OTSUKA Atsushi

Researcher Information

J-Global ID

• 201401047838530502

Research Interests

• melanoma   atopic dermatitis   allergy   

Research Areas

• Life sciences / Dermatology

Published Papers

• Increased type I interferon expression from T cells in lesional skin of Degos disease.

  Yuki Honda Keith; Atsushi Otsuka; Toshiaki Kogame; Hiroyuki Ito; Shunya Usui; Masakazu Fujimoto; Keita Jinnouchi; Masahiro Hirata; Kazumitsu Sugiura; Kenji Kabashima

  The Journal of dermatology 50 (5) 720 - 722 2023/05
• Efficacy of salvage therapies for advanced acral melanoma after anti-PD-1 monotherapy failure: a multicenter retrospective study of 108 Japanese patients.

  Tatsuhiko Mori; Kenjiro Namikawa; Naoya Yamazaki; Yukiko Kiniwa; Osamu Yamasaki; Shusuke Yoshikawa; Takashi Inozume; Hiroshi Kato; Yasuo Nakai; Satoshi Fukushima; Tatsuya Takenouchi; Takeo Maekawa; Shigeto Matsushita; Atsushi Otsuka; Motoo Nomura; Natsuki Baba; Taiki Isei; Shintaro Saito; Noriki Fujimoto; Ryo Tanaka; Takahide Kaneko; Yutaka Kuwatsuka; Taisuke Matsuya; Kotaro Nagase; Masazumi Onishi; Takehiro Onuma; Yasuhiro Nakamura

  Frontiers in medicine 10 1229937 - 1229937 2023 

  BACKGROUND: Anti-programmed cell death protein 1 (PD-1) monotherapy is one of the standard systemic therapies for advanced melanoma; however, the efficacy of salvage systemic therapies after PD-1 monotherapy failure (PD-1 MF), particularly in acral melanoma (AM), the main clinical melanoma type in Japanese patients, is unclear. This study aimed to investigate the efficacy of salvage systemic therapies in Japanese patients with AM after PD-1 MF. PATIENTS AND METHODS: The study included 108 patients with advanced AM (palm and sole, 72; nail apparatus, 36) who underwent salvage systemic therapy at 24 Japanese institutions. We mainly assessed the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-six (33%) patients received ipilimumab, 23 (21%) received nivolumab and ipilimumab (nivo/ipi), 10 (9%) received cytotoxic chemotherapy, 4 (4%) received BRAF and MEK inhibitors (BRAFi/MEKi), and the remaining 35 (32%) continued with PD-1 monotherapy after disease progression. The ORRs in the ipilimumab, nivo/ipi, cytotoxic chemotherapy, and BRAFi/MEKi groups were 8, 17, 0, and 100%, respectively. The nivo/ipi group showed the longest OS (median, 18.9 months); however, differences in ORR, PFS, and OS between the groups were insignificant. The OS in the nivo/ipi group was higher in the palm and sole groups than in the nail apparatus group (median: not reached vs. 8.7 months, p < 0.001). Cox multivariate analysis demonstrated that nail apparatus melanoma independently predicted unfavorable PFS and OS (p = 0.006 and 0.001). The total OS (from PD-1 monotherapy initiation to death/last follow-up) was insignificant between the groups. CONCLUSION: Nivo/ipi was not more effective than cytotoxic chemotherapy and ipilimumab after PD-1 MF in patients with advanced AM. The prognosis after PD-1 MF would be poorer for nail apparatus melanoma than for palm and sole melanoma.
• Efficacy comparison between anti-PD-1 antibody monotherapy and anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy for advanced acral melanoma: A retrospective, multicenter study of 254 Japanese patients.

  Yasuhiro Nakamura; Kenjiro Namikawa; Yukiko Kiniwa; Hiroshi Kato; Osamu Yamasaki; Shusuke Yoshikawa; Takeo Maekawa; Shigeto Matsushita; Tatsuya Takenouchi; Takashi Inozume; Yasuo Nakai; Satoshi Fukushima; Shintaro Saito; Atsushi Otsuka; Noriki Fujimoto; Taiki Isei; Natsuki Baba; Taisuke Matsuya; Ryo Tanaka; Takahide Kaneko; Masazumi Onishi; Yutaka Kuwatsuka; Kotaro Nagase; Takehiro Onuma; Motoo Nomura; Yoshiyasu Umeda; Naoya Yamazaki

  European journal of cancer (Oxford, England : 1990) 176 78 - 87 2022/11 

  BACKGROUND: Although anti-PD-1 antibody monotherapy (PD-1) is commonly used to treat advanced acral melanoma (AM), its efficacy is limited. Further, data on the efficacy of PD-1 plus anti-CTLA-4 antibody (PD-1+CTLA-4) for the treatment of AM are limited. Therefore, we compared the efficacy of PD-1+CTLA-4 and PD-1 in the treatment of Japanese patients with advanced AM. METHODS: This retrospective study evaluated patients with advanced AM who were treated with PD-1 or PD-1+CTLA-4 as first-line immunotherapy in 24 Japanese institutions between 2014 and 2020. Treatment efficacy focussing on the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was compared between the two groups. RESULTS: In total, 254 patients (palm and sole melanoma [PSM], n = 180; nail apparatus melanoma [NAM], n = 74) were included. Among the patients with PSM, the ORR (19% vs. 31%; P = 0.44), PFS (5.9 vs. 3.2 months; P = 0.74), and OS (23.1 vs. not reached; P = 0.55) did not differ significantly between the PD-1 and PD-1+CTLA-4 groups. Among the patients with NAM, the ORR (61% vs. 10%; P < 0.001) was significantly higher and PFS was longer (6.4 vs. 3.8 months; P = 0.10) in the PD-1+CTLA-4 group than in the PD-1 group. Cox multivariate analysis demonstrated that PD-1+CTLA-4 is an independent predictor of a favourable PFS in patients with NAM (P = 0.002). CONCLUSIONS: The efficacy of PD-1+CTLA-4 is not superior to that of PD-1 for the treatment of advanced PSM. However, PD-1+CTLA-4 may be more efficacious than PD-1 for the treatment of advanced NAM.
• Cronkhite-Canada Syndrome Mimicking COVID-19-related Symptoms.

  Kayo Miyawaki; Takaya Komori; Yoshihiro Ishida; Yuri Sakaguchi; Hajime Honjo; Masatoshi Kudo; Atsushi Otsuka

  Acta dermato-venereologica 2022/10
• Filaggrin-deficient rats generated using zinc-finger nucleases spontaneously exhibit dry scaly skin.

  Chisa Nakashima; Hiromi Doi; Saeko Nakajima; Tomoji Mashimo; Toru Oga; Akemi Ishida-Yamamoto; Tetsuya Honda; Yoshihiro Ishida; Atsushi Otsuka; Kenji Kabashima

  Allergology international : official journal of the Japanese Society of Allergology 71 (4) 545 - 547 2022/10
• A Phenotypic Analysis of Involucrin-Membrane-Bound Ovalbumin Mice after Adoptive Transfer of Ovalbumin-Specific CD8+ T Cells.

  Yujin Nakagawa; Gyohei Egawa; Toshiya Miyake; Saeko Nakajima; Atsushi Otsuka; Takashi Nomura; Akihiko Kitoh; Teruki Dainichi; Jun-Ichi Sakabe; Akihiko Shibaki; Yoshiki Tokura; Tetsuya Honda; Kenji Kabashima

  JID innovations : skin science from molecules to population health 2 (5) 100127 - 100127 2022/09 

  To investigate the mechanism of autoimmunity and peripheral tolerance in the skin, several transgenic mouse strains expressing membrane-bound ovalbumin (mOVA) as an epidermal self-antigen under the control of keratinocyte-specific promotors, such as keratin 5 and keratin 14, were employed in combination with adoptive transfer of CD8+ T cells from OT-I mice (OT-I T cells) that recognize an ovalbumin-derived peptide. However, these strains showed bodyweight loss and required additional inflammatory stimuli, such as γ-irradiation and tape-stripping, to induce skin inflammation. In this study, we generated a mouse strain expressing mOVA under the control of human involucrin promoter (involucrin-mOVA mice). In contrast to previous strains, involucrin-mOVA mice spontaneously developed skin inflammation after the transfer of OT-I T cells in the absence of external stimuli without significant bodyweight loss. We focused on the skin infiltration process of OT-I T cells and found that transferred OT-I T cells accumulated around the hair follicles in the early phase of skin inflammation, and in the later phase, the skin inflammation spontaneously resolved despite the remaining OT-I T cells in the skin. Our involucrin-mOVA mice will provide a promising tool to investigate the pathogenesis and the tolerance mechanisms of cytotoxic skin autoimmunity.
• 食道全長にわたって粘膜びらん・潰瘍をきたした尋常性天疱瘡の1例

  岩津 理世; 佐藤 雅子; 加藤 麻衣子; 柳原 茂人; 大磯 直毅; 川田 暁; 大塚 篤司

  皮膚の科学 日本皮膚科学会-大阪地方会・京滋地方会 21 (2) 108 - 113 1347-1813 2022/06 

  52歳,男性。7年前に尋常性天疱瘡と診断され当科に通院していたが,背部の皮膚と両側頬粘膜のびらんが徐々に増悪したため入院となった。入院時のPemphigus Disease Area Index(PDAI)は皮膚10点,粘膜2点と中等症であったが難治であり,入院後激しい咽頭痛,呼吸困難感が生じ上部消化管内視鏡検査を施行したところ,食道全長にわたって粘膜びらん・潰瘍・裂創を認めた。抗デスモグレイン1抗体630U/mL,抗デスモグレイン3抗体2,540U/mLと上昇を認め,さらに粘膜びらんと潰瘍が食道全体に散発していたため,尋常性天疱瘡の食道粘膜病変と考え,ステロイドパルス療法,全身投与,免疫抑制剤内服,血漿交換療法,免疫グロブリン大量静注療法を行ったところ,皮膚症状と口腔内粘膜症状は改善した。上部消化管内視鏡検査にて食道全長に生じた粘膜病変の改善も確認し,治療効果判定もおこなった。自験例では入院時のは皮膚10点,粘膜2点と中等症であったが難治であり,重度の食道粘膜症状もきたした。口腔粘膜病変を伴う場合,上部消化管内視鏡検査で食道粘膜病変の観察を行うこと,重症例においては積極的に初期治療を行うことが重要であると考える。(著者抄録)
• 抗ラミニンγ1類天疱瘡と抗ラミニン332型粘膜類天疱瘡を合併した1例

  岩津 理世; 佐藤 雅子; 加藤 麻衣子; 柳原 茂人; 大磯 直毅; 立石 千晴; 橋本 隆; 鶴田 大輔; 川田 暁; 大塚 篤司

  皮膚の科学 日本皮膚科学会-大阪地方会・京滋地方会 21 (2) 126 - 132 1347-1813 2022/06 

  77歳,男性。初診の1週間前から手足に紅斑と水疱を認めた。その後皮疹が全身に拡大し,粘膜にもびらんを認めたため,精査加療目的で当科に紹介された。初診時,体幹・四肢に紅斑と水疱が多発しており,口唇・口腔内・陰茎にびらんを認めた。抗BP180-NC16A部位抗体,抗デスモグレイン1,3抗体は陰性であった。病理組織にて好酸球浸潤を伴う表皮下水疱,蛍光抗体直接法で表皮基底膜部にC3の線状沈着を認めた。1M食塩水剥離皮膚を基質とした蛍光抗体間接法では,IgG抗体が真皮側に反応した。正常ヒト真皮抽出液を用いた免疫ブロット法にて患者血清IgG抗体は200kDaラミニンγ1(p200)に反応し,ラミニン332リコンビナント蛋白を用いた免疫ブロット法で165kDaラミニンα3に反応した。臨床症状と病理所見,蛍光抗体直接法,蛍光抗体間接法,免疫ブロット法の結果より,抗ラミニンγ1類天疱瘡と抗ラミニン332型粘膜類天疱瘡の合併と診断した。プレドニゾロン1mg/kg/日点滴を行ったところ,新生水疱を認めなくなり,紅斑は退色,びらんは上皮化した。その後,プレドニゾロンを漸減したが,皮膚・粘膜症状は再燃しなかった。自験例では皮膚・粘膜症状は重篤であったが,ステロイド全身投与が速やかに奏効した。(著者抄録)
• 【(新規)抗腫瘍薬〜光と影〜】G-CSF産生悪性黒色腫

  米倉 慧; 高田 麻由実; 小森 崇矢; 遠藤 雄一郎; 加来 洋; 大塚 篤司; 椛島 健治

  皮膚病診療 (株)協和企画 44 (5) 428 - 431 0387-7531 2022/05 

  ＜文献概要＞症例のポイント ・切除可能病変のあるG-CSF産生悪性黒色腫では外科的切除により白血球増多症をコントロールでき,予後延長へ寄与する可能性がある.
• 進行期メラノーマに対するニボルマブ・PAI-1阻害薬併用療法の安全性・有効性の検討

  藤村 卓; 吉野 公二; 加藤 裕史; 福島 聡; 大塚 篤司; 松下 茂人; 神林 由美; 橋本 彰; 藤澤 康弘

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 132 (5) 1314 - 1314 0021-499X 2022/05
• Anti-allergic effect of ascorbic acid derivative DDH-1 in a mouse model of atopic dermatitis.

  Kosuke Kitahata; Kazuhiko Matsuo; Masako Sato; Yoko Susami; Yuta Hara; Toshio Morikawa; Naoki Oiso; Akira Kawada; Atsushi Otsuka; Takashi Nakayama

  Experimental dermatology 31 (8) 1234 - 1242 2022/04 

  Atopic dermatitis (AD) is the most common inflammatory skin disease, which is characterized by excessive Th2 immune responses. In AD patients, the expression of the chemokines CCL17 and CCL22 is increased in skin lesions, leading to the infiltration of Th2 cells. In addition, typical pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, have also been shown to be associated with the pathogenesis of AD. Recently, DDH-1, an ascorbic acid derivative, has been synthesized and demonstrated to have a more stabilized structure and better skin penetrability. Furthermore, DDH-1 has been shown to suppress pro-inflammatory cytokine expression in vitro and in vivo. Therefore, using an AD mouse model, we evaluated the effect of DDH-1 to reduce allergic skin inflammation. We found that cutaneous administration of DDH-1 significantly reduced the expression levels of TNF-α, IL-1β and IL-6 in the skin lesions of AD-like mice. Additionally, DDH-1 administration also significantly reduced the expression levels of CCL17 and CCL22, resulting in decreased skin infiltration of Th2 cells. Consequently, DDH-1 reduced ear and epidermal thickness, the serum IgE levels and the number of infiltrating inflammatory cells and mast cells into the AD-like skin lesions. Combination treatment with DDH-1 and corticosteroid more efficiently improved the skin lesions compared with corticosteroid alone. Collectively, our results suggest that DDH-1 has an anti-allergic effect in an AD mouse model by reducing not only the pro-inflammatory cytokine expression but also the Th2-associated chemokine expression. Thus, DDH-1 may be beneficial for AD treatment and prevention as a monotherapy or in combination with corticosteroids.
• ニボルマブ投与中に生じたnon-bullous pemphigoidの1例

  千田 晃嘉; 小森 崇矢; 石田 雄大; 村田 光麻; 大塚 篤司; 椛島 健治

  皮膚の科学 日本皮膚科学会-大阪地方会・京滋地方会 21 (1) 68 - 69 1347-1813 2022/03
• ニボルマブによるStevens-Johnson症候群の1例

  廣田 菜々子; 鈴木 緑; 加藤 麻衣子; 柳原 茂人; 遠藤 英樹; 大磯 直毅; 川田 暁; 大塚 篤司; 田中 薫; 藤田 岳

  皮膚の科学 日本皮膚科学会-大阪地方会・京滋地方会 21 (1) 1 - 5 1347-1813 2022/03 

  64歳,女性。初診の1年前に右外耳道癌と診断され,右外側側頭骨切除術,術後放射線療法ならびに化学療法を施行していた。術後1年後に右外耳道癌の再発を認めたため,ニボルマブ投与開始となった。開始後12日後より口唇びらんが出現し,四肢・体幹に紅斑が拡大したため,当科紹介受診となった。臨床症状,病理組織所見よりニボルマブによるStevens-Johnson症候群と診断した。ステロイドパルス療法,血漿交換,免疫グロブリン大量静注療法にて改善した。ニボルマブに関連する有害事象の重症化を防ぐためには早期の治療介入や集学的治療が必要であり,今後同様の症例報告の集積が望まれる。(著者抄録)
• Decreased peripheral basophil counts in urticaria and mouse model of oxazolone-induced hypersensitivity, the latter suggesting basopenia reflecting migration to skin.

  Izumi Kishimoto; Ni Ma; Riko Takimoto-Ito; Chisa Nakashima; Atsushi Otsuka; Andrew F Walls; Hideaki Tanizaki; Naotomo Kambe

  Frontiers in immunology 13 1014924 - 1014924 2022 

  A decrease in the number of basophils in the peripheral blood, or basopenia, has been noted, reflecting the activity of chronic spontaneous urticaria (CSU). Infiltration of basophils into the skin has also been reported, but the mechanism of basopenia in CSU has not been clarified. The phenomenon of basopenia during the active phase of urticaria was confirmed, and basophil numbers increased following symptom improvement in 15 out of 17 patients treated with omalizumab and in 13 of 15 patients treated with antihistamines. Our examination by immunostaining also revealed basophil infiltration of the CSU lesions, as in previous reports, but since most of our patients were already taking oral steroids, it was not considered appropriate to examine the relationship between basophil numbers in tissue and peripheral blood. Then, we used mouse model of contact hypersensitivity with a single application of oxazolone, which is known to stimulate basophil infiltration, and investigated basophil counts in the skin, peripheral blood, and bone marrow. In this model, a decrease in peripheral blood basophil numbers was observed one day after challenge, but not after 2 days, reflecting supplementation from the bone marrow. Indeed, when cultured basophils expressing GFP were transplanted into the peripheral blood, GFP-positive basophil numbers in the peripheral blood remained low even after 2 days of challenge. Despite differences among species and models, these results suggest that one reason for the decrease of basophils in the peripheral blood in CSU may involve migration of circulating basophils into the skin.
• Innovation in the treatment of atopic dermatitis: Emerging topical and oral Janus kinase inhibitors.

  Chisa Nakashima; Shigeto Yanagihara; Atsushi Otsuka

  Allergology international : official journal of the Japanese Society of Allergology 71 (1) 40 - 46 2022/01 

  Atopic dermatitis (AD) is characterized by chronic, eczematous, severe pruritic skin lesions. The knowledge on the pathogenesis of AD is driving the development of new drugs. From the research results, it has been revealed that Th2 cell-mediated immunity, skin barrier dysfunction, and pruritus cause a vicious cycle of AD. On the other hand, the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway are one of the essential signaling pathways in various inflammatory diseases including AD. In particular, TSLP, IL-4, IL-13 and IL-22 occupy an important position for Th2 cell-mediated immune reaction. Moreover, experimentally pan-JAK inhibitor suppress the STAT3 activation and improved the skin barrier function. Furthermore TSLP, IL-4, IL-13 and IL-31 contribute a lot to chronic pruritus of AD, and transmitted via JAK-STAT pathway. Therefore, JAK inhibitors are promising candidates for the treatment of severe AD. Here we review clinical trials of topical dergocitinib; a pan-JAK inhibitor, ruxolitinib; a JAK1 and JAK2 inhibitor, and tofacitinib; a JAK1, JAK2, and JAK3 inhibitor and oral baricitinib; a JAK1 and JAK2 inhibitor, abrocitinib and upadacitinib; JAK1 inhibitor. Significant improvements in the symptoms were obtained by each drug with low frequency of adverse events. In particular, oral JAK inhibitors have the ability to improve the pruritus and skin symptoms quickly. Therefore, the emergence of these topical and oral JAK inhibitors would be regarded as an innovation in the treatment of atopic dermatitis.
• LAD-1に対するIgG抗体陽性となった粘膜類天疱瘡の1例

  松尾 彩子; 岩津 理世; 佐藤 雅子; 柳原 茂人; 遠藤 英樹; 大磯 直毅; 川田 暁; 大塚 篤司; 立石 千晴; 橋本 隆; 鶴田 大輔

  皮膚の科学 日本皮膚科学会-大阪地方会・京滋地方会 20 (4) 375 - 375 1347-1813 2021/12
• Prolonged high-intensity exercise induces fluctuating immune responses to herpes simplex virus infection via glucocorticoids

  Akimasa Adachi; Tetsuya Honda; Teruki Dainichi; Gyohei Egawa; Yosuke Yamamoto; Takashi Nomura; Saeko Nakajima; Atsushi Otsuka; Masamitsu Maekawa; Nariyasu Mano; Naoto Koyanagi; Yasushi Kawaguchi; Toshiaki Ohteki; Takashi Nagasawa; Koichi Ikuta; Akihiko Kitoh; Kenji Kabashima

  Journal of Allergy and Clinical Immunology Elsevier BV 148 (6) 1575 - 1588.e7 0091-6749 2021/12
• Real-world efficacy of anti-PD-1 antibody or combined anti-PD-1 plus anti-CTLA-4 antibodies, with or without radiotherapy, in advanced mucosal melanoma patients: A retrospective, multicenter study.

  Yoshiyasu Umeda; Shusuke Yoshikawa; Yukiko Kiniwa; Takeo Maekawa; Osamu Yamasaki; Taiki Isei; Shigeto Matsushita; Motoo Nomura; Yasuo Nakai; Satoshi Fukushima; Shintaro Saito; Tatsuya Takenouchi; Ryo Tanaka; Hiroshi Kato; Atsushi Otsuka; Taisuke Matsuya; Natsuki Baba; Kotaro Nagase; Takashi Inozume; Takehiro Onuma; Yutaka Kuwatsuka; Noriki Fujimoto; Takahide Kaneko; Masazumi Onishi; Kenjiro Namikawa; Naoya Yamazaki; Yasuhiro Nakamura

  European journal of cancer (Oxford, England : 1990) 157 361 - 372 2021/11 

  BACKGROUND: Immune checkpoint inhibitors (ICIs) have a lower efficacy in mucosal melanoma (MUM) than in cutaneous melanoma. The use of combination treatments with radiotherapy (RT) to improve the efficacy in MUM, however, requires further investigation. METHODS: We retrospectively evaluated 225 advanced MUM patients treated with anti-PD-1 monotherapy (PD1; 115) or anti-PD-1 + anti-CTLA-4 combination therapy (PD1+CTLA4; 42) with or without RT (56 and 12, respectively). Treatment efficacy was estimated by determining the objective response rate (ORR) and survival rate with the Kaplan-Meier analysis. RESULTS: The baseline characteristics between the two groups in each ICI cohort were similar, except for Eastern Cooperative Oncology Group performance status in the PD1 cohort. No significant differences in ORR, progression-free survival (PFS), and overall survival (OS) were observed between the PD1 alone and PD1+RT groups in the PD1 cohort (ORR 26% versus 27%, P > 0.99; median PFS 6.2 versus 6.8 months, P = 0.63; median OS 19.2 versus 23.1 months, P = 0.70) or between the PD1+CTLA alone and PD1+CTLA4+RT groups in the PD1+CTLA4 cohort (ORR 28% vs 25%, P = 0.62; median PFS 5.8 versus 3.5 months, P = 0.21; median OS 31.7 versus 19.8 months, P = 0.79). Cox multivariate analysis indicated that RT in addition to PD1 or PD1+CTLA4 did not have a positive impact on the PFS or OS. CONCLUSIONS: A prolonged survival benefit with RT in combination with ICIs was not identified for advanced MUM patients, although RT may improve local control of the tumour and relieve local symptoms.
• Pituitary adenylate cyclase-activating polypeptide promotes cutaneous dendritic cell functions in contact hypersensitivity.

