治療法の開発

  住友基礎科学研究助成：

  Date (from‐to) : 2007 -2007 

  Author : 渡邉 智裕
• 細菌性抗原受容体NOD2の免疫制御機構を利用した炎症性腸疾患新規治療法の開発

  持田記念医学薬学振興財団：

  Date (from‐to) : 2007 -2007 

  Author : 渡邉 智裕
• NOD1/NOD2の機能解析とその消化器疾患における役割

  清水免疫学振興財団：

  Date (from‐to) : 2006 -2006 

  Author : 渡邉 智裕
• 海外留学補助金

  病態代謝研究会：

  Date (from‐to) : 2003 -2003 

  Author : 渡邉 智裕

Other link

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https://researchmap.jp/7000008670