  Yasuo Yamamoto; Atsushi Otsuka; Yoshihiro Ishida; Lai San Wong; Judith A Seidel; Yumi Nonomura; Chisa Nakashima; Saeko Nakajima; Akihiko Kitoh; Takashi Nomura; Teruki Dainichi; Tetsuya Honda; Wataru Amano; Noriko Konishi; Mikio Hayashi; Mutsuyoshi Matsushita; Kenji Kabashima

  The Journal of allergy and clinical immunology 148 (3) 858 - 866 2021/09 

  BACKGROUND: Sensory nerves regulate cutaneous local inflammation indirectly through induction of pruritus and directly by acting on local immune cells. The underlying mechanisms for how sensory nerves influence cutaneous acquired immune responses remain to be clarified. OBJECTIVE: This study aimed to explore the effect of peripheral nerves on cutaneous immune cells in cutaneous acquired immune responses. METHODS: We analyzed contact hypersensitivity (CHS) responses as a murine model of delayed-type hypersensitivity in absence or presence of resiniferatoxin-induced sensory nerve denervation. We conducted ear thickness measurements, flow cytometric analyses, and mRNA expression analyses in CHS. RESULTS: CHS responses were attenuated in mice that were denervated during the sensitization phase of CHS. By screening neuropeptides, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA expression was decreased in the dorsal root ganglia after denervation. Administration of PACAP restored attenuated CHS response in resiniferatoxin-treated mice, and pharmacological inhibition of PACAP suppressed CHS. Flow cytometric analysis of skin-draining lymph nodes showed that cutaneous dendritic cell migration and maturation were reduced in both denervated mice and PACAP antagonist-treated mice. The expression of chemokine receptors CCR7 and CXCR4 of dendritic cell s was enhanced by addition of PACAP in vitro. CONCLUSION: These findings indicate that a neuropeptide PACAP promotes the development of CHS responses by inducing cutaneous dendritic cell functions during the sensitization phase.
• A case of metastatic eccrine porocarcinoma without actionable mutations treated with carboplatin and epirubicin chemotherapy.

  Jumpei Tahara; Yoshihiro Ishida; Atsushi Otsuka; Takayoshi Komatsu-Fujii; Kentaro Yamamura; Yo Kaku; Yuichiro Endo; Takashi Nomura; Hiroyuki Irie; Kenji Kabashima

  The Australasian journal of dermatology 2021/03
• Unbiased Detection of Driver Mutations in Extramammary Paget Disease.

  Yoshihiro Ishida; Nobuyuki Kakiuchi; Kenichi Yoshida; Yoshikage Inoue; Hiroyuki Irie; Tatsuki R Kataoka; Masahiro Hirata; Takeru Funakoshi; Shigeto Matsushita; Hiroo Hata; Hiroshi Uchi; Yuki Yamamoto; Yasuhiro Fujisawa; Taku Fujimura; Ryunosuke Saiki; Kengo Takeuchi; Yuichi Shiraishi; Kenichi Chiba; Hiroko Tanaka; Atsushi Otsuka; Satoru Miyano; Kenji Kabashima; Seishi Ogawa

  Clinical cancer research : an official journal of the American Association for Cancer Research 27 (6) 1756 - 1765 2021/03 

  PURPOSE: Extramammary Paget disease (EMPD) is an uncommon skin malignancy whose genetic alterations are poorly characterized. Previous reports identified mutations in chromatin remodeling genes and PIK3CA. In order to unambiguously determine driver mutations in EMPD, we analyzed 87 EMPD samples using exome sequencing in combination with targeted sequencing. EXPERIMENTAL DESIGN: First, we analyzed 37 EMPD samples that were surgically resected using whole-exome sequencing. Based on several in silico analysis, we built a custom capture panel of putative driver genes and analyzed 50 additional formalin-fixed, paraffin-embedded samples using target sequencing. ERBB2 expression was evaluated by HER2 immunohisotochemistry. Select samples were further analyzed by fluorescence in situ hybridization. RESULTS: A median of 92 mutations/sample was identified in exome analysis. A union of driver detection algorithms identified ERBB2, ERBB3, KMT2C, TP53, PIK3CA, NUP93, AFDN, and CUX1 as likely driver mutations. Copy-number alteration analysis showed regions spanning CDKN2A as recurrently deleted, and ERBB2 as recurrently amplified. ERBB2, ERBB3, and FGFR1 amplification/mutation showed tendency toward mutual exclusivity. Copy-number alteration load was associated with likelihood to recur. Mutational signatures were dominated by aging and APOBEC activation and lacked evidence of ultraviolet radiation. HER2 IHC/fluorescence in situ analysis validated ERBB2 amplification but was underpowered to detect mutations. Tumor heterogeneity in terms of ERBB2 amplification status was observed in some cases. CONCLUSIONS: Our comprehensive, unbiased analysis shows EMPD is characterized by alterations involving the PI3K-AKT pathway. EMPD is distinct from other skin cancers in both molecular pathways altered and etiology behind mutagenesis.
• PD-L1 on mast cells suppresses effector CD8+ T-cell activation in the skin in murine contact hypersensitivity.

  Tomoko Hirano; Tetsuya Honda; Shuto Kanameishi; Yuki Honda; Gyohei Egawa; Akihiko Kitoh; Saeko Nakajima; Atsushi Otsuka; Takashi Nomura; Teruki Dainichi; Tomonori Yaguchi; Takashi Inozume; Tatsuki R Kataoka; Koji Tamada; Kenji Kabashima

  The Journal of allergy and clinical immunology 2021/02 

  BACKGROUND: The programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) pathway is known to inhibit the activation of effector CD8+ T cells. However, just how this regulatory pathway is involved in the pathophysiology of CD8+ T-cell-mediated inflammatory skin diseases remains unclear. OBJECTIVE: Our aim was to elucidate the mechanisms by which the PD-1/PD-L1 pathway exerts its regulatory roles in CD8+ T-cell-mediated cutaneous immune responses. METHODS: PD-L1-deficient (Pdl1-/-) mice were used for the murine contact hypersensitivity model. Inflammatory responses such as IFN-γ production from CD8+ T cells in the skin was evaluated by flow cytometry. RESULTS: Compared with wild-type mice, Pdl1-/- mice exhibited exacerbated ear swelling and increased numbers of IFN-γ+ CD8+ T cells in the skin. Adoptive T-cell transfer experiments revealed the involvement of the PD-1/PD-L1 pathway in the elicitation phase of contact hypersensitivity. Bone marrow chimera experiments showed that PD-L1 on radioresistant cells was responsible for this regulatory pathway. Flow cytometric analysis revealed that among the radioresistant cells in the skin, PD-L1 was most highly expressed on mast cells (MCs) before and after elicitation. Administration of anti-PD-L1 blocking antibody during the elicitation phase significantly enhanced ear swelling responses and increased the number of IFN-γ+CD8+ T cells in the skin of wild-type mice, whereas no significant effects were observed in MC-deficient (WBB6F1/J-KitW/KitW-v/J and C57BL/6-KitW-sh/W-sh) mice. The high level of expression of PD-L1 on human skin MCs was confirmed by database analysis and immunohistochemical analysis. CONCLUSION: PD-L1 on MCs negatively regulates CD8+ T-cell activation in the skin.
• 皮膚悪性腫瘍診療ガイドライン第3版 皮膚血管肉腫診療ガイドライン2021

  藤澤 康弘; 浅越 健治; 増澤 真実子; 大塚 篤司; 内 博史; 松下 茂人; 秦 洋郎; 早川 和重; 古賀 弘志; 菅谷 誠; 公益社団法人日本皮膚科学会, 一般社団法人日本皮膚悪性腫瘍学会皮膚悪性腫瘍診療ガイドライン改訂委員会(皮膚血管肉腫診療ガイドライングループ)

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 131 (2) 245 - 277 0021-499X 2021/02
• Inducible skin-associated lymphoid tissue (iSALT) in a patient with Schnitzler syndrome who manifested wheals on recurrent localized erythema.

  H Kamido; D Shimomiya; T Kogame; R Takimoto-Ito; T R Kataoka; M Hirata; C Ueshima; A Otsuka; F M Ghazawi; T Nomura; N Kambe; K Kabashima

  The British journal of dermatology 2021/01 

  Schnitzler syndrome is characterized by a chronic urticarial rash with an intermittent fever, and is considered to be an acquired form of autoinflammatory syndrome because its clinical phenotypes are similar to cryopyrin-associated periodic syndrome with a gain-of-function mutation in NLRP3.1 Patients with Schnitzler syndrome also exhibit IgM monoclonal gammopathy, and 15-20% of patients eventually develop a lymphoproliferative disorder resembling Waldenström macroglobulinemia with an MYD88 mutation.2 At present, the precise pathogenesis of Schnitzler syndrome remains unknown.
• エピルビシンとカルボプラチンの併用療法に反応したエクリン汗孔癌の1例

  田原 純平; 大塚 篤司; 小松 貴義; 山村 健太郎; 加来 洋; 遠藤 雄一郎; 江川 形平; 野村 尚史; 椛島 健治

  日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 (一社)日本皮膚悪性腫瘍学会 36回 148 - 148 2020/12
• Photosensitive Dermatitis Induced by Nivolumab/Ipilimumab Combination Therapy in a Patient with Malignant Melanoma.

  Yuri Sakaguchi; Takaya Komori; Megumi Aoki; Atsushi Otsuka; Kenji Kabashima; Shigeto Matsushita

  Acta dermato-venereologica 100 (18) adv00335  2020/11
• Anti-PD-1 antibody therapy for epithelial skin malignancies: An investigator-initiated, open-label, single-arm, multicenter, phase II clinical trial (NMSC-PD1 Study).

  Maki Ishii; Ikuko Hirai; Keiji Tanese; Takayuki Fusumae; Yoshio Nakamura; Keitaro Fukuda; Hiroshi Uchi; Kenji Kabashima; Atsushi Otsuka; Kenji Yokota; Naoya Yamazaki; Kenjiro Namikawa; Taku Fujimura; Tatsuya Takenouchi; Yuki Yamamoto; Mana Nishiguchi; Yasunori Sato; Masayuki Amagai; Takeru Funakoshi

  Medicine 99 (44) e22913  2020/10 

  INTRODUCTION: Malignant cutaneous epithelial tumors comprise various skin malignancies originating from the cutaneous epithelium, including cutaneous squamous cell carcinoma, basal cell carcinoma, and malignant cutaneous adnexal tumors. Treatment options are limited, as the rarity of these tumors, especially among Asians, renders well-controlled clinical trials extremely challenging to conduct. Thus, we designed a clinical trial to evaluate the efficacy and safety of the anti-programmed cell death-1 (PD-1) monoclonal antibody nivolumab in patients with metastatic cutaneous squamous cell carcinomas and other rare metastatic cutaneous epithelial tumors. METHODS AND ANALYSIS: This is an open-label, single-arm, multicenter, phase 2 clinical trial involving patients with metastatic malignant cutaneous epithelial tumors. Nivolumab (480 mg) will be administered intravenously every 4 weeks for a maximum of 26 doses. The primary outcome of the study will be the response rate based on response evaluation criteria in solid tumors, version 1.1. Assuming a null hypothesis of a response rate ≤5% and an alternative hypothesis of a 25% response rate, a minimum of 26 patients are required to achieve a 5% two-sided type I error and 80% power based on the exact binomial distribution. Finally, a target cohort size of 30 patients was determined as some patient dropout will be expected. DISCUSSION: This is the first phase 2 clinical trial evaluating the efficacy and safety of the PD-1 inhibitor nivolumab in Asian patients with metastatic malignant cutaneous epithelial tumors. The findings of the study will contribute to the development of novel treatment approaches for patients with rare cutaneous malignancies, which remains an unmet clinical need. TRIAL REGISTRATION: Registry number: jRCT 2031190048.
• Demographic and clinical characteristics of extramammary Paget's disease patients in Japan from 2000 to 2019

  F.M. Ghazawi; N. Iga; R. Tanaka; Y. Fujisawa; K. Yoshino; C. Yamashita; Y. Yamamoto; T. Fujimura; T. Yanagi; H. Hata; S. Matsushita; M. Le; S.F. Roy; F. Lagacé; Y. Ishida; K. Kabashima; A. Otsuka

  Journal of the European Academy of Dermatology and Venereology Wiley 2020/09 [Refereed]
  
• Atypical blue nevus of the labium minus confirmed by whole-exome sequencing.

  Kosuke Katsuo; Yo Kaku; Kentaro Yamamura; Yoshihiro Ishida; Yuichiro Endo; Gyohei Egawa; Atsushi Otsuka; Kenji Kabashima

  Journal of the European Academy of Dermatology and Venereology : JEADV 2020/07 [Refereed]
   

  Blue nevus is a subset of benign melanocytic tumors typically located on the dorsal aspects of extremities, scalp, and buttocks. It is also reported to occur rarely even at the oral and genital mucosa. Herein, we report a case of blue nevus of the labium minus with atypical clinical manifestations, which was confirmed by whole-exome sequencing.
• Increased expression of dermal LL37 may trigger migration of CCR7+ regulatory T cells in extramammary Paget's disease.

  Chunbing Lyu; Taku Fujimura; Ryo Amagai; Kentaro Ohuchi; Yota Sato; Kayo Tanita; Shigeto Matsushita; Yasuhiro Fujisawa; Atsushi Otsuka; Yuki Yamamoto; Toshiya Takahashi; Setsuya Aiba

  Journal of dermatological science 99 (1) 65 - 68 2020/07
• Immune checkpoint inhibitor-induced vitiligo in advanced melanoma could be related to increased levels of CCL19

  T. Fujimura; K. Tanita; Y. Sato; C. Lyu; Y. Kambayashi; Y. Fujisawa; H. Uchi; Y. Yamamoto; A. Otsuka; K. Yoshino; S. Matsushita; T. Funakoshi; S. Fukushima; H. Hata; A. Hashimoto; S. Aiba

  British Journal of Dermatology 182 (5) 1297 - 1300 0007-0963 2020/05
• Severe Demyelinating Neuropathy in an Advanced Melanoma Patient Treated with Nivolumab plus Ipilimumab Combined Therapy

  Yumi Kambayashi; Taku Fujimura; Hiroshi Kuroda; Atsushi Otsuka; Hiroyuki Irie; Setsuya Aiba

  Case Reports in Oncology S. Karger AG 13 (1) 474 - 477 2020/04
• IGF2BP3 (IMP3) expression in angiosarcoma, epithelioid hemangioendothelioma, and benign vascular lesions.

  Misuzu Okabayshi; Tatsuki R Kataoka; Marina Oji; Satoko Mibayashi; Kentaro Odani; Atsushi Otsuka; Hironori Haga

  Diagnostic pathology 15 (1) 26 - 26 2020/03 [Refereed]
   

  BACKGROUND: Insulin-like growth factor-2 messenger RNA-binding protein 3 (IGF2BP3 or IMP3) is an oncofetal protein that is expressed in various cancer types, and its expression is often associated with poor prognosis. IGF2BP3 expression has not been fully settled in vascular lesions. METHODS: We evaluated the expression of IGF2BP3 in malignant (angiosarcoma and epithelioid hemangioendothelioma [EHE]) and benign (hemangioma, granulation tissue cappilaries, and pyogenic granuloma) vascular lesions using immunohistochemistry. IGF2BP3 expression was scored as negative (0% of endothelial/neoplastic cells), equivocal (1-25%), or positive (> 26%). RESULTS: Eight of 30 (26.7%) cases of angiosarcoma and two of five (40%) cases of epithelioid hemangioendothelioma were positive for IGF2BP3. In contrast, hemangiomas (10 cases) and granulation tissue capillaries (12 cases) were all negative for IGF2BP3, and some cases of pyogenic granuloma (six of 14 cases) was scored as equivocal. In angiosarcoma, IGF2BP3 expression was independent of age, gender, location, morphological pattern, prognosis, presence of metastatic foci, and PD-L1 expression. CONCLUSIONS: IGF2BP3 is a useful marker to distinguish between malignant and benign vascular lesions.
• The efficacy of eribulin mesylate for patients with cutaneous angiosarcoma previously treated with taxane: a multi-center, prospective, observational study

  Fujisawa Y; Fujimura T; Matsushita S; Yamamoto Y; Uchi H; Otsuka A; Funakoshi T; Miyagi T; Hata H; Gosho M; Kambayashi Y; Aoki M; Yanagi T; Ohira A; Nakamura Y; Maeda T; Yoshino K

  British Journal of Dermatology 2020/03 [Refereed]
  
• Dupilumab improved atypical fibrotic skin plaques in atopic dermatitis

  C. Nakashima; Y. Ishida; Y. Kaku; E.H. Epstein; A. Otsuka; K. Kabashima

  British Journal of Dermatology Wiley 182 (2) 487 - 488 0007-0963 2020/02
• Janus kinase inhibitor delgocitinib suppresses pruritus and nerve elongation in an atopic dermatitis murine model.

  Yasuo Yamamoto; Atsushi Otsuka; Chisa Nakashima; Yoshihiro Ishida; Tetsuya Honda; Gyohei Egawa; Wataru Amano; Kenji Usui; Yuji Hamada; Masashi Wada; Atsuo Tanimoto; Noriko Konishi; Mikio Hayashi; Mutsuyoshi Matsushita; Kenji Kabashima

  Journal of dermatological science 97 (2) 161 - 164 2020/02
• Editorial: Recent Developments in Therapies and Diagnostic Tools for Melanoma and Non-melanoma Skin Cancer.

  Taku Fujimura; Yasuhiro Fujisawa; Atsushi Otsuka; Nikolas K Haass

  Frontiers in medicine 7 613152 - 613152 2020
• Interaction of peripheral nerves and mast cells, eosinophils, and basophils in the development of pruritus.

  Chisa Nakashima; Yoshihiro Ishida; Akihiko Kitoh; Atsushi Otsuka; Kenji Kabashima

  Experimental dermatology 28 (12) 1405 - 1411 2019/12 

  Mast cells, eosinophils and basophils are central effector immune cells in allergic skin inflammation including atopic dermatitis (AD). Recent studies revealed that the bidirectional interaction between these three immune cell types (mast cells, eosinophils and basophils) and the nervous system is involved in the pathogenesis of neurogenic inflammation, pain and pruritus. Emerging evidence shows that these cells are the main source of pruritogens such as histamine, neuropeptides and cytokines, which are potential new therapeutic targets for drug development in chronic pruritus. For instance, many Th2 cytokines including interleukin (IL)-4, 13 and 31 have been recognized as some of the most promising targets for the treatment of chronic pruritus in AD. In this review, we highlight the link between these three immune cell subsets and peripheral nerves, with emphasis on the development of chronic pruritus such as AD. We present cytokines and receptors of these three immune cells and peripheral nerves, and discuss the therapeutic potential of targeting these neuro-immunological processes.
• Abl family tyrosine kinases govern IgG extravasation in the skin in a murine pemphigus model

  Sachiko Ono; Gyohei Egawa; Takashi Nomura; Akihiko Kitoh; Teruki Dainichi; Atsushi Otsuka; Saeko Nakajima; Masayuki Amagai; Fumi Matsumoto; Mami Yamamoto; Yoshiaki Kubota; Toshiyuki Takai; Tetsuya Honda; Kenji Kabashima

  Nature Communications 10 (1) 2019/12 [Refereed]
   

  © 2019, The Author(s). The pathway of homeostatic IgG extravasation is not fully understood, in spite of its importance for the maintenance of host immunity, the management of autoantibody-mediated disorders, and the use of antibody-based biologics. Here we show in a murine model of pemphigus, a prototypic cutaneous autoantibody-mediated disorder, that blood-circulating IgG extravasates into the skin in a time- and dose-dependent manner under homeostatic conditions. This IgG extravasation is unaffected by depletion of Fcγ receptors, but is largely attenuated by specific ablation of dynamin-dependent endocytic vesicle formation in blood endothelial cells (BECs). Among dynamin-dependent endocytic vesicles, IgG co-localizes well with caveolae in cultured BECs. An Abl family tyrosine kinase inhibitor imatinib, which reduces caveolae-mediated endocytosis, impairs IgG extravasation in the skin and attenuates the murine pemphigus manifestations. Our study highlights the kinetics of IgG extravasation in vivo, which might be a clue to understand the pathological mechanism of autoantibody-mediated autoimmune disorders.
• 免疫チェックポイント阻害薬使用中に発症した光沢苔癬の1例 免疫組織染色による病態解析

  小松 貴義; 中島 沙恵子; 加来 洋; 趙 マリア; 大塚 篤司; 片岡 竜貴; 平田 勝啓; 大日 輝記; 野村 尚史; 椛島 健治

  日本皮膚免疫アレルギー学会雑誌 (一社)日本皮膚免疫アレルギー学会 3 (1) 228 - 228 2433-7846 2019/11
• Variable indoleamine 2,3-dioxygenase expression in acral/mucosal melanoma and its possible link to immunotherapy.

  Natsuko Iga; Atsushi Otsuka; Masahiro Hirata; Tatsuki R Kataoka; Hiroyuki Irie; Chisa Nakashima; Shigeto Matsushita; Hiroshi Uchi; Yuki Yamamoto; Takeru Funakoshi; Yasuhiro Fujisawa; Koji Yoshino; Taku Fujimura; Hiroo Hata; Yoshihiro Ishida; Kenji Kabashima

  Cancer science Cancer Science 110 (11) 3434 - 3441 1347-9032 2019/11 

  © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Immune checkpoint inhibitors have improved the prognosis of advanced melanoma. Although anti–programmed death ligand-1 (PD-L1) is a well-studied biomarker for response to anti–programmed death-1 PD-1 therapy in melanoma, its clinical relevance remains unclear. It has been established that the high expression of indoleamine 2,3-dioxygenase (IDO) is correlated to a response to anti–CTLA-4 treatment in melanoma. However, it is still unknown whether the IDO expression is associated with response to anti–PD-1 therapy in advanced melanoma. In addition, acral and mucosal melanomas, which comprise a great proportion of all melanomas in Asians, are genetically different subtypes from cutaneous melanomas; however, they have not been independently analyzed due to their low frequency in Western countries. To evaluate the association of IDO and PD-L1 expression with response to anti–PD-1 antibody in acral and mucosal melanoma patients, we analyzed 32 Japanese patients with acral and mucosal melanomas treated with anti–PD-1 antibody from the perspective of IDO
• Percutaneous sensitization is limited by in situ inhibition of cutaneous dendritic cell migration through skin-resident regulatory T cells

  Sho Hanakawa; Akihiko Kitoh; Rintaro Shibuya; Teruki Dainichi; Takashi Nomura; Tetsuya Honda; Gyohei Egawa; Atsushi Otsuka; Saeko Nakajima; Mitsugu Fujita; Kenji Kabashima

  Journal of Allergy and Clinical Immunology 144 (5) 1343 - 1353.e8 0091-6749 2019/11 [Refereed]
   

  © 2019 American Academy of Allergy, Asthma & Immunology Background: Percutaneous sensitization is associated with various allergic diseases, including asthma and food allergies. However, the immunologic mechanisms underlying how the skin regulates percutaneous sensitization are still unclear. Objective: We aimed to investigate whether and how CD4+Foxp3+ regulatory T (Treg) cells residing in the skin regulate percutaneous sensitization in the skin. Methods: Selective reduction of numbers of cutaneous Treg cells was achieved by means of intradermal injection of diphtheria toxin into the ear skin of Foxp3DTR mice, in which Treg cells specifically express the diphtheria toxin receptor fused with green fluorescent protein. Results: Thirty percent to 40% of cutaneous Treg cells were capable of IL-10 production in both mice and human subjects. Selective reduction of cutaneous Treg cells at the sensitization site promoted migration of antigen-bearing dendritic cells (DCs) to the draining lymph nodes (dLNs). Accordingly, sensitization through the skin with reduced numbers of Treg cells led to enhanced antigen-specific immune responses in the dLNs, including both effector T-cell differentiation and T cell–dependent B-cell responses, such as the development of germinal center B cells expressing IgG1 and IgE. Furthermore, antigen-bearing cutaneous DC migration was enhanced in mice with IL-10 deficiency restricted to the cutaneous Treg cell compartment, suggesting an important role of cutaneous IL-10+ Treg cells in limiting percutaneous sensitization. Treg cells with a skin-homing phenotype in skin dLNs expressed high levels of IL-10, suggesting that they contribute to renewal and maintenance of the cutaneous IL-10+ Treg cell population. Conclusion: Skin-resident Treg cells limit percutaneous sensitization by suppressing antigen-bearing DC migration through in situ IL-10 production.
• Prostaglandin E2 (PGE2)-EP2 signaling negatively regulates murine atopic dermatitis-like skin inflammation by suppressing thymic stromal lymphopoietin expression.

  Yu Sawada; Tetsuya Honda; Satoshi Nakamizo; Saeko Nakajima; Yumi Nonomura; Atsushi Otsuka; Gyohei Egawa; Tomohiro Yoshimoto; Motonobu Nakamura; Shuh Narumiya; Kenji Kabashima

  The Journal of allergy and clinical immunology 144 (5) 1265 - 1273 0091-6749 2019/11 [Refereed]
   

  BACKGROUND: Atopic dermatitis (AD) is a common and chronic inflammatory skin disease of type 2 immunity. Keratinocyte-derived cytokines, including thymic stromal lymphopoietin (TSLP) and IL-33, are considered to induce the development of AD. Production of prostanoids, a family of lipid mediators, is increased in AD lesions. However, their physiologic functions remain to be clarified. OBJECTIVES: We sought to elucidate the functions of prostanoids in the development of AD. METHODS: The roles of prostanoids were investigated in a mouse model of AD induced by repeated application of hapten and PAM212, a keratinocyte cell line. RESULTS: Application of indomethacin, which blocks prostanoid synthesis, leads to enhanced TSLP and IL-33 production in the skin, increased serum IgE levels, and exacerbation of skin inflammation in this AD model. The skin inflammation was attenuated in TSLP receptor-deficient mice but not in IL-33-deficient mice, and the indomethacin-enhanced type 2 immune responses were abolished in TSLP receptor-deficient mice. Indomethacin increased protease-activated receptor 2-mediated TSLP production in keratinocytes in vitro, and prostaglandin E2 reversed the increase in TSLP levels through its receptor, the prostaglandin E2 receptor (EP2), by downregulating surface expression of protease-activated receptor 2. Administration of an EP2 agonist canceled indomethacin-enhanced TSLP production and type 2 immune responses in the skin, whereas an EP2 antagonist caused an enhancement of TSLP production and type 2 immune responses in the skin. CONCLUSION: Prostaglandin E2-EP2 signaling negatively regulates murine AD-like skin inflammation by suppressing TSLP expression.
• 局所進行粘膜黒色腫に対するニボルマブの検討

  野村 基雄; 大塚 篤司; 土井 恵太郎; 加来 洋; 松本 繁巳; 武藤 学

  日本癌治療学会学術集会抄録集 (一社)日本癌治療学会 57回 P160 - 3 2019/10 [Refereed]
  
• 局所進行粘膜黒色腫に対するニボルマブの検討

  野村 基雄; 大塚 篤司; 土井 恵太郎; 加来 洋; 松本 繁巳; 武藤 学

  日本癌治療学会学術集会抄録集 (一社)日本癌治療学会 57回 P160 - 3 2019/10 [Refereed]
  
• Advanced Invasive Extramammary Paget's Disease Concomitant with Cecal Cancer Possessing Rare Variant of TP53 Single Nucleotide Polymorphism.

  Kambayashi Y; Fujimura T; Ohuchi K; Tono H; Ishida Y; Otsuka A; Aiba S

  Case reports in oncology 12 (3) 855 - 860 2019/09 [Refereed]
  
• Malassezia-derived aryl hydrocarbon receptor ligands enhance the CCL20/Th17/soluble CD163 pathogenic axis in extra-mammary Paget's disease.

  Yota Sato; Taku Fujimura; Kayo Tanita; Lyu Chunbing; Shigeto Matsushita; Yasuhiro Fujisawa; Atsushi Otsuka; Yuki Yamamoto; Takanori Hidaka; Setsuya Aiba

  Experimental dermatology 28 (8) 933 - 939 0906-6705 2019/08 [Refereed]
   

  Malassezia yeast play a role in the pathogenesis of chronic dermatitis, especially in apocrine areas, by polarizing the local immunologic background to a Th2/Th17 state through aryl hydrocarbon receptor (AhR)-dependent pathways. Extra-mammary Paget's disease (EMPD) is an adenocarcinoma of apocrine origin, and except for cases associated with Malassezia yeast and their metabolites, the lesions typically develop in areas not exposed to environmental material. The purpose of this study was to investigate (a) the immunomodulatory effects of Malassezia metabolites on normal human keratinocytes (NHKCs), focusing on interleukin (IL)-17 and related cytokines/chemokines (IL-23, IL-36γ, CCL20), (b) the expression of these factors in lesion-affected skin in EMPD and (c) the activation of tumor-associated macrophages (TAMs) by these factors. Malassezia metabolites augmented the expression of cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), CCL20 and IL-36γ mRNA in NHKCs in vitro. In lesion-affected skin of patients with EMPD, epidermal keratinocytes expressed CYP1A1 and CCL20. In addition, Paget cells expressed CCL20 and IL-23. IL-17-producing cells were distributed adjacent to Paget cells. Compared to healthy donors, patients with EMPD exhibited significantly increased serum levels of soluble (s)CD163, CXCL5, CXCL10 and CCL20. In addition, serum levels of sCD163 decreased significantly following tumor resection. Our study demonstrates a possible mechanism for the development of EMPD involving AhR-mediated signalling by epidermal keratinocytes and RANKL-induced recruitment of Th17 cells and TAMs.
• Murine neonatal skin mast cells are phenotypically immature and minimally sensitized with transplacentally transferred IgE

  Yuki Honda; Sachiko Ono; Tetsuya Honda; Tatsuki R. Kataoka; Gyohei Egawa; Akihiko Kitoh; Atsushi Otsuka; S. Nakajima; Takashi Nomura; Teruki Dainichi; K. Kabashima

  Journal of Allergy and Clinical Immunology 144 (2) 617 - 620.e5 0091-6749 2019/08 [Refereed]
  
• 円形脱毛症に対するステロイドハーフパルス療法の治療反応性および副作用発現の規定因子 105例の検討

  大日 輝記; 藤井 弘子; 遠藤 雄一郎; 大塚 篤司; 藤澤 章弘; 谷岡 未樹; 宮地 良樹; 椛島 健治

  Aesthetic Dermatology (一社)日本美容皮膚科学会 29 (2) 182 - 182 1341-5530 2019/07 [Refereed]
  
• Severe bullous pemphigoid in a metastatic lung cancer patient treated with pembrolizumab.

  Adachi E; Honda T; Nonoyama S; Irie H; Yamamura K; Otsuka A; Kabashima K

  The Journal of dermatology 46 (7) e232 - e233 0385-2407 2019/07 [Refereed]
  
• Diffuse hair loss following anti-programmed cell death-1 antibody treatment: a case report with immunohistochemical analysis.

  Komatsu-Fujii T; Otsuka A; Ishida Y; Kaku Y; Yamashita C; Hata A; Kataoka T; Honda T; Kabashima K

  European journal of dermatology : EJD 29 (3) 326 - 327 1167-1122 2019/06 [Refereed]
  
• Response to imatinib in vaginal melanoma with KIT p.Val559Gly mutation previously treated with nivolumab, pembrolizumab and ipilimumab.

  Takayoshi Komatsu-Fujii; Motoo Nomura; Atsushi Otsuka; Yoshihiro Ishida; Keitaro Doi; Shigemi Matsumoto; Manabu Muto; Kenji Kabashima

  The Journal of dermatology 46 (6) e203-e204 - e204 0385-2407 2019/06 [Refereed]
  
• Predictive factors of response to pulse methylprednisolone therapy in patients with alopecia areata: A follow-up study of 105 Japanese patients

  Hiroko Fujii; Yuichiro Endo; Teruki Dainichi; Atsushi Otsuka; Akihiro Fujisawa; Miki Tanioka; Yoshiki Miyachi; Kenji Kabashima

  Journal of Dermatology 46 (6) 522 - 525 0385-2407 2019/06 [Refereed]
   

  © 2019 Japanese Dermatological Association Pulse corticosteroid therapy is effective for alopecia areata (AA) in the early stage. The risk and efficacy of this therapy for patients with several backgrounds, however, remains controversial. To explore the predictive factors of the response and risk factors of this therapy, data from 105 AA patients treated with methylprednisolone (500 mg) i.v. for 3 days consecutively in our facility were retrospectively analyzed. Among good responders, longer time from the onset to therapy was correlated with longer time required for hair regrowth (P = 0.037, n = 27). Multivariate models demonstrated that “severity”, “relapse” and longer “duration from the latest onset” were significantly and independently associated with poorer outcome (P < 0.01). “History of atopic dermatitis (AD)” was also associated with poorer outcome, but this correlation could be explained by the effect that duration from the latest onset of AA was longer among participants with AD. We propose that earlier initiation of pulse corticosteroid therapy is preferable for better outcome of AA, particularly among patients with AD. Clinicians should be mindful of the occurrence of mild adverse effects in the elderly patients.
• Inverse responses of the skin and nail lesions of psoriatic arthritis to an anti-interleukin-17A antibody and an anti-tumor necrosis factor-α antibody.

  Komatsu-Fujii T; Honda T; Otsuka A; Kabashima K

  The Journal of dermatology 0385-2407 2019/06 [Refereed]
  
• Improvement of nail lesions in a patient with psoriatic arthritis by switching the treatment from an anti-interleukin-17A antibody to an anti-tumor necrosis factor-α antibody.

  Komatsu-Fujii T; Honda T; Otsuka A; Kabashima K

  The Journal of dermatology 46 (5) e158 - e160 0385-2407 2019/05 [Refereed]
  
• Nail pitting and splinter hemorrhage possibly induced by zolpidem.

  Komori T; Otsuka A; Cho M; Honda T; Kabashima K

  The Journal of dermatology 46 (5) e151 - e152 0385-2407 2019/05 [Refereed]
  
• メルケル細胞癌におけるPET-CTのFDG集積に関する細胞学的検討

  北村 真也; 柳 輝希; 高島 有香; 今福 恵輔; 秦 洋郎; 清水 宏; 平田 健司; 上原 治朗; 石田 雄大; 大塚 篤司

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 129 (3) 353 - 353 0021-499X 2019/03
• Predicting marker for early progression in unresectable melanoma treated with nivolumab.

  Tomohiro Kondo; Motoo Nomura; Atsushi Otsuka; Yumi Nonomura; Yo Kaku; Shigemi Matsumoto; Manabu Muto

  International journal of clinical oncology 24 (3) 323 - 327 2019/03 [Refereed]
   

  BACKGROUND: The objective of this study was to identify predictive markers, including inflammatory and nutritional status measures, of early progressive disease (EPD) in unresectable melanoma patients treated with nivolumab. METHODS: A retrospective review was performed on 39 consecutive patients with unresectable melanoma treated with nivolumab. EPD was defined as progressive disease within 60 days after starting nivolumab according to Response Evaluation Criteria in Solid Tumors version 1.1. The predictive index model [melanoma inflammation index (MII)] was determined by the number of predictive factors. RESULTS: Seventeen patients had cutaneous melanoma and 22 patients had mucosal melanoma. The overall response rate was 18.4%, and the response rates for cutaneous and mucosal melanoma were 29.4% and 9.5%, respectively. EPD was observed in 13 patients (34.2%). By multivariate analysis, body mass index (BMI) and C-reactive protein to albumin ratio (CAR) were independently and significantly associated with EPD, disease control rate, progression-free survival, and overall survival. Low BMI (cutoff 20) and high CAR (cutoff 0.0055) were predictive factors of EPD and were determined to be prognostic factors. MII, from 0 to 2, was determined by the number of these factors. The incidence of EPD was 0% in the low-risk group (MII = 0), 50% in the intermediate-risk group (MII = 1), and 83% in the high-risk group (MII = 2). CONCLUSIONS: An MII status of low BMI and high CAR may be used to predict EPD in unresectable melanoma patients treated with nivolumab.
• Ten-year follow up of longitudinal melanonychia in childhood: A case report

  Kimika Taniguchi; Yo Kaku; Mayumi Fukuda; Akihiro Fujisawa; Miki Tanioka; Teruki Dainichi; Yoshiki Miyachi; Atsushi Otsuka; Tetsuya Honda; Kenji Kabashima

  Journal of Dermatology 46 (3) e89 - e90 0385-2407 2019/03 [Refereed]
  
• DIHS/DRESS-like eruption possibly induced by amoxicillin during treatment with nivolumab

  Riko Takimoto; Tetsuya Honda; Tatsuki R. Kataoka; Chiyuki Ueshima; Atsushi Otsuka; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 29 (2) 228 - 229 1167-1122 2019/03 [Refereed]
  
• Scleroderma-like syndrome associated with nivolumab treatment in malignant melanoma.

  Maria Cho; Yumi Nonomura; Yo Kaku; Shuichiro Nakabo; Yuichiro Endo; Atsushi Otsuka; Kenji Kabashima

  The Journal of dermatology 46 (1) e43-e44 - e44 0385-2407 2019/01 [Refereed]
  
• Accumulation of exhausted CD8+ T cells in extramammary Paget's disease

  Natsuko Iga; Atsushi Otsuka; Yosuke Yamamoto; Chisa Nakashima; Tetsuya Honda; Akihiko Kitoh; Saeko Nakajima; Gyohei Egawa; Takashi Nomura; Teruki Dainichi; Shigeto Matsushita; Hideaki Tanizaki; Yuki Yamamoto; Takeru Funakoshi; Yasuhiro Fujisawa; Taku Fujimura; Hiroo Hata; Yoshihiro Ishida; Kenji Kabashima

  PLoS ONE 14 (1) e0211135  2019/01 [Refereed]
   

  Copyright: © 2019 Iga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Cancer immunotherapy has highlighted the clinical relevance of enhancing anti-tumor response of CD8+ T cells in several cancer types. Little is known, however, about the involvement of the immune system in extramammary Paget's disease (EMPD). We examined the cytotoxicity and the effector functions of CD8+ T cells using paired samples of peripheral blood and tumors by flow cytometry. Expression levels of perforin, granzyme B, IFN-g, TNF-a, and IL-2 in CD8+ tumor-infiltrating lymphocytes (TILs) were significantly lower than those in CD8+ T cells of peripheral blood. Significantly higher expression of PD-1 was found in CD8+TILs than in CD8+ T cells of peripheral blood. A high number of CD8+ cells was significantly associated with poor overall survival (OS) adjusted with age, sex, and clinical stage (hazard ratio [HR] = 5.03, P = 0.045, 95% confidence interval [CI] 1.03-24.4). On the other hand, the number of PD-1+ cells was not associated with OS or disease-free survival (DFS). Moreover, we found that tumor cells produced immunosuppressive molecule indoleamine 2,3-dyoxygenae (IDO). In conclusion, CD8+ TILs displayed an exhausted phenotype in EMPD. IDO expression seemed more relevant in inducing CD8 exhaustion than PD-1 upregulation or PD-L1 expression by immune cells. Restoring the effector functions of CD8+ TILs could be an effective treatment strategy for advanced EMPD.
• Real-time 3D photoacoustic visualization system with a wide field of view for imaging human limbs [version 2; referees: 2 approved]

  Kenichi Nagae; Yasufumi Asao; Yoshiaki Sudo; Naoyuki Murayama; Yuusuke Tanaka; Katsumi Ohira; Yoshihiro Ishida; Atsushi Otsuka; Yoshiaki Matsumoto; Susumu Saito; Moritoshi Furu; Koichi Murata; Hiroyuki Sekiguchi; Masako Kataoka; Aya Yoshikawa; Tomoko Ishii; Kaori Togashi; Tsuyoshi Shiina; Kenji Kabashima; Masakazu Toi; Takayuki Yagi

  F1000Research 7 1813  2046-1402 2019 [Refereed]
   

  © 2019 Nagae K et al. Background: A breast-specific photoacoustic imaging (PAI) system prototype equipped with a hemispherical detector array (HDA) has been reported as a promising system configuration for providing high morphological reproducibility for vascular structures in living bodies. Methods: To image the vasculature of human limbs, a newly designed PAI system prototype (PAI-05) with an HDA with a higher density sensor arrangement was developed. The basic device configuration mimicked that of a previously reported breast-specific PAI system. A new imaging table and a holding tray for imaging a subject's limb were adopted. Results: The device’s performance was verified using a phantom. Contrast of 8.5 was obtained at a depth of 2 cm, and the viewing angle reached up to 70 degrees, showing sufficient performance for limb imaging. An arbitrary wavelength was set, and a reasonable PA signal intensity dependent on the wavelength was obtained. To prove the concept of imaging human limbs, various parts of the subject were scanned. High-quality still images of a living human with a wider size than that previously reported were obtained by scanning within the horizontal plane and averaging the images. The maximum field of view (FOV) was 270 mm × 180 mm. Even in movie mode, one-shot 3D volumetric data were obtained in an FOV range of 20 mm in diameter, which is larger than values in previous reports. By continuously acquiring these images, we were able to produce motion pictures. Conclusion: We developed a PAI prototype system equipped with an HDA suitable for imaging limbs. As a result, the subject could be scanned over a wide range while in a more comfortable position, and high-quality still images and motion pictures could be obtained.
• Association of Baseline Serum Levels of CXCL5 With the Efficacy of Nivolumab in Advanced Melanoma.

  Taku Fujimura; Yota Sato; Kayo Tanita; Chunbing Lyu; Yumi Kambayashi; Ryo Amagai; Atsushi Otsuka; Yasuhiro Fujisawa; Koji Yoshino; Shigeto Matsushita; Hiroshi Uchi; Yuki Yamamoto; Hiroo Hata; Takeru Funakoshi; Yumi Nonomura; Ryota Tanaka; Hisako Okuhira; Naoko Wada; Akira Hashimoto; Setsuya Aiba

  Frontiers in medicine 6 86 - 86 2019 [Refereed]
   

  Anti-programmed cell death protein 1 (PD1) antibodies are in wide use for the treatment of various cancers. PD1 antibody-based immunotherapy, co-administration of nivolumab and ipilimumab, is one of the optimal immunotherapies, especially in advanced melanoma with high tumor mutation burden. Since this combined therapy leads to a high frequency of serious immune-related adverse events (irAEs) in patients with advanced melanoma, biomarkers are needed to evaluate nivolumab efficacy to avoid serious irAEs caused by ipilimumab. This study analyzed baseline serum levels of CXCL5, CXCL10, and CCL22 in 46 cases of advanced cutaneous melanoma treated with nivolumab. Baseline serum levels of CXCL5 were significantly higher in responders than in non-responders. In contrast, there were no significant differences in baseline serum levels of CXCL10 and CCL22 between responders and non-responders. These results suggest that baseline serum levels of CXCL5 may be useful as a biomarker for identifying patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.
• Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab.

  Ichiro Yamauchi; Akihiro Yasoda; Shigemi Matsumoto; Yuichi Sakamori; Young Hak Kim; Motoo Nomura; Atsushi Otsuka; Toshinari Yamasaki; Ryoichi Saito; Morimasa Kitamura; Toshio Kitawaki; Masakatsu Hishizawa; Nobuko Kawaguchi-Sakita; Toshihito Fujii; Daisuke Taura; Masakatsu Sone; Nobuya Inagaki

  PloS one 14 (5) e0216954  2019 [Refereed]
   

  BACKGROUND: Blocking the PD-1 pathway induces immune-related adverse events (irAEs) which often involve the thyroid gland (thyroid irAEs). Clinical features of a thyroid irAE including its predictability and relationship to prognosis remain to be elucidated. METHODS: Two hundred consecutive patients treated with nivolumab at Kyoto University Hospital between September 1, 2014 and August 31, 2017 were included in a retrospective cohort study. We systematically determined and classified subclinical and overt thyroid irAEs based on data collected of serum free T4 and TSH levels. Baseline characteristics and detailed clinical data were analyzed, and analyses of overall survival (OS) excluded patients censored within 1 month from the first administration of nivolumab. RESULTS: Sixty-seven patients (33.5%) developed thyroid irAEs and these were divided into a subclinical thyroid irAE group (n = 40, 20.0%) and an overt thyroid irAE group (n = 27, 13.5%). Patients with thyroid uptake of FDG-PET before treatment showed high incidences of overt thyroid irAE (adjusted odds ratio 14.48; 95% confidence interval [CI] 3.12-67.19), while the same relationship was not seen with subclinical thyroid irAE. Regarding the total cohort, the thyroid irAE (+) group had a significantly longer median OS than the thyroid irAE (-) group (16.1 versus 13.6 months, hazard ratio [HR] 0.61; 95% CI 0.39-0.93). In 112 non-excluded patients with lung cancer, the thyroid irAE (+) group similarly had a longer median OS than the thyroid irAE (-) group (not reached versus 14.2 months, HR 0.51; 95% CI 0.27-0.92). However, this observation was not seen in 41 non-excluded patients with malignant melanoma (12.0 versus 18.3 months, HR 1.54; 95% CI 0.67-3.43). CONCLUSIONS: By thyroid uptake of FDG-PET, overt thyroid irAEs could be predicted before nivolumab therapy. Thyroid irAEs related to good prognosis in lung cancer but might be inconclusive in malignant melanoma.
• The epithelial immune microenvironment (EIME) in atopic dermatitis and psoriasis

  Teruki Dainichi; Akihiko Kitoh; Atsushi Otsuka; Saeko Nakajima; Takashi Nomura; Daniel H. Kaplan; Kenji Kabashima

  Nature Immunology 19 (12) 1286 - 1298 1529-2908 2018/12 [Refereed]
   

  © 2018, Springer Nature America, Inc. The skin provides both a physical barrier and an immunologic barrier to external threats. The protective machinery of the skin has evolved to provide situation-specific responses to eliminate pathogens and to provide protection against physical dangers. Dysregulation of this machinery can give rise to the initiation and propagation of inflammatory loops in the epithelial microenvironment that result in inflammatory skin diseases in susceptible people. A defective barrier and microbial dysbiosis drive an interleukin 4 (IL-4) loop that underlies atopic dermatitis, while in psoriasis, disordered keratinocyte signaling and predisposition to type 17 responses drive a pathogenic IL-17 loop. Here we discuss the pathogenesis of atopic dermatitis and psoriasis in terms of the epithelial immune microenvironment—the microbiota, keratinocytes and sensory nerves—and the resulting inflammatory loops.
• A Case of Pityriasis Rubra Pilaris Treated Successfully with the Phosphodiesterase-4 Inhibitor Apremilast.

  Cho M; Honda T; Ueshima C; Kataoka T; Otsuka A; Kabashima K

  Acta dermato-venereologica 98 (10) 975 - 976 0001-5555 2018/11 [Refereed]
  
• Mild dystrophic epidermolysis bullosa associated with homozygous gene mutation c.6216+5G>T in type VII collagen ultrastructurally suggestive of the decreased number of anchoring fibrils

  Takaya Komori; Teruki Dainichi; Atsushi Otsuka; Hajime Nakano; Daisuke Sawamura; Akemi Ishida-Yamamoto; Kenji Kabashima

  Journal of Dermatology 45 (11) e305 - e306 0385-2407 2018/11 [Refereed]
  
• Killer immunoglobulin-like receptor genotype did not correlate with response to anti-PD-1 antibody treatment in a Japanese cohort.

  Yoshihiro Ishida; Chisa Nakashima; Hiroto Kojima; Hidenori Tanaka; Taku Fujimura; Shigeto Matsushita; Yuki Yamamoto; Koji Yoshino; Yasuhiro Fujisawa; Atsushi Otsuka; Kenji Kabashima

  Scientific reports 8 (1) 15962 - 15962 2018/10 [Refereed]
   

  Immune checkpoint blockade (ICB) induces a remarkable response in patients with certain cancers. However, the response rate is not yet satisfactory. Biomarkers that help physicians identify patients who would benefit from ICB need to be developed. Killer immunoglobulin-like receptors (KIRs) are a class of receptors that are mainly expressed by natural killer cells. KIR genotypes have been shown to influence the outcomes of patients with neuroblastoma and hematopoietic malignancies. KIRs may thus influence the clinical outcomes of melanoma patients receiving nivolumab. We aimed to identify the KIR genotype, or KIR/KIR-ligand combinations, which influence the outcomes of melanoma patients receiving nivolumab. We genotyped 112 melanoma patients who were treated with nivolumab for KIR and human leukocyte antigen. The clinical records of the patients were analyzed to determine if they showed a response to nivolumab, and whether or not they experienced adverse events. Our analysis showed that no KIR gene was associated with a response to nivolumab. The KIR/KIR-ligand combination did not correlate with a response to nivolumab. KIR genes were not predictive of experiencing adverse events of grade 2 or greater. We conclude that the KIR genotype or KIR/KIR-ligand genotype do not show predictive value in melanoma patients receiving nivolumab.
• Angiolymphoid hyperplasia with eosinophilia: A case of spontaneous partial regression post-biopsy.

  Maria Cho; Yo Kaku; Kazuya Goto; Yuichiro Endo; Tatsuki Kataoka; Atsushi Otsuka; Kenji Kabashima

  The Journal of dermatology 45 (10) e284-e285 - e285 0385-2407 2018/10 [Refereed]
  
• A case of possible chemical leukoderma secondary to usage of skin whitening agents.

  Cho M; Otsuka A; Irie H; Kataoka T; Kabashima K

  European journal of dermatology : EJD 28 (5) 701 - 702 1167-1122 2018/10 [Refereed]
  
• Epithelial TRAF6 drives IL-17-mediated psoriatic inflammation

  Reiko Matsumoto; Teruki Dainichi; Soken Tsuchiya; Takashi Nomura; Akihiko Kitoh; Matthew S. Hayden; Ken J. Ishii; Mayuri Tanaka; Tetsuya Honda; Gyohei Egawa; Atsushi Otsuka; Saeko Nakajima; Kenji Sakurai; Yuri Nakano; Takashi Kobayashi; Yukihiko Sugimoto; Kenji Kabashima

  JCI insight 3 (15) 2018/08 [Refereed]
   

  Epithelial cells are the first line of defense against external dangers, and contribute to induction of adaptive immunity including Th17 responses. However, it is unclear whether specific epithelial signaling pathways are essential for the development of robust IL-17-mediated immune responses. In mice, the development of psoriatic inflammation induced by imiquimod required keratinocyte TRAF6. Conditional deletion of TRAF6 in keratinocytes abrogated dendritic cell activation, IL-23 production, and IL-17 production by γδ T cells at the imiquimod-treated sites. In contrast, hapten-induced contact hypersensitivity and papain-induced IgE production were not affected by loss of TRAF6. Loss of psoriatic inflammation was not solely due to defective imiquimod sensing, as subcutaneous administration of IL-23 restored IL-17 production but did not reconstitute psoriatic pathology in the mutant animals. Thus, TRAF6 was required for the full development of IL-17-mediated inflammation. Therefore, epithelial TRAF6 signaling plays an essential role in both triggering and propagating IL-17-mediated psoriatic inflammation.
• Resolvin E1 attenuates murine psoriatic dermatitis.

  Yu Sawada; Tetsuya Honda; Satoshi Nakamizo; Atsushi Otsuka; Narihito Ogawa; Yuichi Kobayashi; Motonobu Nakamura; Kenji Kabashima

  Scientific reports 8 (1) 11873 - 11873 2018/08 [Refereed]
   

  The potential of omega-3 poly-unsaturated fatty acids (PUFAs) as a therapeutic target for psoriasis, a chronic inflammatory skin disease of IL-23/IL-17 axis, is a long-disputed question, since various epidemiological studies have suggested the association between high-intake of omega-3 PUFAs and the reduced frequency and severity of psoriasis. However, their actual significance and the molecular mechanisms remain largely unknown. To address these issues, we focused on resolvin E1 (RvE1), an omega-3 PUFAs-derived metabolite, and examined its effects on psoriatic dermatitis, using an imiquimod-induced mouse psoriasis model. RvE1 potently suppressed the inflammatory cell infiltration and epidermal hyperplasia in the psoriatic skin. RvE1 decreased the mRNA expression of IL-23 in the skin. Consistently, RvE1 inhibited IL-23 production by dendritic cells (DCs) in vitro. Furthermore, RvE1 exerted inhibitory effects on migration of cutaneous DCs and γδ T cells, a major IL-17-producing cell population in mouse, both in vivo and in vitro. These suppressive effects of RvE1 were mediated by its antagonistic function on BLT1, a receptor of leukotriene B4, and were also observed in human DCs, Th17 and Tc17 cells. Our results indicate a novel mechanism of omega-3 PUFA-mediated amelioration of psoriasis, and suggest a potential of RvE1 as a therapeutic target for psoriasis.
• p.Glu477Lys mutation in keratin 5 is not necessarily mortal in generalized severe epidermolysis bullosa simplex

  Takaya Komori; Teruki Dainichi; Yuka Masuno; Atsushi Otsuka; Hajime Nakano; Daisuke Sawamura; Akemi Ishida-Yamamoto; Kenji Kabashima

  Journal of Dermatology 45 (8) e209 - e210 0385-2407 2018/08 [Refereed]
  
• Thromboxane A2 facilitates IL-17A production from Vγ4⁺ γδ T cells and promotes psoriatic dermatitis in mice

  Yuri Ueharaguchi; Tetsuya Honda; Nobuhiro Kusuba; Sho Hanakawa; Akimasa Adachi; Yu Sawada; Atsushi Otsuka; Akihiko Kitoh; Teruki Dainichi; Gyohei Egawa; Chisa Nakashima; Saeko Nakajima; Teruasa Murata; Sachiko Ono; Makoto Arita; Shuh Narumiya; Yoshiki Miyachi; Kenji Kabashima

  Journal of Allergy and Clinical Immunology 142 (2) 680 - 683.e2 0091-6749 2018/08 [Refereed]
  
• The effect of oral royal jelly administration on skin barrier function: a double-blind randomized placebo-controlled trial.

  Chisa Nakashima; Atsushi Otsuka; Judith A Seidel; Kenji Kabashima

  European journal of dermatology : EJD 28 (4) 563 - 564 1167-1122 2018/08 [Refereed]
  
• Recent advancement in the mechanism of basophil activation

  Chisa Nakashima; Atsushi Otsuka; Kenji Kabashima

  Journal of Dermatological Science Elsevier Ireland Ltd 91 (1) 3 - 8 1873-569X 2018/07 [Refereed]
   

  Basophils have been recognized as crucial players in allergic inflammation. Basophils have the potential to initiate and expand inflammation through the production of specific cytokines and proteases, and are associated with T helper 2 (Th2) immune responses. In addition, recent studies revealed the heterogeneity in basophil populations. Basophils have been clarified important roles in not only IgE-mediated allergic inflammation but also TSLP-mediated and IgE-independent inflammation. Moreover, basophils infiltrate in many human cutaneous diseases. Basophils are responsible for recruiting other inflammatory cells such as macrophages, eosinophils, and fibroblasts. In this review, we discuss recent advances in our understanding of basophil activation and migration in allergic inflammation.
• HLA-DRB1*04:05 in two cases of Vogt-Koyanagi-Harada disease-like uveitis developing from an advanced melanoma patient treated by sequential administration of nivolumab and dabrafenib/trametinib therapy.

  Taku Fujimura; Yumi Kambayashi; Kayo Tanita; Yota Sato; Takanori Hidaka; Astushi Otsuka; Hidenori Tanaka; Sadanori Furudate; Akira Hashimoto; Setsuya Aiba

  The Journal of dermatology 45 (6) 735 - 737 0385-2407 2018/06 [Refereed]
   

  Although uveitis is reported as a rare adverse event (AE) associated with dabrafenib/trametinib therapy or nivolumab, the occurrence of severe uveitis is extremely rare. We describe two cases of Vogt-Koyanagi-Harada (VKH)-like uveitis developing after the sequential administration of nivolumab and dabrafenib/trametinib therapy. Interestingly, both cases had HLA-DRB1*04:05, which is strongly associated with VKH disease, and achieved biologically complete remission after the treatment for uveitis. Our cases suggest a possible correlation between VKH-like uveitis as an AE and the clinical outcomes of sequential administration of nivolumab and dabrafenib/trametinib therapy for the treatment of advanced melanoma.
• Assessment of the methods used to detect HER2-positive advanced extramammary Paget's disease.

  Ikuko Hirai; Keiji Tanese; Yoshio Nakamura; Atsushi Otsuka; Yasuhiro Fujisawa; Yuki Yamamoto; Hiroo Hata; Taku Fujimura; Shigeto Matsushita; Koji Yoshino; Kaori Kameyama; Masayuki Amagai; Takeru Funakoshi

  Medical oncology (Northwood, London, England) Medical Oncology 35 (6) 92 - 92 1357-0560 2018/05 [Refereed]
   

  © 2018, Springer Science+Business Media, LLC, part of Springer Nature. The human epidermal growth factor receptor 2 (HER2) is recognized as an oncogene as well as a therapeutic target in various cancers. Certain patients with advanced extramammary Paget’s disease (EMPD) have also been reported to express HER2, which is therefore considered a therapeutic target for EMPD. However, an accurate methodology to determine HER2-positive EMPD has not been established. To assess the optimal methods for detection of HER2-positive EMPD, 73 EMPD samples were analyzed by immunohistochemical (IHC) staining, fluorescence in situ hybridization (FISH), and the HER2 testing algorithm for breast cancer of the American Society of Clinical Oncology/College of American Pathologists, which combined the results of IHC staining and FISH. The results showed discordance in the rate of positive IHC staining and FISH results. While 68.6% (24/35) of the metastatic samples showed equivocal or positive IHC staining, only 37.1% (13/35) were positive by FISH. To assess the accuracy of these methods, the degree of HER2 expression detected by each method was correlated with the staining profiles of activated downst
• Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab

  Motoo Nomura; Atsushi Otsuka; Michio Yoshimura; Yumi Nonomura; Yo Kaku; Shigemi Matsumoto; Manabu Muto

  CANCER CHEMOTHERAPY AND PHARMACOLOGY SPRINGER 81 (5) 823 - 827 0344-5704 2018/05 [Refereed]
   

  The objective of this study was to evaluate the efficacy and safety of concurrent immune checkpoint inhibitor therapy and radiotherapy (immunoradiotherapy) in patients with metastatic melanoma after progression on nivolumab.A retrospective review was performed on 16 consecutive patients with metastatic melanoma treated with concurrent immunoradiotherapy after progression on nivolumab. Best responses to immunoradiotherapy were assessed either inside or outside of the radiation fields. The target lesions ratio (the sum of the diameters of the target lesions inside the irradiated fields/all target lesions) was also assessed.Among the patients, seven received ipilimumab and radiotherapy (Ipi-RT), six received nivolumab and radiotherapy (Nivo-RT), and three sequentially received Ipi-RT and Nivo-RT. The overall response rate (all patients regardless of inside or outside radiation fields) was 30%. The response rate inside the radiation fields was 68.8% for all patients combined. The response rates of Ipi-RT and Nivo-RT inside the radiation fields were 37.5 and 100% (P = 0.03), respectively. Grade 3 adverse events were observed in three patients treated with Ipi-RT. The target lesions ratio was a predictive marker of disease control rate among patients treated with Nivo-RT.This study showed that concurrent immunoradiotherapy is an option for patients with metastatic melanoma after progression on nivolumab.
• Effects of DLC1 Deficiency on Endothelial Cell Contact Growth Inhibition and Angiosarcoma Progression.

  Sánchez-Martín D; Otsuka A; Kabashima K; Ha T; Wang D; Qian X; Lowy DR; Tosato G

  Journal of the National Cancer Institute 110 (4) 390 - 399 0027-8874 2018/04 [Refereed]
  
• Interleukin-31 and interleukin-31 receptor: New therapeutic targets for atopic dermatitis

  Chisa Nakashima; Atsushi Otsuka; Kenji Kabashima

  Experimental Dermatology Blackwell Publishing Ltd 27 (4) 327 - 331 1600-0625 2018/04 [Refereed]
   

  Atopic dermatitis (AD) is characterized by chronic, eczematous, severe pruritic skin lesions caused by skin barrier dysfunction and T helper (Th)2 cell-mediated immunity. Interleukin (IL)-31 is a potent pruritogenic cytokine primarily produced by Th2 cells. Both IL-31 transgenic mice and wild-type mice treated with IL-31 exhibit AD-like skin lesions and scratching behaviour. IL-31 receptor α-chain (IL-31RA) is also expressed in peripheral nerves and epidermal keratinocytes, and the roles of IL-31 on pruritus and skin barrier have been investigated. Recently, an anti–IL-31 receptor antibody was shown to significantly improve pruritus in AD patients. This review focuses on IL-31 and IL-31RA in AD.
• Anti-PD-1 and anti-CTLA-4 therapies in cancer: Mechanisms of action, efficacy, and limitations

  Judith A. Seidel; Atsushi Otsuka; Kenji Kabashima

  Frontiers in Oncology Frontiers Media S.A. 8 86  2234-943X 2018/03 [Refereed]
   

  Melanoma, a skin cancer associated with high mortality rates, is highly radio- and chemotherapy resistant but can also be very immunogenic. These circumstances have led to a recent surge in research into therapies aiming to boost anti-tumor immune responses in cancer patients. Among these immunotherapies, neutralizing antibodies targeting the immune checkpoints T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are being hailed as particularly successful. These antibodies have resulted in dramatic improvements in disease outcome and are now clinically approved in many countries. However, the majority of advanced stage melanoma patients do not respond or will relapse, and the hunt for the "magic bullet" to treat the disease continues. This review examines the mechanisms of action and the limitations of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies which are the two types of checkpoint inhibitors currently available to patients and further explores the future avenues of their use in melanoma and other cancers.
• 【頸部・項部の皮膚病】<臨床例>汎発型モルフェアが先行し、びまん性筋膜炎を生じた症例

  後藤 和哉; 大塚 篤司; 加来 洋; 鬼頭 昭彦; 大日 輝記; 椛島 健治

  皮膚病診療 (株)協和企画 40 (3) 277 - 280 0387-7531 2018/03 

  ＜症例のポイント＞汎発型モルフェアが先行し、びまん性筋膜炎を発症した1例を経験した。一般的にはびまん性筋膜炎が先行する場合が多いが、自験例では汎発型モルフェアが先行した点が特徴的であった。モルフェアを伴うびまん性筋膜炎はCRPの上昇を認めることが多く、治療はステロイド内服に加え、病勢に応じて免疫抑制薬の追加が必要である。(著者抄録)
• Inhibition of IL-17–committed T cells in a murine psoriasis model by a vitamin D analogue

  Nobuhiro Kusuba; Akihiko Kitoh; Teruki Dainichi; Tetsuya Honda; Atsushi Otsuka; Gyohei Egawa; Saeko Nakajima; Yoshiki Miyachi; Kenji Kabashima

  Journal of Allergy and Clinical Immunology 141 (3) 972 - 981.e10 0091-6749 2018/03 [Refereed]
   

  © 2017 American Academy of Allergy, Asthma & Immunology Background: A better understanding of the means by which topical vitamin D analogues exert their therapeutic effect on psoriasis is of theoretical and practical importance. Objective: We sought to clarify whether and how the topical vitamin D analogue calcipotriol (CAL) controls the IL-17A–mediated pathogenesis of murine psoriasis-like dermatitis in vivo. Methods: Psoriasis-like dermatitis was induced by the topical application of an imiquimod (IMQ)–containing cream on the murine ear for 4 to 6 consecutive days. For topical CAL treatment, mice were treated daily with CAL solution on the ear before IMQ application. Results: Mice treated topically with CAL exhibited much milder IMQ-induced psoriasis-like dermatitis compared with vehicle-treated mice, with impaired accumulation of IL-17A–committed T (T17) cells in the lesional skin. The IMQ-induced upregulation of Il12b and Il23a was marked in the epidermis and was abrogated by CAL application, suggesting CAL-mediated suppression of IL-23 expression. CAL inhibited Il12b and Il23a expression by Langerhans cells ex vivo stimulated with IMQ and CD40 cross-linking. Topical CAL also inhibited T17 cell expansion in the draining lymph nodes of IMQ-treated skin, implying a possible effect on T17 cell–mediated dermatitis at distant sites. In fact, topical CAL application on the IMQ-treated left ear resulted in amelioration of T17 cell accumulation and psoriasis-like dermatitis in the right ear subsequently treated with IMQ. Conclusion: Topical CAL can exert its antipsoriatic effect on CAL-treated lesions and, concomitantly, distant lesions by attenuating the T17 cell accumulation in both CAL-treated lesions and draining lymph nodes.
• Generalized lichen nitidus following anti-PD-1 antibody treatment

  Maria Cho; Yumi Nonomura; Yo Kaku; Teruki Dainichi; Atsushi Otsuka; Kenji Kabashima

  JAMA Dermatology 154 (3) 367 - 369 2168-6068 2018/03 [Refereed]
  
• Decrease of superficial serine and lactate in the stratum corneum due to repetitive frictional trauma

  Lai San Wong; Atsushi Otsuka; Hideaki Tanizaki; Yumi Nonomura; Chisa Nakashima; Yosuke Yamamoto; Yu Ta Yen; Pawinee Rerknimitr; Tetsuya Honda; Kenji Kabashima

  International Journal of Dermatology Blackwell Publishing Ltd 57 (3) 299 - 305 1365-4632 2018/03 [Refereed]
   

  Background: Repetitive frictional trauma can be induced in daily and occupational activities, such as daily ablutions with washcloths. The influence of frictional trauma on the skin barrier function, especially in the perspective of the components of stratum corneum (SC), has not yet been studied in detail. Raman spectroscopy is a noninvasive optical technique based on inelastic light scattering that is capable of measuring several components in the skin. In this study, we used Raman spectroscopy to investigate the change in natural moisturizing factor (NMF) components in the SC following repetitive physical friction. Methods: Six healthy volunteers, who were included in the study after obtaining an informed consent, performed repetitive washing with soap using nylon towels on the forearm twice a day for 2 weeks and used Raman spectroscopy to investigate the change in NMF components in the SC. Results: Compared with the control, which was washed with soap at the same frequency on the opposite forearm, a significant increase in the transepidermal water loss (TEWL) and a decrease in NMF, serine, and total lactate, responsible for maintenance the SC hydration and structuring and maintaining the epidermal barrier function, in the SC were found. Conclusions: Increased TEWL and decreased NMF are considered as an etiology of atopic dermatitis (AD) therefore, our findings provide evidence that daily activities with repetitive frictional trauma may be related to the predisposition of AD.
• Cutaneous angiosarcoma: Update on biology and latest treatment

  Yoshihiro Ishida; Atsushi Otsuka; Kenji Kabashima

  Current Opinion in Oncology Lippincott Williams and Wilkins 30 (2) 107 - 112 1531-703X 2018/03 [Refereed]
   

  Purpose of review The present review aims to provide readers with the latest updates on the biology and clinical management of cutaneous angiosarcoma (cAS). Recent findings The genomic alteration of cAS is heterogeneous. Mutations are enriched in the mitosis-activated kinase (MAPK) pathway. Functional analysis has identified molecules that may serve as potential markers and therapeutic targets of angiosarcoma. These molecules include survivin, HSP90, FOXM1, miR-497-5p, KCa3.1, and miR210. This body of knowledge has not yet transferred to clinical practice. The mainstay of treatment for cAS remains surgery followed by postoperative radiotherapy. The efficacy of paclitaxel as an adjuvant chemotherapy is suggested. For patients with advanced cAS, paclitaxel is the treatment of choice. There are also second-line treatment options that are supported by evidence of varying strength. A multikinase inhibitor, pazopanib, has been assessed in several studies, most of which support its efficacy for angiosarcoma. Bevacizumab monotherapy may be effective for angiosarcoma. The efficacy of eribulin mesylate and trabectedin for angiosarcoma is currently being assessed. Recent publications highlighted the role of the immune system in the biology of cAS. Summary Future research efforts should focus on the following aspects of cAS: drug development directed at recent molecular targets, clinical trials designed specifically for patients with cAS, and the role of immunotherapy for cAS.
• Biomarkers for evaluation of mast cell and basophil activation

  Kenji Kabashima; Chisa Nakashima; Yumi Nonomura; Atsushi Otsuka; Chiara Cardamone; Roberta Parente; Giulia De Feo; Massimo Triggiani

  Immunological Reviews Blackwell Publishing Ltd 282 (1) 114 - 120 1600-065X 2018/03 [Refereed]
   

  Mast cells and basophils play a pathogenetic role in allergic, inflammatory, and autoimmune disorders. These cells have different development, anatomical location and life span but share many similarities in mechanisms of activation and type of mediators. Mediators secreted by mast cells and basophils correlate with clinical severity in asthma, chronic urticaria, anaphylaxis, and other diseases. Therefore, effective biomarkers to measure mast cell and basophil activation in vivo could potentially have high diagnostic and prognostic values. An ideal biomarker should be specific for mast cells or basophils, easily and reproducibly detectable in blood or biological fluids and should be metabolically stable. Markers of mast cell and basophil include molecules secreted by stimulated cells and surface molecules expressed upon activation. Some markers, such as histamine and lipid mediators are common to mast cells and basophils whereas others, such as tryptase and other proteases, are relatively specific for mast cells. The best surface markers of activation expressed on mast cells and basophils are CD63 and CD203. While these mediators and surface molecules have been associated to a variety of diseases, none of them fulfills requirements for an optimal biomarker and search for better indicators of mast cell/basophil activation in vivo is ongoing.
• TRPA1 channel participates in tacrolimus-induced pruritus in a chronic contact hypersensitivity murine model

  Lai San Wong; Atsushi Otsuka; Yasuo Yamamoto; Yumi Nonomura; Chisa Nakashima; Naomi Kitayama; Kenji Usui; Tetsuya Honda; Kenji Kabashima

  JOURNAL OF DERMATOLOGICAL SCIENCE ELSEVIER IRELAND LTD 89 (2) 207 - 209 0923-1811 2018/02 [Refereed]
  
• Total cell necrosis of metastatic malignant melanoma at the regional lymph node in a patient treatment with nivolumab

  Takaya Komori; Atsushi Otsuka; Yo Kaku; Hiroyuki Irie; Tetsuya Honda; Masahiro Hirata; Tatsuki R. Kataoka; Kenji Kabashima

  Journal of Dermatology Blackwell Publishing Ltd 45 (1) e11 - e12 1346-8138 2018/01 [Refereed]
  
• Drastic effect on giant lung metastatic melanoma by sequential administration of nivolumab with ipilimumab/radiation combination therapy

  Takaya Komori; Atsushi Otsuka; Hiroyuki Irie; Ayumi Horiguchi; Tetsuya Honda; Kenji Kabashima

  Journal of Dermatology Blackwell Publishing Ltd 45 (1) e7 - e8 1346-8138 2018/01 [Refereed]
  
• Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: Analysis of 60 Japanese patients.

  Yasuhiro Fujisawa; Koji Yoshino; Atsushi Otsuka; Takeru Funakoshi; Hiroshi Uchi; Taku Fujimura; Shigeto Matsushita; Hiroo Hata; Hisako Okuhira; Ryota Tanaka; Kojiro Nagai; Yoshihiro Ishida; Yoshio Nakamura; Sadanori Furudate; Kentaro Yamamura; Keisuke Imafuku; Yuki Yamamoto

  Journal of dermatological science 89 (1) 60 - 66 0923-1811 2018/01 [Refereed]
   

  BACKGROUND: Due to resistance and immune-related adverse events (irAE) some melanoma patients require ipilimumab after nivolumab therapy. However, little is known about the result of this switching. OBJECTIVE: Investigate the outcome of ipilimumab switching in Japanese patients. METHODS: We retrospectively collected 60 patients who were treated with ipilimumab after nivolumab from 9 institutes in Japan. Information of the primary tumor, treatment, response, irAE), and survival was collected. RESULTS: In our cohort, acral lentiginous and mucosal melanoma accounted for 53% of the cases. The most common reason for initiating ipilimumab was disease progression (93%). Median interval from the last nivolumab administration to first ipilimumab administration was 29days. Only 38% of patients completed 4 injections of ipilimumab. The best overall response was 3.6%. IrAE occurred in 78% of patients and 70% of those were of grade 3/4 (G3/4) and 31% of patients experienced 2 or more irAEs. An within interval of 28days or less between the last nivolumab administration and ipilimumab administration was correlated with the development of G3/4 pyrexia and 3 or more irAEs, but irAE occurrence did not affect survival. Multivariate analysis showed that endocrine irAE (relative risk=0.22, P=0.015) and skin irAE (relative risk=2.78, P=0.048) were significant factors associated with survival. CONCLUSION: In our study, the response ratio to ipilimumab after nivolumab was unsatisfactory and associated with a high frequency of severe irAEs. As there are few second-line treatment options for patients with BRAF wild-type advanced melanoma after nivolumab failure, patients should be closely monitored if ipilimumab is initiated.
• No recurrence of nivolumab-induced idiopathic thrombocytopenic purpura in a metastatic melanoma patient switched to ipilimumab

  Riko Takimoto; Atsushi Otsuka; Yo Kaku; Tetsuya Honda; Kenji Kabashima

  European Journal of Dermatology John Libbey Eurotext 28 (1) 84 - 85 1952-4013 2018/01 [Refereed]
  
• Serum levels of soluble CD163 and CXCL5 may be predictive markers for immune-related adverse events in patients with advanced melanoma treated with nivolumab: A pilot study

  Taku Fujimura; Yota Sato; Kayo Tanita; Yumi Kambayashi; Atsushi Otsuka; Yasuhiro Fujisawa; Koji Yoshino; Shigeto Matsushita; Takeru Funakoshi; Hiroo Hata; Yuki Yamamoto; Hiroshi Uchi; Yumi Nonomura; Ryota Tanaka; Megumi Aoki; Keisuke Imafuku; Hisako Okuhira; Sadanori Furudate; Takanori Hidaka; Setsuya Aiba

  Oncotarget Impact Journals LLC 9 (21) 15542 - 15551 1949-2553 2018 [Refereed]
   

  Antibodies against PD-1, such as nivolumab and pembrolizumab, are widely used in the treatment of various cancers including advanced melanoma. The anti- PD-1 Ab significantly prolongs survival in patients with metastatic melanoma, and its administration in combination with local or systemic therapy may also lead to improved outcomes. Although anti-PD-1 Ab-based combined therapy might be effective for the treatment of advanced melanoma, the associated risk of irAEs is an important consideration. Therefore, being able to predict irAEs is of great interest to oncologists. The purpose of this study was to evaluate the value of using serum levels of sCD163 and CXCL5 to predict irAEs in patients with advanced melanoma who were administered nivolumab. To this end, we analyzed these serum levels in 46 cases of advanced melanoma treated with nivolumab. In addition, the tumor stroma was evaluated by immunohistochemistry and immunofluorescence. We measured the serum levels of sCD163 and CXCL5 on day 0 (immediately before nivolumab administration) and day 42. The serum absolute levels of sCD163 were significantly increased in patients who developed AEs (p = 0.0018). Although there was no significant difference in serum levels of CXCL5, the absolute value of CXCL5 could at least be a supportive marker for the increased absolute levels of serum sCD163. This study suggests that sCD163 and CXCL5 may serve as possible prognostic biomarkers for irAEs in patients with advanced melanoma treated with nivolumab.
• Serum Level of Soluble CD163 May Be a Predictive Marker of the Effectiveness of Nivolumab in Patients With Advanced Cutaneous Melanoma.

  Taku Fujimura; Yota Sato; Kayo Tanita; Yumi Kambayashi; Atsushi Otsuka; Yasuhiro Fujisawa; Koji Yoshino; Shigeto Matsushita; Takeru Funakoshi; Hiroo Hata; Yuki Yamamoto; Hiroshi Uchi; Yumi Nonomura; Ryota Tanaka; Megumi Aoki; Keisuke Imafuku; Hisako Okuhira; Naoko Wada; Hiroyuki Irie; Takanori Hidaka; Akira Hashimoto; Setsuya Aiba

  Frontiers in oncology 8 530 - 530 2018 [Refereed]
   

  Antibodies against programmed cell death protein 1, such as nivolumab and pembrolizumab, are widely used for treating various cancers, including advanced melanoma. Nivolumab significantly prolongs survival in patients with metastatic melanoma, and sequential administration with lipilimumab may improve outcomes when switched at the appropriate time. Biomarkers are therefore needed to evaluate nivolumab efficacy soon after first administration. This study analyzed serum levels of soluble cluster of differentiation 163 (sCD163) in 59 cases of advanced cutaneous melanoma and 16 cases of advanced mucosal melanoma treated using nivolumab. Serum levels of sCD163 were significantly increased after 6 weeks in responders compared to non-responders after initial administration of nivolumab for cutaneous melanoma. In contrast, no significant difference between responders and non-responders was seen among patients with non-cutaneous melanoma. These results suggest that sCD163 may be useful as a biomarker for selecting patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.
• ニボルマブ開始後光沢苔癬を発症した1例

  趙 マリア; 野々村 優美; 加来 洋; 大日 輝記; 大塚 篤司; 椛島 健治

  皮膚の科学 日本皮膚科学会-大阪地方会・京滋地方会 16 (6) 449 - 449 1347-1813 2017/12
• Case of diffuse panbronchiolitis developed in a patient with epidermodysplasia verruciformis

  Naomi Kitayama; Satoshi Nakamizo; Yumi Nonomura; Yo Kaku; Yuichiro Endo; Teruki Dainichi; Masae Okura; Tokimasa Hida; Toshiharu Yamashita; Atsushi Otsuka; Kenji Kabashima

  JOURNAL OF DERMATOLOGY WILEY 44 (12) e363 - e364 0385-2407 2017/12 [Refereed]
  
• Fluctuations in routine blood count might signal severe immune-related adverse events in melanoma patients treated with nivolumab

  Yasuhiro Fujisawa; Koji Yoshino; Atsushi Otsuka; Takeru Funakoshi; Taku Fujimura; Yuki Yamamoto; Hiroo Hata; Masahiko Gosho; Ryota Tanaka; Kei Yamaguchi; Yumi Nonomura; Ikuko Hirai; Sadanori Furudate; Hisako Okuhira; Keisuke Imafuku; Megumi Aoki; Shigeto Matsushita

  JOURNAL OF DERMATOLOGICAL SCIENCE ELSEVIER IRELAND LTD 88 (2) 225 - 231 0923-1811 2017/11 [Refereed]
   

  Background: Although nivolumab significantly prolongs survival of metastatic melanoma, about 10% of patients experience severe, even fatal immune-related adverse events (irAEs). Biomarkers to predict irAEs are, therefore, of great interest. Objective: We aimed to correlate changes in routine blood count parameters to the occurrence of serious irAEs (grade 3/4 [G3/4] or lung/gastrointestinal [lung/GI] irAEs) in patients with melanoma who were treated with nivolumab. Methods: We retrospectively analyzed data from 101 patient with melanoma treated with nivolumab from 8 institutes in Japan. We used logistic regression analyses to investigate associations between severe irAEs and fluctuations in routine blood count parameters (total white blood cell [WBC] count, relative neutrophil, monocyte, lymphocyte, and eosinophil count) during the treatment. Receiver operating characteristic curve was used to determine a cutoff value for the blood count parameters and area under the curve (AUC). Results: Univariate analysis revealed that G3/4 irAEs were associated with increased total WBC count (P = 0.034, cutoff value = +27%, AUC= 0.68, odds ratio [OR] = 1.58) and decreased relative lymphocyte count (RLC, P= 0.042, cutoff value = -23%, AUC= 0.65, OR= 1.65). However, multivariate analysis showed that the same factors, increased WBC count (P = 0.014, cutoff value = +59.1%, AUC = 0.79, OR= 6.04) and decreased RLC (P = 0.012, cutoff value = 32.3%, AUC= 0.81, OR= 5.01) were independent factors associated with lung/GI irAEs. Conclusions: Our results suggest that increased WBC count and decreased RLC are associated with G3/4 and lung/GI irAEs. Our analysis was based on the data point at which irAE occurrence was noticed and, therefore, these factors are not predictive, however, they could be a "signal" of severe irAE occurrence in patients with melanoma treated with nivolumab. (C) 2017 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
• HLA-A*26 Is Correlated With Response to Nivolumab in Japanese Melanoma Patients

  Yoshihiro Ishida; Atsushi Otsuka; Hidenori Tanaka; Mitchell P. Levesque; Reinhard Dummer; Kenji Kabashima

  JOURNAL OF INVESTIGATIVE DERMATOLOGY ELSEVIER SCIENCE INC 137 (11) 2443 - 2444 0022-202X 2017/11 [Refereed]
  
• Efficacy and safety of retreatment with nivolumab in metastatic melanoma patients previously treated with nivolumab

  Motoo Nomura; Atsushi Otsuka; Tomohiro Kondo; Hiroki Nagai; Yumi Nonomura; Yo Kaku; Shigemi Matsumoto; Manabu Muto

  CANCER CHEMOTHERAPY AND PHARMACOLOGY SPRINGER 80 (5) 999 - 1004 0344-5704 2017/11 [Refereed]
   

  Nivolumab is a monoclonal antibody directed against programmed death-1 that has been shown to improve survival in patients with metastatic melanoma. However, the efficacy of nivolumab and other agents in melanoma remains limited. The objective of this study was to evaluate the efficacy and safety of retreatment with nivolumab in metastatic melanoma patients who previously progressed on nivolumab. A retrospective review was performed on eight consecutive metastatic melanoma patients retreated with nivolumab who progressed on previous nivolumab. These patients received nivolumab 2 mg/kg every 3 weeks. Best responses to each treatment were assessed using RECIST 1.1. Of eight metastatic melanoma patients, three patients received chemotherapy before first nivolumab. The median first nivolumab treatment period was 4.1 months. During first nivolumab, 3 (37.5%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. First nivolumab was discontinued due to disease progression in seven patients and grade 3 colitis in 1 patient. Patients were subsequently treated with ipilimumab (n = 6), vemurafenib (n = 1), or no other medical treatment (n = 1). The median treatment period between first and second nivolumab was 3.0 months. Four patients received radiation therapy between first and second nivolumab. The median second nivolumab treatment period was 4.3 months. Among the eight patients who received second nivolumab, 2 (25%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. Second nivolumab was discontinued due to disease progression in seven patients. One patient continues to receive second nivolumab. Among the four patients treated with ipilimumab and radiotherapy between first and second nivolumab, the response rate was 50% and the disease control rate was 75%. This study showed that retreatment with nivolumab is an option for select metastatic melanoma patients after previous nivolumab treatment.
• 京都大学附属病院におけるメラノーマユニット

  野村 基雄; 大塚 篤司; 永井 宏樹; 野々村 優美; 加来 洋; 松本 繁巳

  日本癌治療学会学術集会抄録集 (一社)日本癌治療学会 55回 P123 - 5 2017/10 [Refereed]
  
• High fat diet exacerbates murine psoriatic dermatitis by increasing the number of IL-17-producing gamma delta T cells

  Satoshi Nakamizo; Tetsuya Honda; Akimasa Adachi; Takahiro Nagatake; Jun Kunisawa; Akihiko Kitoh; Atsushi Otsuka; Teruki Dainichi; Takashi Nomura; Florent Ginhoux; Koichi Ikuta; Gyohei Egawa; Kenji Kabashima

  SCIENTIFIC REPORTS NATURE PUBLISHING GROUP 7 (1) 14076  2045-2322 2017/10 [Refereed]
   

  Psoriasis is a common, chronic inflammatory skin disease characterized by epidermal hyperplasia via the IL-23/IL-17 axis. Various studies have indicated the association between obesity and psoriasis, however, the underlying mechanisms remains unclarified. To this end, we focused on high-fat diet (HFD) in this study, because HFD is suggested as a contributor to obesity, and HFD-fed mice exhibit exacerbated psoriatic dermatitis. Using murine imiquimod (IMQ)-induced psoriasis and HFD-induced obesity models, we have revealed a novel mechanism of HFD-induced exacerbation of psoriatic dermatitis. HFD-fed mice exhibited aggravated psoriatic dermatitis, which was accompanied with increased accumulation of IL-17A-producing V gamma 4(+) gamma delta T cells in the skin. HFD also induced the increase of V gamma 4(+) gamma delta T cells in other organs such as skin draining lymph nodes, which preceded the increase of them in the skin. In addition, HFD-fed mice displayed increased expression of several gamma delta T cell-recruiting chemokines in the skin. On the other hand, ob/ob mice, another model of murine obesity on normal diet, did not exhibit aggravated psoriatic dermatitis nor accumulation of gamma delta T cells in the dermis. These results indicate that HFD is a key element in exacerbation of IMQ-induced psoriatic dermatitis, and further raise the possibility of HFD as a factor that links obesity and psoriasis.
• Basophil and M2 macrophage infiltration in lesional skin of eosinophilic granulomatosis with polyangiitis

  Chisa Nakashima; Atsushi Otsuka; Naomi Kitayama; Tetsuya Honda; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 27 (5) 552 - 553 1167-1122 2017/09 [Refereed]
  
• Rapid regression of metastatic brain tumours in a melanoma patient after dabrafenib/trametinib therapy

  Takaya Komori; Atsushi Otsuka; Nobuhiro Kusuba; Kimika Taniguchi; Yuichiro Endo; Tetsuya Honda; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 27 (5) 548 - 549 1167-1122 2017/09 [Refereed]
  
• Efficacy of intravenous immunoglobulins for the treatment of mucous membrane pemphigoid-like epidermolysis bullosa acquisita

  Takaya Komori; Teruki Dainichi; Nobuhiro Kusuba; Atsushi Otsuka; Takashi Hashimoto; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 27 (5) 563 - 564 1167-1122 2017/09 [Refereed]
  
• Receptor-interacting protein kinase 3 controls keratinocyte activation in a necroptosis-independent manner and promotes psoriatic dermatitis in mice

  Tetsuya Honda; Osamu Yamamoto; Yu Sawada; Gyohei Egawa; Akihiko Kitoh; Atsushi Otsuka; Teruki Dainichi; Saeko Nakajima; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY MOSBY-ELSEVIER 140 (2) 619 - + 0091-6749 2017/08 [Refereed]
  
• Three-dimensional evaluation of subclinical extension of extramammary Paget disease: visualization of the histological border and its comparison to the clinical border

  T. Murata; T. Honda; G. Egawa; A. Kitoh; T. Dainichi; A. Otsuka; S. Nakajima; S. Kore-eda; Y. Kaku; S. Nakamizo; Y. Endo; A. Fujisawa; Y. Miyachi; K. Kabashima

  British Journal of Dermatology 177 (1) 229 - 237 0007-0963 2017/07 [Refereed]
   

  © 2016 British Association of Dermatologists Background: In extramammary Paget disease (EMPD), Paget cells are sometimes detected outside the clinical border (subclinical extension). However, the spreading pattern of Paget cells in subclinical extension remains unclear. In addition, the macroscopic appearances of lesions accompanied by subclinical extension are totally unknown. Objectives: To characterize the spreading pattern of Paget cells as well as the macroscopic appearance of lesions of EMPD with subclinical extension. Methods: Nineteen patients with primary anogenital EMPD underwent mapping biopsies and excisional surgeries; biopsy samples were then taken at the periphery of well-demarcated lesions. Samples were transparentized and subjected to whole-mount immunostaining with anticytokeratin 7 antibody to label Paget cells. The histological border was evaluated in three dimensions by two-photon microscopy. The shape and location of the histological border were compared with those of the clinical border. Results: In 21 samples taken at the lesion where subclinical extension was not shown by mapping biopsy, the shape and location of the histological border were almost identical to those of the clinical border. However, two samples exhibited small foci of Paget cells outside the clinical border, showing subclinically extended satellite lesions. In the two samples taken at the lesions where subclinical extension was shown by mapping biopsy, a continuous arrangement of Paget cells extending beyond the clinical border was identified. Subclinically extended Paget cells were detected solely outside hypopigmented patches with erythema. Conclusions: In EMPD, at least two patterns of subclinical extension exist: continuous and satellite lesions. Subclinical extension might exist preferentially outside hypopigmented patches with erythema.
• The interplay between genetic and environmental factors in the pathogenesis of atopic dermatitis

  Atsushi Otsuka; Takashi Nomura; Pawinee Rerknimitr; Judith A. Seidel; Tetsuya Honda; Kenji Kabashima

  IMMUNOLOGICAL REVIEWS WILEY 278 (1) 246 - 262 0105-2896 2017/07 [Refereed]
   

  Atopic dermatitis (AD) is a chronic skin disorder characterized by pruritus and recurrent eczematous lesions that are accompanied by T-helper (Th)2-dominated inflammation. AD Etiology is not yet completely understood, but it is multifactorial. Moreover, the disease is characterized by complex interactions between genetic and environmental factors, such as skin barrier dysfunctions, allergy/immunity, and pruritus. For example, filaggrin is a key protein involved in skin barrier function. Th2 cells produce interleukin (IL)-31, which provokes pruritus, and other Th2 cytokines decrease filaggrin expression by keratinocytes. Dupilumab has recently been developed for AD treatment; its mechanism of action is to bind to IL-4 receptor alpha and inhibit downstream signaling induced by IL-4 and IL-13. This review summarizes the etiopathogenesis of AD and provides the rationale for selecting a novel targeted therapy.
• Local inflammation exacerbates cutaneous manifestations in a murine autoimmune pemphigus model

  Sachiko Ono; Gyohei Egawa; Akihiko Kitoh; Teruki Dainichi; Atsushi Otsuka; Saeko Nakajima; Tetsuya Honda; Kenji Kabashima

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY MOSBY-ELSEVIER 139 (6) 2026 - + 0091-6749 2017/06 [Refereed]
  
• Dermoscopic changes in malignant melanoma after successful treatment with nivolumab: A case report

  Kentaro Yamamura; Atsushi Otsuka; Yo Kaku; Judith A. Seidel; Motoo Nomura; Hiroki Nagai; Shigemi Matsumoto; Kenji Kabashima

  JOURNAL OF DERMATOLOGY WILEY 44 (5) 547 - 548 0385-2407 2017/05 [Refereed]
  
• Case of pityriasis rubra pilaris with annular pattern as an early manifestation

  Naomi Kitayama; Satoshi Nakamizo; Yo Kaku; Yuichiro Endo; Akihiro Fujisawa; Atsushi Otsuka; Kenji Kabashima

  JOURNAL OF DERMATOLOGY WILEY 44 (4) 478 - 479 0385-2407 2017/04 [Refereed]
  
• Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor-alpha is a biomarker of nivolumab recativity

  Ryota Tanaka; Naoko Okiyama; Mari Okune; Yosuke Ishitsuka; Rei Watanabe; Junichi Furuta; Mikio Ohtsuka; Atsushi Otsuka; Hiroshi Maruyama; Yasuhiro Fujisawa; Manabu Fujimoto

  JOURNAL OF DERMATOLOGICAL SCIENCE ELSEVIER IRELAND LTD 86 (1) 71 - 73 0923-1811 2017/04 [Refereed]
  
• Oral lichen planus associated with candidiasis during secukinumab treatment

  Takaya Komori; Tetsuya Honda; Yuichiro Endo; Yo Kaku; Atsushi Otsuka; Kenji Kabashima

  JOURNAL OF DERMATOLOGY WILEY 44 (4) E60 - E61 0385-2407 2017/04 [Refereed]
  
• Successful hair regrowth in an acute diffuse form of alopecia areata during oral tacrolimus treatment in a patient with rheumatoid arthritis

  S. Kanameishi; T. Dainichi; Y. Endo; A. Otsuka; M. Tanioka; K. Kabashima

  Journal of the European Academy of Dermatology and Venereology 31 (3) e137 - e138 0926-9959 2017/03
• Lichen Planus in Irradiated Skin During Nivolumab Treatment

  Takaya Komori; Tetsuya Honda; Hiroyuki Irie; Atsushi Otsuka; Kenji Kabashima

  ACTA DERMATO-VENEREOLOGICA ACTA DERMATO-VENEREOLOGICA 97 (3) 391 - 392 0001-5555 2017/03 [Refereed]
  
• Adult-onset asthma and periocular xanthogranuloma associated with IgG4-related disease with infiltration of regulatory T cells

  Y. Honda; S. Nakamizo; T. Dainichi; R. Sasai; T. Mimori; M. Hirata; T. R. Kataoka; Y. Murata; A. Otsuka; K. Kabashima

  Journal of the European Academy of Dermatology and Venereology 31 (2) e124 - e125 0926-9959 2017/02
• Infiltration of PD-1-positive cells in combination with tumor site PD-L1 expression is a positive prognostic factor in cutaneous angiosarcoma

  Yuki Honda; Atsushi Otsuka; Sachiko Ono; Yosuke Yamamoto; Judith A. Seidel; Satoshi Morita; Masahiro Hirata; Tatsuki R. Kataoka; Tatsuya Takenouchi; Kazuyasu Fujii; Takuro Kanekura; Yuko Okubo; Kenzo Takahashi; Teruki Yanagi; Daichi Hoshina; Hiroo Hata; Riichiro Abe; Taku Fujimura; Takeru Funakoshi; Koji Yoshino; Mamiko Masuzawa; Yasuyuki Amoh; Ryota Tanaka; Yasuhiro Fujisawa; Tetsuya Honda; Kenji Kabashima

  ONCOIMMUNOLOGY TAYLOR & FRANCIS INC 6 (1) 2162-402X 2017 [Refereed]
   

  Cutaneous angiosarcoma (CAS) is a malignant sarcoma with poor prognosis. Programmed cell death-1 (PD-1)/programmed cell death-1 ligand-1 (PD-L1) expression reflects antitumor immunity, and is associated with patient prognosis in various cancers. The purpose of this study is to investigate the relationship between PD-1/PD-L1 expression and CAS prognosis. CAS cases (n D 106) were immunohistochemically studied for PD-L1 and PD-1 expression, and the correlation with patient prognosis was analyzed. PD-L1 expression was assessed by flow cytometry on three CAS cell lines with or without IFNg stimulation. A total of 30.2% of patients' samples were positive for PD-L1, and 17.9% showed a high infiltration of PD-1-positive cells. Univariate analysis showed a significant relationship between a high infiltration of PD-1-positive cells with tumor site PD-L1 expression and favorable survival in stage 1 patients (p D 0.014, log-rank test). Multivariable Cox-proportional hazard regression analysis also showed that patients with a high infiltration of PD-1-positive cells with tumor site PD-L1 expression were more likely to have favorable survival, after adjustment with possible confounders (hazard ratio (HR) D 0.38, p D 0.021, 95% confidence interval (CI) 0.16-0.86). Immunofluorescence staining of CAS samples revealed that PD-L1-positive cells were adjacent to PD-1-positive cells and/or tumor stroma with high IFN gamma expression. In vitro stimulation with IFN gamma increased PD-L1 expression in two out of three established CAS cell lines. Our results suggest that PD-1/PD-L1 expression is related to CAS progression, and the treatment with antiPD-1 antibodies could be a new therapeutic option for CAS.
• Decreased Filaggrin Level May Lead to Sweat Duct Obstruction in Filaggrin Mutant Mice

  Pawinee Rerknimitr; Hideaki Tanizaki; Yasuo Yamamoto; Wataru Amano; Saeko Nakajima; Chisa Nakashima; Yumi Nonomura; Jade Wititsuwannakul; Yoshiki Miyachi; Atsushi Otsuka; Kenji Kabashima

  JOURNAL OF INVESTIGATIVE DERMATOLOGY ELSEVIER SCIENCE INC 137 (1) 248 - 251 0022-202X 2017/01 [Refereed]
  
• Linking air pollution to atopic dermatitis

  Kenji Kabashima; Atsushi Otsuka; Takashi Nomura

  Nature Immunology Nature Publishing Group 18 (1) 5 - 6 1529-2916 2017/01 [Refereed]
  
• Infiltration of PD-1-positive cells in combination with tumor site PD-L1 expression is a positive prognostic factor in cutaneous angiosarcoma.

  Yuki Honda; Atsushi Otsuka; Sachiko Ono; Yosuke Yamamoto; Judith A Seidel; Satoshi Morita; Masahiro Hirata; Tatsuki R Kataoka; Tatsuya Takenouchi; Kazuyasu Fujii; Takuro Kanekura; Yuko Okubo; Kenzo Takahashi; Teruki Yanagi; Daichi Hoshina; Hiroo Hata; Riichiro Abe; Taku Fujimura; Takeru Funakoshi; Koji Yoshino; Mamiko Masuzawa; Yasuyuki Amoh; Ryota Tanaka; Yasuhiro Fujisawa; Tetsuya Honda; Kenji Kabashima

  Oncoimmunology 6 (1) e1253657  2162-4011 2017 [Refereed]
   

  Cutaneous angiosarcoma (CAS) is a malignant sarcoma with poor prognosis. Programmed cell death-1 (PD-1)/programmed cell death-1 ligand-1 (PD-L1) expression reflects antitumor immunity, and is associated with patient prognosis in various cancers. The purpose of this study is to investigate the relationship between PD-1/PD-L1 expression and CAS prognosis. CAS cases (n = 106) were immunohistochemically studied for PD-L1 and PD-1 expression, and the correlation with patient prognosis was analyzed. PD-L1 expression was assessed by flow cytometry on three CAS cell lines with or without IFNγ stimulation. A total of 30.2% of patients' samples were positive for PD-L1, and 17.9% showed a high infiltration of PD-1-positive cells. Univariate analysis showed a significant relationship between a high infiltration of PD-1-positive cells with tumor site PD-L1 expression and favorable survival in stage 1 patients (p = 0.014, log-rank test). Multivariable Cox-proportional hazard regression analysis also showed that patients with a high infiltration of PD-1-positive cells with tumor site PD-L1 expression were more likely to have favorable survival, after adjustment with possible confounders (hazard ratio (HR) = 0.38, p = 0.021, 95% confidence interval (CI) 0.16-0.86). Immunofluorescence staining of CAS samples revealed that PD-L1-positive cells were adjacent to PD-1-positive cells and/or tumor stroma with high IFNγ expression. In vitro stimulation with IFNγ increased PD-L1 expression in two out of three established CAS cell lines. Our results suggest that PD-1/PD-L1 expression is related to CAS progression, and the treatment with anti-PD-1 antibodies could be a new therapeutic option for CAS.
• The etiopathogenesis of atopic dermatitis: barrier disruption, immunological derangement, and pruritus.

  Rerknimitr P; Otsuka A; Nakashima C; Kabashima K

  Inflammation and regeneration 37 14  1880-9693 2017 [Refereed]
  
• Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients

  Yumi Nonomura; Atsushi Otsuka; Chisa Nakashima; Judith A. Seidel; Akihiko Kitoh; Teruki Dainichi; Saeko Nakajima; Yu Sawada; Shigeto Matsushita; Megumi Aoki; Tatsuya Takenouchi; Taku Fujimura; Naohito Hatta; Satoshi Koreeda; Satoshi Fukushima; Tetsuya Honda; Kenji Kabashima

  OncoImmunology 5 (12) e1248327  2162-4011 2016/12 [Refereed]
   

  © 2016 Taylor & Francis Group, LLC. Although nivolumab is associated with a significant improvement in overall survival and progression-free survival, only 20 to 40% of patients experience long-term benefit. It is therefore of great interest to identify a predictive marker of clinical benefit for nivolumab. To address this issue, the frequencies of CD4+ T cell subsets (Treg, Th1, Th2, Th9, Th17 and Th22), CD8+ T cells, and serum cytokine levels (IFNγ, IL-4, IL-9, IL-10, TGF-β) were assessed in 46 patients with melanoma. Eighteen patients responded to nivolumab, and the other 28 patients did not. An early increase in Th9 cell counts during the treatment with nivolumab was associated with an improved clinical response. Before the first nivolumab infusion, the responders displayed elevated serum concentrations of TGF-β compared to non-responders. Th9 induction by IL-4 and TGF-β was enhanced by PD-1/PD-L1 blockade in vitro. The role of IL-9 in disease progression was further assessed using a murine melanoma model. In vivo IL-9 blockade promoted melanoma progression in mice using an autochthonous mouse melanoma model, and the cytotoxic ability of murine melanoma-specific CD8+ T cells was enhanced in the presence of IL-9 in vitro. These findings suggest that Th9 cells, which produce IL-9, play an important role in the successful treatment of melanoma patients with nivolumab. Th9 cells therefore represent a valid biomarker to be further developed in the setting of anti-PD-1 therapy.
• Novel MEFV variant Q311H in an incomplete Behçet's disease patient with recurrent epididymitis.

  Yamashita C; Otsuka A; Dainichi T; Kabashima K

  Journal of the European Academy of Dermatology and Venereology : JEADV 30 (11) e173 - e174 0926-9959 2016/11 [Refereed]
  
• Keratitis-ichthyosis-deafness syndrome with recurrent pneumonia but no mucocutaneous infection

  Chisato Yamashita; Atsushi Otsuka; Yutaka Shimomura; Tetsuya Honda; Kenji Kabashima

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 43 (11) 1386 - 1387 0385-2407 2016/11 [Refereed]
  
• Case of unilateral epidermal nevi without extracutaneous anomalies

  Naomi Kitayama; Atsushi Otsuka; Yo Kaku; Yumi Matsumura; Yutaka Shimomura; Yuichiro Endo; Akihiro Fujisawa; Teruki Dainichi; Kenji Kabashima

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 43 (10) 1241 - 1242 0385-2407 2016/10 [Refereed]
  
• Roles of basophils and mast cells in cutaneous inflammation

  Atsushi Otsuka; Yumi Nonomura; Kenji Kabashima

  SEMINARS IN IMMUNOPATHOLOGY SPRINGER HEIDELBERG 38 (5) 563 - 570 1863-2297 2016/09 [Refereed]
   

  Mast cells and basophils are associated with T helper 2 (Th2) immune responses. Newly developed mast cell-deficient mice have provided evidence that mast cells initiate contact hypersensitivity via activating dendritic cells. Studies using basophil-deficient mice have also revealed that basophils are responsible for cutaneous Th2 skewing to haptens and peptide antigens but not to protein antigens. Recently, several studies reported the existence of innate lymphoid cells (ILCs), which differ from classic T cells in that they lack the T cell receptor. Mast cells and basophils can interact with ILCs and play some roles in the pathogenesis of Th2 responses. Basophil-derived interleukin (IL)-4 enhances the expression of the chemokine CCL11, as well as IL-5, IL-9, and IL-13 in ILC2s, leading to the accumulation of eosinophils in allergic reactions. IL-33-stimulated mast cells can play a regulatory role in the development of ILC2-mediated non-antigen-specific protease-induced acute inflammation. In this review, we discuss the recent advances in our understanding of mast cells and basophils in immunity and inflammation.
• Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation

  Franklin L. Zhong; Ons Mamai; Lorenzo Sborgi; Lobna Boussofara; Richard Hopkins; Kim Robinson; Ildiko Szeverenyi; Takuya Takeichi; Reshmaa Balaji; Aristotle Lau; Hazel Tye; Keya Roy; Carine Bonnard; Patricia J. Ahl; Leigh Ann Jones; Paul J. Baker; Lukas Lacina; Atsushi Otsuka; Pierre R. Fournie; Francois Malecaze; E. Birgitte Lane; Masashi Akiyama; Kenji Kabashima; John E. Connolly; Seth L. Masters; Vincent J. Soler; Salma Samir Omar; John A. McGrath; Roxana Nedelcu; Moez Gribaa; Mohamed Denguezli; Ali Saad; Sebastian Hiller; Bruno Reversade

  CELL CELL PRESS 167 (1) 187 - + 0092-8674 2016/09 [Refereed]
   

  Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen-and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasomedisorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.
• Exacerbation of depression in a psoriatic arthritis patient possibly induced by secukinumab

  Takaya Komori; Atsushi Otsuka; Yuki Honda; Shuto Kanameishi; Tetsuya Honda; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 26 (5) 506 - 507 1167-1122 2016/09 [Refereed]
  
• CCR5 and CXCR3 expression in a case of subcutaneous panniculitis-like T-cell lymphoma.

  Honda Y; Otsuka A; Nonomura Y; Kaku Y; Dainichi T; Miyachi Y; Kabashima K

  Journal of the European Academy of Dermatology and Venereology : JEADV 30 (8) 1413 - 1415 0926-9959 2016/08 [Refereed]
  
• Vascular endothelial growth factor partially induces pruritus via epidermal hyperinnervation in imiquimod-induced psoriasiform dermatitis in mice

  Lai San Wong; Atsushi Otsuka; Yasuo Yamamoto; Yumi Nonomura; Chisa Nakashima; Testuya Honda; Teruki Dainichi; Akihiko Kitoh; Saeko Nakajima; Satoshi Hirakawa; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF DERMATOLOGICAL SCIENCE ELSEVIER IRELAND LTD 83 (2) 148 - 151 0923-1811 2016/08 [Refereed]
  
• Pyoderma gangrenosum of the penis possibly associated with pazopanib treatment.

  Usui S; Otsuka A; Kaku Y; Dainichi T; Kabashima K

  Journal of the European Academy of Dermatology and Venereology : JEADV 30 (7) 1222 - 1223 0926-9959 2016/07 [Refereed]
  
• Novel insights into cutaneous immune systems revealed by in vivo imaging

  Tetsuya Honda; Atsushi Otsuka; Kenji Kabashima

  ALLERGOLOGY INTERNATIONAL JAPANESE SOCIETY ALLERGOLOGY 65 (3) 228 - 234 1323-8930 2016/07 [Refereed]
   

  In vivo imaging is a novel experimental approach for biological research. Multiphoton microscopy (MPM), a type of fluorescence microscopy, is a new tool for in vivo imaging analysis. MPM allows observation of both tissue structures and cell behaviors or cell-cell interactions in living animals in real time. Skin is an ideal tissue for MPM analysis as it is directly accessible to the microscope. In the skin, immune cells cooperate to maintain skin homeostasis or to exert immune responses against foreign antigens. In vivo imaging by MPM analysis provides precise information on cell dynamics in the skin, and has significantly expanded our knowledge of the cutaneous immune system. In this review, we will discuss recent insights related to the mechanisms of allergic skin inflammation that have been revealed by MPM analysis. Copyright (C) 2016, Japanese Society of Allergology. Production and hosting by Elsevier B.V.
• Stevens-Johnson syndrome-like erosive dermatitis possibly related to afatinib

  Yuki Honda; Yukari Hattori; Satoshi Katsura; Tsuyoshi Terashima; Toshiaki Manabe; Atsushi Otsuka; Yoshiki Miyachi

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 26 (4) 413 - 414 1167-1122 2016/07 [Refereed]
  
• Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages

  Roman Huber; Barbara Meier; Atsushi Otsuka; Gabriele Fenini; Takashi Satoh; Samuel Gehrke; Daniel Widmer; Mitchell P. Levesque; Joanna Mangana; Katrin Kerl; Christoffer Gebhardt; Hiroko Fujii; Chisa Nakashima; Yumi Nonomura; Kenji Kabashima; Reinhard Dummer; Emmanuel Contassot; Lars E. French

  SCIENTIFIC REPORTS NATURE PUBLISHING GROUP 6 29914  2045-2322 2016/07 [Refereed]
   

  Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products ( RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target.
• 悪性黒色腫に対してニボルマブによる加療後にメラノファージの残存と脱色素斑の出現を認めた一例

  山村 健太郎; 大塚 篤司; 加来 洋; 椛島 健治; 野村 基雄

  日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 (一社)日本皮膚悪性腫瘍学会 32回 115 - 115 2016/05 [Refereed]
  
• Successful treatment with anti-TNF-alpha antibody for localised lipodystrophy

  Naomi Kitayama; Atsushi Otsuka; Yo Kaku; Yuichiro Endo; Akihiro Fujisawa; Takao Fujii; Tatsuki Kataoka; Masahiro Hirata; Hiroyuki Murota; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 26 (3) 316 - 317 1167-1122 2016/05 [Refereed]
  
• Case with Brunsting-Perry-like localized subepidermal blisterformations and immunoglobulin G antibodies against unidentified basement membrane zone antigen

  Mami Sato-Shibuya; Teruki Dainichi; Gyohei Egawa; Tetsuya Honda; Atsushi Otsuka; Norito Ishii; Takashi Hashimoto; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 43 (4) 426 - 428 0385-2407 2016/04 [Refereed]
   

  Brunsting-Perry type bullous pemphigoid is defined by the blister formation limited to the head and neck, and autoantibodies to type VII collagen are detected in several cases. However, the pathomechanisms and autoantigens in this condition remain unknown. We report a 20-year-old female patient with a more than 2-year history of recurrent tense blisters localized on the face with no distinct atrophic scar formation. The patient had neither extensive sun exposure nor a history suggestive of contact dermatitis. Oral betamethasone was effective on the skin lesions. Histopathology revealed subepidermal blister formation with dermal infiltrates of neutrophils. Although direct and indirect immunofluorescence tests detected immunoglobulin G antibodies to the basement membrane zone (BMZ), no known dermal or epidermal autoantigens were detected in immunoblot analyses. Therefore, this case may be a rare variant of Brunsting-Perry type localized bullous pemphigoid with autoantibodies to an undetermined BMZ antigen.
• Mast Cells and Basophils

  Atsushi Otsuka

  Immunology of the Skin: Basic and Clinical Sciences in Skin Immune Responses Springer Japan 131 - 146 2016/01 [Refereed]
   

  Mast cells and basophils are potent effector cells of the innate immune system and are functionally similar to cell types that are generally associated with T helper 2 (Th2) immune responses. Although their in vitro functions are well studied, these functions remain poorly understood. Recently, newly genetically modified mouse strains that specifically target mast cells or basophils have been developed. These advances have expanded our knowledge of cutaneous immune responses over the past few years. For example, the role of mast cells in contact hypersensitivity has become apparent through studies of mice engineered to deplete mast cells conditionally. In addition, studies of newly developed basophil-deficient mice have revealed that basophils cause IgG1-mediated systemic anaphylaxis, that they contribute to protective immunity against Trichuris muris, and that they enhance humoral memory responses in the spleen. In this review, we discuss the recent advances related to mast cells and basophils in cutaneous immune responses and discuss the development and future direction of this updated mechanism.
• Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients

  Yumi Nonomura; Atsushi Otsuka; Chisa Nakashima; Judith A. Seidel; Akihiko Kitoh; Teruki Dainichi; Saeko Nakajima; Yu Sawada; Shigeto Matsushita; Megumi Aoki; Tatsuya Takenouchi; Taku Fujimura; Naohito Hatta; Satoshi Koreeda; Satoshi Fukushima; Tetsuya Honda; Kenji Kabashima

  ONCOIMMUNOLOGY TAYLOR & FRANCIS INC 5 (12) 2162-402X 2016 [Refereed]
   

  Although nivolumab is associated with a significant improvement in overall survival and progression-free survival, only 20 to 40% of patients experience long-term benefit. It is therefore of great interest to identify a predictive marker of clinical benefit for nivolumab. To address this issue, the frequencies of CD4(+) T cell subsets (Treg, Th1, Th2, Th9, Th17 and Th22), CD8(+) T cells, and serum cytokine levels (IFN gamma, IL-4, IL-9, IL-10, TGF-beta) were assessed in 46 patients with melanoma. Eighteen patients responded to nivolumab, and the other 28 patients did not. An early increase in Th9 cell counts during the treatment with nivolumab was associated with an improved clinical response. Before the first nivolumab infusion, the responders displayed elevated serum concentrations of TGF-beta compared to non-responders. Th9 induction by IL-4 and TGF-beta was enhanced by PD-1/PD-L1 blockade in vitro. The role of IL-9 in disease progression was further assessed using a murine melanoma model. In vivo IL-9 blockade promoted melanoma progression in mice using an autochthonous mouse melanoma model, and the cytotoxic ability of murine melanoma-specific CD8(+) T cells was enhanced in the presence of IL-9 in vitro. These findings suggest that Th9 cells, which produce IL-9, play an important role in the successful treatment of melanoma patients with nivolumab. Th9 cells therefore represent a valid biomarker to be further developed in the setting of anti-PD-1 therapy.
• Up-regulation of Activation Markers on Basophils in Patients with Papuloerythroderma

  Hikari Otake; Atsushi Otsuka; Yumi Nonomura; Natsuko Iga; Kenji Kabashima

  ACTA DERMATO-VENEREOLOGICA ACTA DERMATO-VENEREOLOGICA 96 (3) 410 - 411 0001-5555 2016 [Refereed]
  
• A case of rosacea fulminans staining negative for LL-37

  Hiroka Sasaki; Atsushi Otsuka; Natsuko Iga; Pawinee Rerknimitr; Saeko Nakajima; Yo Kaku; Takaki Sakurai; Teruki Dainichi; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 26 (1) 101 - 102 1167-1122 2016/01 [Refereed]
  
• Dual CD4/CD8-positive Ichthyosiform Mycosis Fungoides with Lymph Node, Peripheral Blood and Cardiac Involvement: A Case Report

  Yo Kaku; Atsushi Otsuka; Hideaki Tanizaki; Rintaro Shibuya; Yuichiro Endo; Yumi Nonomura; Masahiro Hirata; Masakazu Fujimoto; Katsuyuki Ohmori; Takaki Sakurai; Kenji Kabashima

  ACTA DERMATO-VENEREOLOGICA ACTA DERMATO-VENEREOLOGICA 96 (4) 564 - 565 0001-5555 2016 [Refereed]
  
• External dental fistula caused by denosumab-related osteonecrosis of the jaw

  Yuki Honda; Yukari Hattori; Shinichiro Tomimori; Yoshizou Tsuda; Atsushi Otsuka; Yoshiki Miyachi

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 42 (12) 1202 - 1204 0385-2407 2015/12 [Refereed]
  
• Perifollicular elastolysis associated with pseudofolliculitis of Behçet's disease.

  Yuki Honda; Atsushi Otsuka; Natsuko Iga; Yo Kaku; Takaki Sakurai; Yoshiki Miyachi; Kenji Kabashima

  The Journal of dermatology 42 (10) 1017 - 8 2015/10 [Refereed]
  
• Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses

  Yu Sawada; Tetsuya Honda; Sho Hanakawa; Satoshi Nakamizo; Teruasa Murata; Yuri Ueharaguchi-Tanada; Sachiko Ono; Wataru Amano; Saeko Nakajima; Gyohei Egawa; Hideaki Tanizaki; Atsushi Otsuka; Akihiko Kitoh; Teruki Dainichi; Narihito Ogawa; Yuichi Kobayashi; Takehiko Yokomizo; Makoto Arita; Motonobu Nakamura; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF EXPERIMENTAL MEDICINE ROCKEFELLER UNIV PRESS 212 (11) 1921 - 1930 0022-1007 2015/10 [Refereed]
   

  Resolvin E1 (RvE1) is a lipid mediator derived from omega 3 polyunsaturated fatty acids that exerts potent antiinflammatory roles in several murine models. The antiinflammatory mechanism of RvE1 in acquired immune responses has been attributed to attenuation of cytokine production by dendritic cells (DCs). In this study, we newly investigated the effect of RvE1 on DC motility using two-photon microscopy in a contact hypersensitivity (CHS) model and found that RvE1 impaired DC motility in the skin. In addition, RvE1 attenuated T cell priming in the draining lymph nodes and effector T cell activation in the skin, which led to the reduced skin inflammation in CHS. In contrast, leukotriene B4 (LTB4) induced actin filament reorganization in DCs and increased DC motility by activating Cdc42 and Rac1 via BLT1, which was abrogated by RvE1. Collectively, our results suggest that RvE1 attenuates cutaneous acquired immune responses by inhibiting cutaneous DC motility, possibly through LTB4-BLT1 signaling blockade.
• The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling

  Wataru Amano; Saeko Nakajima; Hayato Kunugi; Yasuharu Numata; Akihiko Kitoh; Gyohei Egawa; Teruki Dainichi; Tetsuya Honda; Atsushi Otsuka; Yukari Kimoto; Yasuo Yamamoto; Atsuo Tanimoto; Mutsuyoshi Matsushita; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY MOSBY-ELSEVIER 136 (3) 667 - + 0091-6749 2015/09 [Refereed]
   

  Background: Barrier disruption and the resulting continuous exposure to allergens are presumed to be responsible for the development of atopic dermatitis (AD). However, the mechanism through which skin barrier function is disrupted in patients with AD remains unclear. Objectives: Taking into account the fact that the T(H)2 milieu impairs keratinocyte terminal differentiation, we sought to clarify our hypothesis that the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a critical role in skin barrier function and can be a therapeutic target for AD. Methods: We analyzed the mechanism of keratinocyte differentiation using a microarray and small interfering RNA targeting STATs. We studied the effect of the JAK inhibitor JTE-052 on keratinocyte differentiation using the human skin equivalent model and normal human epidermal keratinocytes. We applied topical JAK inhibitor onto NC/Nga mice, dry skin model mice, and human skin grafted to immunocompromised mice. Results: IL-4 and IL-13 downregulated genes involved in keratinocyte differentiation. STAT3 and STAT6 are involved in keratinocyte differentiation and chemokine production by keratinocytes, respectively. Topical application of the JAK inhibitor suppressed STAT3 activation and improved skin barrier function, permitting increases in levels of terminal differentiation proteins, such as filaggrin, and natural moisturizing factors in models of AD and dry skin and in human skin. Conclusion: STAT3 signaling is a key element that regulates keratinocyte differentiation. The JAK inhibitor can be a new therapeutic tool for the treatment of disrupted barrier function in patients with AD.
• Multiple neurological abnormalities, including pontine hemorrhage, multiple sclerosis and aseptic meningitis, during anti-TNF-alpha therapy in psoriatic arthritis

  Yuki Honda; Atsushi Otsuka; Gyohei Egawa; Yutaka Inoue; Akira Kuzuya; Ryosuke Takahashi; Yoshiki Miyachi; Kenji Kabashinia

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 25 (5) 487 - 488 1167-1122 2015/09 [Refereed]
  
• Histological evaluation of a "residual" metastasis after ipilimumab therapy in a patient with advanced melanoma

  Shigeto Matsushita; Lukas Kraehenbuehl; Atsushi Otsuka; Daniela Mihic-Probst; Phil Cheng; Reinhard Dummer; Simone M. Goldinger

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 42 (9) 927 - 928 0385-2407 2015/09 [Refereed]
  
• Contribution of basophils to cutaneous immune reactions and Th2-mediated allergic responses

  Atsushi Otsuka; Kenji Kabashima

  FRONTIERS IN IMMUNOLOGY FRONTIERS MEDIA SA 6 393  1664-3224 2015/08 [Refereed]
   

  Basophils are potent effector cells of innate immunity and also play a role in T helper 2 (Th2)-mediated allergic responses. But, although their in vitro functions are well studied, their in vivo functions remain largely unknown. However, several mouse models of basophil depletion have recently been developed and used to investigate basophil functions. For example, in a croton oil-induced model of irritant contact dermatitis in conditionally basophil-depleted transgenic mice, we found that basophils rapidly infiltrate inflamed skin and subsequently induce infiltration of eosinophils. We also showed that basophils induce Th2 skewing upon epicutaneous sensitization with various haptens and peptide antigens. Intriguingly, basophils also promoted Th2 polarization upon protein antigen exposure in the presence of dendritic cells (DCs). The dermal DC subset associated with Th2 skewing was recently identified as CD301b(+) DC. Such studies with basophil-deficient mouse models have significantly improved our understanding of the mechanisms involved in human immune-related diseases. In this review, we will focus on the relative contribution of basophils and DCs to Th2-mediated allergic responses.
• CCR5およびCXCR3の発現を認めた皮下脂肪織様T細胞リンパ腫の1例

  本田 由貴; 大塚 篤司; 野々村 優美; 加来 洋; 大日 輝記; 椛島 健治

  日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 (一社)日本皮膚悪性腫瘍学会 31回 130 - 130 2015/07
• Pathological characterization of pachydermia in pachydermoperiostosis

  Tanese, K; Niizeki, H; Seki, A; Otsuka, A; Kabashima, K; Kosaki, K; Kuwahara, M; Miyakawa, S; Miyasaka, M; Matsuoka, K; Okuyama, T; Shiohama, A; Sasaki, T; Kudoh, J; Amagai, M; Ishiko, A

  J Dermatol 42 (7) 710 - 4 1346-8138 2015/07 

  Pachydermoperiostosis is a rare hereditary disease, which presents with the cutaneous manifestations of pachydermia and cutis verticis gyrata. Histological findings in pachydermia frequently include dermal edema, mucin deposition, elastic fiber degeneration, dermal fibrosis and adnexal hyperplasia. However, the severity of these findings varies between clinical reports, and a systematic multiple-case clinicopathological correlative analysis has not been performed to date. In the present study, we reviewed the skin biopsy specimens obtained from the pachydermia of six pachydermoperiostosis patients. The severity of the characteristic histological features was semiquantitatively evaluated and correlated with the grade of pachydermia. Dermal edema, mucin deposition and elastic fiber degeneration were observed in all cases. Patients with severe pachydermia had sebaceous gland hyperplasia and fibrosis. These results suggest that the triad of mucin deposition, dermal edema and elastic fiber degeneration are found from very early stage pachydermia, and could be considered diagnostic findings. To ensure an earlier diagnosis of pachydermoperiostosis, a biopsy should be taken when a patient
• Pathological characterization of pachydermia in pachydermoperiostosis

  Keiji Tanese; Hironori Niizeki; Atsuhito Seki; Atsushi Otsuka; Kenji Kabashima; Keisuke Kosaki; Masamitsu Kuwahara; Shun-ichi Miyakawa; Mikiko Miyasaka; Kentaro Matsuoka; Torayuki Okuyama; Aiko Shiohama; Takashi Sasaki; Jun Kudoh; Masayuki Amagai; Akira Ishiko

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 42 (7) 710 - 714 0385-2407 2015/07 [Refereed]
   

  Pachydermoperiostosis is a rare hereditary disease, which presents with the cutaneous manifestations of pachydermia and cutis verticis gyrata. Histological findings in pachydermia frequently include dermal edema, mucin deposition, elastic fiber degeneration, dermal fibrosis and adnexal hyperplasia. However, the severity of these findings varies between clinical reports, and a systematic multiple-case clinicopathological correlative analysis has not been performed to date. In the present study, we reviewed the skin biopsy specimens obtained from the pachydermia of six pachydermoperiostosis patients. The severity of the characteristic histological features was semiquantitatively evaluated and correlated with the grade of pachydermia. Dermal edema, mucin deposition and elastic fiber degeneration were observed in all cases. Patients with severe pachydermia had sebaceous gland hyperplasia and fibrosis. These results suggest that the triad of mucin deposition, dermal edema and elastic fiber degeneration are found from very early stage pachydermia, and could be considered diagnostic findings. To ensure an earlier diagnosis of pachydermoperiostosis, a biopsy should be taken when a patient has grade 1 pachydermia to determine the presence of this histological triad.
• Generalized morphea with preceding severe pain and coexistent early primary biliary cirrhosis

  Natsuko Iga; Atsushi Otsuka; Masashi Iwata; Yoshihide Ueda; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 25 (4) 365 - 366 1167-1122 2015/07 [Refereed]
  
• A plaque-type solitary reticulohistiocytoma in a two-year-old boy

  Rintaro Shibuya; Hideaki Tanizaki; Yo Kaku; Masao Yonezawa; Yuri Ryu; Atsushi Otsuka; Kenji Kabashima; Yoshiki Miyachi

  Case Reports in Dermatology S. Karger AG 7 (1) 7 - 9 1662-6567 2015/05 [Refereed]
   

  Reticulohistiocytoma (RH) is a dermal histiocytic infiltration composed of large histiocytes with eosinophilic glassy cytoplasm. RH is classified into three clinical forms: solitary RH, diffuse cutaneous RH without systemic involvement and multicentric reticulohistiocytosis with systemic diseases. Solitary RH generally manifests as a nodular lesion in adults without accompanying systemic diseases. Herein, we describe a case of solitary RH with an atypical clinical manifestation as a red-brown-colored plaque in a 2-year-old boy. Atypical presentations of RH may pose diagnostic difficulty unless RH is considered. A correct diagnosis of RH can ensure avoidance of unnecessary invasive procedures.
• Hedgehog signaling in basal cell carcinoma

  Atsushi Otsuka; Mitchell P. Levesque; Reinhard Dummer; Kenji Kabashima

  JOURNAL OF DERMATOLOGICAL SCIENCE ELSEVIER IRELAND LTD 78 (2) 95 - 100 0923-1811 2015/05 [Refereed]
   

  Basal cell carcinoma (BCC), the most common type of skin cancer, is occasionally aggressive with deep invasion, destruction of adjacent structures, recurrence and, on very rare occasions, regional and distant metastases. Mutations that occur in BCC in hedgehog (Hh) pathway genes primarily involve the genes encoding patched homolog (PTCH) and smoothened homolog (SMO). Several animal models have demonstrated the functional relevance of genetic alterations in the Hh pathway during tumorigenesis. Recently, targeted therapy has become available both commercially and in the context of human clinical trials. Interestingly, Hh pathway inhibitors not only suppress BCC progression but also promote acquired immune responses. Since immune responses are crucial for long-term tumor control, new clinical trials, such as those involving a combination of Hh inhibitors with immune modifiers, are needed to supplement standard methods of tumor control. (C) 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
• Dermal V gamma 4(+) gamma delta T Cells Possess a Migratory Potency to the Draining Lymph Nodes and Modulate CD8(+) T-Cell Activity through TNF-alpha Production

  Satoshi Nakamizo; Gyohei Egawa; Michio Tomura; Shunsuke Sakai; Soken Tsuchiya; Akihiko Kitoh; Tetsuya Honda; Atsushi Otsuka; Saeko Nakajima; Teruki Dainichi; Hideaki Tanizaki; Masao Mitsuyama; Yukihiko Sugimoto; Kazuhiro Kawai; Yasunobu Yoshikai; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF INVESTIGATIVE DERMATOLOGY NATURE PUBLISHING GROUP 135 (4) 1007 - 1015 0022-202X 2015/04 [Refereed]
   

  A large number of gamma delta T cells (gamma delta T cells) are located within epithelial tissues including the skin. In mice, epidermal and dermal gamma delta T cells consist of distinct subsets and have specific roles in cutaneous immune responses. A recent study demonstrated that gamma delta T cells and cutaneous dendritic cells migrate from the skin to the draining lymph nodes (LNs). However, it remains unclear whether they regulate the antigen-specific immune response within the LNs. Herein, we investigated their properties and role in the LNs using the Mycobacterium bovis bacille Calmette-Guerin (BCG) infection model. In vivo cell labeling analysis, revealed that most of the migratory subset comprised dermal V gamma 4(+) cells. This population transmigrated from the skin to the LNs in a Gi-coupled chemokine receptor independent manner. By depleting V gamma 4(+) cells, the intranodal expansion of CD8(+) T cell against BCG was significantly attenuated. In addition, in vitro analysis revealed that V gamma 4(+) cells produced TNF-alpha and enhanced IL-12 production by dendritic cells. Taken together, these findings suggest that dermal V gamma 4(+) cells are a unique subset that possesses a migratory potency to the skin-draining LNs and enhances the dendritic cell function therein.
• Hedgehog Pathway Inhibitors Promote Adaptive Immune Responses in Basal Cell Carcinoma

  Atsushi Otsuka; Jil Dreier; Phil F. Cheng; Mirjam Naegeli; Holger Lehmann; Lea Felderer; Ian J. Frew; Shigeto Matsushita; Mitchell P. Levesque; Reinhard Dummer

  CLINICAL CANCER RESEARCH AMER ASSOC CANCER RESEARCH 21 (6) 1289 - 1297 1078-0432 2015/03 [Refereed]
   

  Purpose: Basal cell carcinomas (BCCs) are tumors ignored by immune surveillance. Activated Hedgehog (Hh) signaling within primary cilia is a key driver in the pathogenesis of BCCs. We examined immune alterations during treatment with systemic Hh inhibitors. Experimental Design: We investigated biopsies from patients with BCC before (23 patients) and after 4 weeks of treatment (5 patients) with Hh signaling inhibitor. Ber-Ep4, BCL-2, Ki-67, CD4, CD8, MHC class I, HLA-DR-class II, and SOX9 were analyzed by immunohistochemistry. Primary cilia were analyzed by double immunofluorescence of acetylated tubulin and SOX9. Differential gene expression for 84 cytokines and chemokines was analyzed in 3 patients. Results: After 4 weeks of treatment, we found reduction of Ki-67, SOX9, Ber-EP4, and BCL-2 expression in tumors associated with morphologic signs of squamous differentiation. In addition, the number of cilia-positive BCC cells was significantly decreased. An upregulation of MHC I expression on the cell membranes of residual tumor cells and an influx of CD4(+), HLA-DR-class II+, and CD8(+) cells with invasion into the tumor cell nests were found. Finally, qPCR arrays showed the differential expression of genes involved in modulating immune responses. Conclusions: We show that Hh pathway inhibitor-induced tumor regression is accompanied by a dynamic change of the microenvironment with a disruption of immune privilege involving an influx of cytotoxic T cells, activation of the adaptive immune functions, and a profound alteration of the local chemokine/cytokine network. (C)2015 AACR.
• 皮膚腫瘍免疫のトピックス

  大塚 篤司

  Skin Cancer The Japanese Skin Cancer Society 30 (2) 58 - 61 0915-3535 2015
• CCR5およびCXCR3の発現を認めた皮下脂肪織様T細胞リンパ腫の1例

  本田 由貴; 大塚 篤司; 野々村 優美; 加来 洋; 大日 輝記; 椛島 健治

  Skin Cancer The Japanese Skin Cancer Society 30 (2) 131 - 131 0915-3535 2015
• IL-31

  大塚 篤司; 椛島 健治

  アレルギー 一般社団法人日本アレルギー学会 64 (1) 68 - 69 0021-4884 2015
• Barrier function and cutaneous immunology

  Atsushi Otsuka; Kenji Kabashima

  Japanese Journal of Allergology Japanese Society of Allergology 64 (9) 1189 - 1195 1347-7935 2015 [Refereed]
  
• Comparison of the Efficacy of Olopatadine and Fexofenadine in Chronic Idiopathic Urticaria Patients: A Crossover Study

  Hideaki Tanizaki; Yosuke Yamamoto; Satoshi Nakamizo; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  PHARMACOLOGY KARGER 95 (1-2) 32 - 35 0031-7012 2015 [Refereed]
   

  Olopatadine is one of the second-generation H-1 antihistamines that were used for treating allergic disorders initially in Asia, and now also in Western countries. Whereas several trials compared the efficacy on chronic urticaria among second-generation H-1 antihistamines, no study has directly compared the clinical efficacy between olopatadine and other H-1 antihistamines in patients with chronic idiopathic urticaria (CIU). In this study, we address this issue for the first time and conclude that olopatadine is a good candidate for the treatment of CIU. (C) 2015 S. Karger AG, Basel
• Response to Lee and Park

  Chihiro Shimizuhira; Atsushi Otsuka; Yosuke Yamamoto; Kenji Kabashima

  Journal of Investigative Dermatology Nature Publishing Group 135 (6) 1687  1523-1747 2015/01 [Refereed]
  
• The inflammasome and IL-1 beta: implications for the treatment of inflammatory diseases

  Takashi Satoh; Atsushi Otsuka; Emmanuel Contassot; Lars E. French

  IMMUNOTHERAPY FUTURE MEDICINE LTD 7 (3) 243 - 254 1750-743X 2015 [Refereed]
   

  The bioactive form of IL-1 beta, a key immunoregulatory and proinflammatory cytokine, is produced by the inflammasome - a caspase-1 activating molecular platform - in response to selected danger-associated molecular patterns and pathogen-associated molecular patterns. Advances in understanding the role of IL-1 beta in inflammatory conditions has resulted in IL-1 beta becoming a therapeutic target for a number of inflammatory diseases beyond the rare monogenic autoinflammatory diseases characterized by aberrant inflammasome function and enhanced bioactive IL-1 beta production. In the monogenic autoinflammatory diseases known as cryopyrin-associated periodic syndromes, neutralization of IL-1 beta results in a rapid and sustained reduction in disease severity without severe side effects, which has consequently driven off-label applications of IL-1 beta-targeted therapy in other inflammatory diseases. This review summarizes inflammatory diseases for which accumulating evidence suggests a therapeutic potential for IL-1 beta antagonists.
• Disseminated Mycobacterium mantenii Infection with Multiple Purulent Cutaneous Lesions

  Yuki Honda; Hideaki Tanizaki; Atsushi Otsuka; Mirei Shirakashi; Yoshitaka Imura; Tsuneyo Mimori; Yoshiki Miyachi; Kenji Kabashima

  ACTA DERMATO-VENEREOLOGICA ACTA DERMATO-VENEREOLOGICA 95 (8) 1028 - 1029 0001-5555 2015 [Refereed]
  
• Natural Killer T Cells Are Essential for the Development of Contact Hypersensitivity in BALB/c Mice

  Chihiro Shimizuhira; Atsushi Otsuka; Tetsuya Honda; Akihiko Kitoh; Gyohei Egawa; Saeko Nakajima; Chisa Nakashima; Hiroshi Watarai; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF INVESTIGATIVE DERMATOLOGY NATURE PUBLISHING GROUP 134 (11) 2709 - 2718 0022-202X 2014/11 [Refereed]
   

  Contact hypersensitivity (CHS) has been widely used to study cutaneous immune responses, as a prototype of delayed-type hypersensitivity. Although natural killer T (NKT) cells have been assumed to have an important role in CHS, their role is controversial. Here, we report the role of NKT cells in the sensitization phase of CHS, by promoting the survival and maturation of dendritic cells (DCs) in the draining lymph nodes (LNs). The CHS response was attenuated with Cd1d1(-/-) and Traj18(-/-) BALB/c mice in which NKT cells were absent. In the draining LNs, the number of effector T cells and cytokine production were significantly reduced with NKT cell-deficient mice. NKT cells activated and colocalized with DCs in the draining LNs after sensitization. The number of migrated and mature DCs was reduced in NKT cell deficient mice 72 hours after FITC application. In in vitro experiments, activated NKT cells enhanced bone marrow derived DC (BMDC) survivability via tumor necrosis factor (TNF) production from BMDCs. In addition, TNF production from BMDCs was partially suppressed by the neutralizing anti-CD54 or CD154 antibodies. Our data demonstrate that DC NKT interaction has a pivotal role in the sensitization phase of CHS.
• Perivascular leukocyte clusters are essential for efficient activation of effector T cells in the skin

  Yohei Natsuaki; Gyohei Egawa; Satoshi Nakamizo; Sachiko Ono; Sho Hanakawa; Takaharu Okada; Nobuhiro Kusuba; Atsushi Otsuka; Akihiko Kitoh; Tetsuya Honda; Saeko Nakajima; Soken Tsuchiya; Yukihiko Sugimoto; Ken J. Ishii; Hiroko Tsutsui; Hideo Yagita; Yoichiro Iwakura; Masato Kubo; Lai Guan Ng; Takashi Hashimoto; Judilyn Fuentes; Emma Guttman-Yassky; Yoshiki Miyachi; Kenji Kabashima

  NATURE IMMUNOLOGY NATURE PUBLISHING GROUP 15 (11) 1064 - 1069 1529-2908 2014/11 [Refereed]
   

  It remains largely unclear how antigen-presenting cells (APCs) encounter effector or memory T cells efficiently in the periphery. Here we used a mouse contact hypersensitivity (CHS) model to show that upon epicutaneous antigen challenge, dendritic cells (DCs) formed clusters with effector T cells in dermal perivascular areas to promote in situ proliferation and activation of skin T cells in a manner dependent on antigen and the integrin LFA-1. We found that DCs accumulated in perivascular areas and that DC clustering was abrogated by depletion of macrophages. Treatment with interleukin 1 alpha (IL-1 alpha) induced production of the chemokine CXCL2 by dermal macrophages, and DC clustering was suppressed by blockade of either the receptor for IL-1 (IL-1R) or the receptor for CXCL2 (CXCR2). Our findings suggest that the dermal leukocyte cluster is an essential structure for elicitating acquired cutaneous immunity.
• The complete type of pachydermoperiostosis: a novel nonsense mutation p.E141* of the SLCO2A1 gene

  Niizeki, H; Shiohama, A; Sasaki, T; Seki, A; Kabashima, K; Otsuka, A; Kosaki, K; Ogo, A; Yamada, T; Miyasaka, M; Matsuoka, K; Hirakiyama, A; Okuyama, T; Matsuda, M; Nakabayashi, K; Tanese, K; Ishiko, A; Amagai, M; Kudoh, J

  J Dermatol Sci 75 (3) 193 - 5 1873-569X 2014/09
• IL-17A as an Inducer for Th2 Immune Responses in Murine Atopic Dermatitis Models

  Saeko Nakajima; Akihiko Kitoh; Gyohei Egawa; Yohei Natsuaki; Satoshi Nakamizo; Catharina Sagita Moniaga; Atsushi Otsuka; Tetsuya Honda; Sho Hanakawa; Wataru Amano; Yoichiro Iwakura; Susumu Nakae; Masato Kubo; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF INVESTIGATIVE DERMATOLOGY NATURE PUBLISHING GROUP 134 (8) 2122 - 2130 0022-202X 2014/08 [Refereed]
   

  Atopic dermatitis (AD) is generally regarded as a type 2 helper T (Th2)-mediated inflammatory skin disease. Although the number of IL-17A-producing cells is increased in the peripheral blood and in acute skin lesion of AD patients, the role of IL-17A in the pathogenesis of AD remains unclear. To clarify this issue, we used murine AD models in an IL-17A-deficient condition. In a repeated hapten application induced AD model, skin inflammation, IL-4 production in the draining lymph nodes (LNs), and hapten-specific IgG1 and IgE induction were suppressed in IL-17A-deficient mice. V gamma 4(+) gamma delta T cells in the skin-draining LNs and V gamma 5(-) dermal gamma delta T cells in the skin were the major sources of IL-17A. Consistently, in flaky-tail (Fig(ft/ft) ma/ma) mice, spontaneous development of AD-like dermatitis and IgE induction were attenuated by IL-17A deficiency. Moreover, Th2 differentiation from naive T cells was promoted in vitro by the addition of IL-17A. Taken together, our results suggest that IL-17A mediates Th2-type immune responses and that IL-17A signal may be a therapeutic target of AD.
• Basophils regulate the recruitment of eosinophils in a murine model of irritant contact dermatitis

  Chisa Nakashima; Atsushi Otsuka; Akihiko Kitoh; Tetsuya Honda; Gyohei Egawa; Saeko Nakajima; Satoshi Nakamizo; Makoto Arita; Masato Kubo; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY MOSBY-ELSEVIER 134 (1) 100 - + 0091-6749 2014/07 [Refereed]
   

  Background: Although eosinophils have been detected in several human skin diseases in the vicinity of basophils, how eosinophils infiltrate the skin and the role of eosinophils in the development of skin inflammation have yet to be examined. Objective: Using murine irritant contact dermatitis (ICD) as a model, we sought to clarify the roles of eosinophils in ICD and the underlying mechanism of eosinophil infiltration of the skin. Methods: We induced croton oil-induced ICD in eosinophil-deficient Delta dblGATA mice with or without a reactive oxygen species (ROS) inhibitor. We performed cocultivation with fibroblasts and bone marrow-derived basophils and evaluated eosinophil migration using a chemotaxis assay. Results: ICD responses were significantly attenuated in the absence of eosinophils or by treatment with the ROS inhibitor. ROS was produced abundantly by eosinophils, and both basophils and eosinophils were detected in human and murine ICD skin lesions. In coculture experiments, basophils attracted eosinophils, especially in the presence of fibroblasts. Moreover, basophils produced IL-4 and TNF-alpha in contact with fibroblasts and promoted the expression of eotaxin/CCL11 from fibroblasts in vitro. Conclusion: Eosinophils mediated the development of murine ICD, possibly through ROS production. Recruitment of eosinophils into the skin was induced by basophils in cooperation with fibroblasts. Our findings introduce the novel concept that basophils promote the recruitment of eosinophils into the skin through fibroblasts in the development of skin inflammation.
• Calcinosis cutis long after rhinoplasty with silicone

  Yuki Honda; Hideaki Tanizaki; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  Case Reports in Dermatology S. Karger AG 6 (3) 288 - 290 1662-6567 2014/05 [Refereed]
   

  Rhinoplasty is a plastic surgery procedure to reconstruct the nose. Silicone alloplastic materials are most widely used as implants for rhinoplasty, but calcification on the surface occurs with long-term usage. Herein, we report a case of gruel-like calcification approximately 50 years after silicone implant rhinoplasty. In this case, calcification on the silicone surface might have transformed into gruel-like deposits, which presented as a subcutaneous mass at the dorsal area of the nose. The precise mechanism is unclear a pH change in the tissue might have occurred during the process of inflammation, leading to the dissolution of calcified deposits.
• The novel SLCO2A1 heterozygous missense mutation p.E427K and nonsense mutation p.R603* in a female patient with pachydermoperiostosis with an atypical phenotype

  Niizeki, H; Shiohama, A; Sasaki, T; Seki, A; Kabashima, K; Otsuka, A; Takeshita, M; Hirakiyama, A; Okuyama, T; Tanese, K; Ishiko, A; Amagai, M; Kudoh, J

  Br J Dermatol 170 (5) 1187 - 9 1365-2133 2014/05
• Metastatic melanoma cell lines do not secrete IL-1 beta but promote IL-1 beta production from macrophages

  Samuel Gehrke; Atsushi Otsuka; Roman Huber; Barbara Meier; Magdalena Kistowska; Gabriele Fenini; Phil Cheng; Reinhard Dummer; Katrin Kerl; Emmanuel Contassot; Lars E. French

  JOURNAL OF DERMATOLOGICAL SCIENCE ELSEVIER IRELAND LTD 74 (2) 167 - 169 0923-1811 2014/05 [Refereed]
  
• The Enzyme Cyp26b1 Mediates Inhibition of Mast Cell Activation by Fibroblasts to Maintain Skin-Barrier Homeostasis

  Yosuke Kurashima; Takeaki Amiya; Kumiko Fujisawa; Naoko Shibata; Yuji Suzuki; Yuta Kogure; Eri Hashimoto; Atsushi Otsuka; Kenji Kabashima; Shintaro Sato; Takeshi Sato; Masato Kubo; Shizuo Akira; Kensuke Miyake; Jun Kunisawa; Hiroshi Kiyono

  IMMUNITY CELL PRESS 40 (4) 530 - 541 1074-7613 2014/04 [Refereed]
   

  Mast cells (MCs) mature locally, thus possessing tissue-dependent phenotypes for their critical roles in both protective immunity against pathogens and the development of allergy or inflammation. We previously reported that MCs highly express P2X7, a receptor for extracellular ATP, in the colon but not in the skin. The ATP-P2X7 pathway induces MC activation and consequently exacerbates the inflammation. Here, we identified the mechanisms by which P2X7 expression on MCs is reduced by fibroblasts in the skin, but not in the other tissues. The retinoic-acid-degrading enzyme Cyp26b1 is highly expressed in skin fibroblasts, and its inhibition resulted in the upregulation of P2X7 on MCs. We also noted the increased expression of P2X7 on skin MCs and consequent P2X7- and MC-dependent dermatitis (so-called retinoid dermatitis) in the presence of excessive amounts of retinoic acid. These results demonstrate a unique skin-barrier homeostatic network operating through Cyp26b1-mediated inhibition of ATP-dependent MC activation by fibroblasts.
• アトピー性皮膚炎のバリア機能の解明と創薬

  大塚 篤司; 椛島 健治

  ファルマシア 公益社団法人 日本薬学会 50 (10) 973 - 977 2014 

  我が国には約40万人のアトピー性皮膚炎（atopic dermatitis；AD）の患者がいるとされる．ADは慢性的なかゆみを伴う皮膚疾患であり，その背景として湿疹ができやすい体質があると考えられている．その体質として皮膚の乾燥が候補因子であったが，十分な解析はなされていなかった．ところが，2006年にADの有病率とフィラグリン遺伝子の相関関係が指摘されたことで，皮膚のバリア機能と免疫とのクロストークが注目を集めることとなった．
• The novel SLCO2A1 heterozygous missense mutation p.E427K and nonsense mutation p.R603* in a female patient with pachydermoperiostosis with an atypical phenotype

  Niizeki H; Shiohama A; Sasaki T; Seki A; Kabashima K; Otsuka A; Takeshita M; Hirakiyama A; Okuyama T; Tanese K; Ishiko A; Amagai M; Kudoh J

  British Journal of Dermatology 170 (5) 1187 - 1189 0007-0963 2014
• The complete type of pachydermoperiostosis

  Niizeki H; Shiohama A; Sasaki T; Seki A; Kabashima K; Otsuka A; Kosaki K; Ogo A; Yamada T; Miyasaka M; Matsuoka K; Hirakiyama A; Okuyama T; Matsuda M; Nakabayashi K; Tanese K; Ishiko A; Amagai M; Kudoh J

  Journal of Dermatological Science 75 (3) 193 - 195 0923-1811 2014
• Serum granulysin as a possible key marker of the activity of alopecia areata

  Sachiko Ono; Atsushi Otsuka; Yosuke Yamamoto; Tatsuki R. Kataoka; Itsuko Koyanagi; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF DERMATOLOGICAL SCIENCE ELSEVIER IRELAND LTD 73 (1) 74 - 79 0923-1811 2014/01 [Refereed]
   

  Background: Alopecia areata (AA) is an organ-restricted autoimmune condition of the hair follicles (HFs) that presents as nonscarring hair loss. A collapse of immunoprivilege for cell-mediated cytotoxicity and following attacks by cytotoxic T cells to anagen HFs are considered to play a major role in the pathogenesis of AA. However, there has been no useful marker for the activity of AA to date. Objective: The aim of this study is to examine whether granulysin, which is known to reflect the activity of cytotoxic immune responses, is related to the disease activity of AA. Methods: We evaluated serum granulysin levels in acute and chronic AA patients compared to healthy controls in the perspective of bald skin areas, prognosis, and co-existence of other allergic diseases. In addition, immunohistochemical analysis for granulysin-, CD4-, CD8-, and CD56-positive cells in the lesional skin of acute and chronic AA patients was performed. Results: Serum granulysin levels were significantly elevated in both acute and chronic AA patients (p = 0.00081 and p = 0.0012, respectively). Intriguingly, serum granulysin levels were significantly associated with the broader bald skin areas (Spearman's r = 0.59, p = 0.017), and poorer prognosis in acute AA patients (p = 0.0080). They were also associated with co-existence of allergic disorders in AA patients (p = 0.026). Immunohistochemical staining demonstrated that perifollicular granulysin-bearing cells were mainly detected in acute AA lesions with dense lymphocytic infiltration, and that these granulysin-bearing cells were consistent with CD8(+) T cells. Conclusion: The serum granulysin level may be a useful and novel marker for the disease activity in the acute phase of AA. (C) 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
• Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression

  Atsushi Otsuka; Hiromi Doi; Gyohei Egawa; Akiko Maekawa; Tomoko Fujita; Satoshi Nakamizo; Chisa Nakashima; Saeko Nakajima; Takeshi Watanabe; Yoshiki Miyachi; Shuh Narumiya; Kenji Kabashima

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY MOSBY-ELSEVIER 133 (1) 139 - + 0091-6749 2014/01 [Refereed]
   

  Background: Nonsense mutations in filaggrin (FLG) represent a significant genetic factor in the cause of atopic dermatitis (AD). Objective: It is of great importance to find drug candidates that upregulate FLG expression and to determine whether increased FLG expression controls the development of AD. Methods: We screened a library of bioactives by using an FLG reporter assay to find candidates that promoted FLG mRNA expression using a human immortalized keratinocyte cell line (HaCaT). We studied the effect of the compound on keratinocytes using the human skin equivalent model. We examined the effect of the compound on AD-like skin inflammation in NC/Nga mice. Results: JTC801 promoted FLG mRNA and protein expression in both HaCaT and normal human epidermal keratinocytes. Intriguingly, JTC801 promoted the mRNA and protein expression levels of FLG but not the mRNA levels of other makers for keratinocyte differentiation, including loricrin, keratin 10, and transglutaminase 1, in a human skin equivalent model. In addition, oral administration of JTC801 promoted the protein level of Flg and suppressed the development of AD-like skin inflammation in NC/Nga mice. Conclusion: This is the first observation that the compound, which increased FLG expression in human and murine keratinocytes, attenuated the development of AD-like skin inflammation in mice. Our findings provide evidence that modulation of FLG expression can be a novel therapeutic target for AD.
• Coexistent Skin Lesions of Vitiligo and Psoriasis Vulgaris. Immunohistochemical Analyses for IL-17A-producing Cells Cells and Regulatory T Cells

  Sachiko Ono; Hideaki Tanizaki; Atsushi Otsuka; Yuichiro Endo; Itsuko Koyanagi; Tatsuki R. Kataoka; Yoshiki Miyachi; Kenji Kabashima

  ACTA DERMATO-VENEREOLOGICA ACTA DERMATO-VENEREOLOGICA 94 (3) 329 - 330 0001-5555 2014 [Refereed]
   

  Vitiligo vulgaris (VV) and psoriasis vulgaris (PV) are common dermatoses, with a worldwide occurrence of 0.5-1% and 1-3%, respectively. An imbalance between effector T cells and regulatory T cells (Tregs) can result in the pathogenesis of cutaneous immune diseases. In VV, interleukin (IL)-17-producing T-helper (Th) 17 cells are increased in the lesional skin as seen in PV (1). However, the number of Tregs is drastically reduced in the lesional skin of VV, which may allow an activation of effector T cells (2). In PV, an increased number of lesional Tregs was indicated (3, 4). While both lesional Th17 cells and Tregs are increased in PV, the ratio of Th17 cells to Tregs was shown to be inversely correlated with the psoriasis area and severity index (PAST). It has recently been proposed that Tregs readily turn into Th17 cells in PV, which potentially perpetuates the inflammatory process that characterises the disease (5). Herein, we present a case with the coexistent skin lesions of VV and PV with immunohistochemical analyses.
• Intractable prurigo nodularis successfully treated with combination therapy with a newly developed excimer laser and topical steroids

  Chisa Nakashima; Hideaki Tanizaki; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  Dermatology Online Journal Dermatology Online Journal 20 (6) 1087-2108 2014 [Refereed]
   

  Prurigo nodularis (PN) is an eruption of lichenified or excoriated nodules related to intractable pruritus. A few reports have shown that a 308-nm excimer lamp/laser (EL) is effective for intractable PN. Herein, we report on two cases of intractable prurigo nodularis successfully treated with a new EL equipped with a filter to cut wavelengths shorter than 297 nm. Because this newly developed EL yields a therapeutic effect with low cumulative dosages of UV and a lower risk of DNA damage, it can be a new treatment option for intractable PN. © 2014 by the article author(s).
• CD39: A new surface marker of mouse regulatory gamma delta T cells

  Atsushi Otsuka; Sho Hanakawa; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY MOSBY-ELSEVIER 132 (6) 1448 - 1451 0091-6749 2013/12 [Refereed]
  
• Sweet's syndrome presenting as drastically spreading generalized erythema with subcorneal pustulosis in myelodysplastic syndrome

  Sachiko Ono; Atsushi Otsuka; Kenji Kabashima; Yoshiki Miyachi; Takao Tachibana

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 40 (12) 1072 - 1073 0385-2407 2013/12 [Refereed]
  
• Pigmented purpuric dermatitis with high expression levels of serum TARC/CCL17 and epidermal TSLP

  Sachiko Ono; Saeko Nakajima; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  European Journal of Dermatology 23 (5) 701 - 702 1167-1122 2013/09 [Refereed]
  
• 尋常性乾癬に対するインフリキシマブの有効性の検討 京都大学皮膚科での使用経験

  遠藤 雄一郎; 谷崎 英昭; 藤澤 章弘; 大塚 篤司; 江川 形平; 荒川 明子; 野村 尚史; 鬼頭 昭彦; 谷岡 未樹; 松村 由実; 椛島 健治; 宮地 良樹

  皮膚の科学 日本皮膚科学会-大阪地方会・京滋地方会 12 (4) 301 - 305 1347-1813 2013/08 [Refereed]
   

  インフリキシマブは,中等症以上の尋常性乾癬,乾癬性紅皮症および関節症性乾癬に対して有効とされる。本研究では当科において乾癬に対してインフリキシマブを用いて加療した11例について分析し,その有効性を検討した。エンドポイントはPASIスコアの90%改善と関節症状の有無とした。関節症の合併は7例,乾癬性紅皮症は3例であった。導入前のPASIスコアは23.0±17.1であった。インフリキシマブ投与後早期に関節症状およびPASIスコアは有意に改善した。PASI 90達成は7例(64%)であり要した期間は17.3±19.3週であった。インフリキシマブは投与早期より重症乾癬に対して有効と示唆された。(著者抄録)
• Severe psoriasis vulgaris exhibiting a high serum thymus and activation-regulated chemokine level: Possible association of T-helper 2 conditions

  Sachiko Ono; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 40 (7) 582 - 583 0385-2407 2013/07 [Refereed]
  
• Basophils are required for the induction of Th2 immunity to haptens and peptide antigens

  Atsushi Otsuka; Saeko Nakajima; Masato Kubo; Gyohei Egawa; Tetsuya Honda; Akihiko Kitoh; Takashi Nomura; Sho Hanakawa; Catharina Sagita Moniaga; Bongju Kim; Satoshi Matsuoka; Takeshi Watanabe; Yoshiki Miyachi; Kenji Kabashima

  NATURE COMMUNICATIONS NATURE PUBLISHING GROUP 4 1739  2041-1723 2013/04 [Refereed]
   

  The relative contributions of basophils and dendritic cells in Th2 skewing to foreign antigen exposure remain unclear. Here we report the ability of basophils to induce Th2 polarization upon epicutaneous sensitization with different antigens using basophil conditionally depleted Bas TRECK transgenic mice. Basophils are responsible for Th2 skewing to haptens and peptide antigens, but not protein antigens in vivo. Consistent with this, basophils cannot take up or process ovalbumin protein in significant quantities, but present ovalbumin peptide to T cells for Th2 differentiation via major histocompatibility complex class II. Intriguingly, basophils promote Th2 skewing upon ovalbumin protein exposure in the presence of dendritic cells. Taken together, our results suggest that basophils alone are able to induce Th2 skewing with haptens and peptide antigens but require dendritic cells for the induction of Th2 for protein antigens upon epicutaneous immunization.
• Effectiveness of infliximab in severe psoriasis: A single center experience

  Y. Endo; H. Tanizaki; A. Fujisawa; A. Otsuka; G. Egawa; A. Arakawa; T. Nomura; A. Kitoh; M. Tanioka; Y. Matsumura; K. Kabashima; Y. Miyachi

  Skin Research 12 (4) 301 - 305 2013 [Refereed]
  
• Basophils Infiltrate the Skin Lesions in Lepromatous Leprosy

  Atsushi Otsuka; Motoaki Ozaki; Yuji Horiguchi; Yozo Murata; Kimiko Kumano; Reiko Nogami; Masamichi Goto; Andrew F. Walls; Norihisa Ishii; Yoshiki Miyachi; Kenji Kabashima

  ACTA DERMATO-VENEREOLOGICA ACTA DERMATO-VENEREOLOGICA 93 (1) 88 - 89 0001-5555 2013 [Refereed]
  
• A case of churg-strauss syndrome: Flow cytometric analysis of the surface activation markers of peripheral eosinophils

  Kyoko Nakahigashi; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima; Miki Tanioka

  Acta Dermato-Venereologica 93 (1) 100 - 101 0001-5555 2013 [Refereed]
  
• Prostaglandin E2 increase in pachydermoperiostosis without 15-hydroprostaglandin dehydrogenase mutations

  Kyoko Nakahigashi; Atsushi Otsuka; Hiromi Doi; Satsuki Tanaka; Yoshiaki Okajima; Hironori Niizeki; Asami Hiraki-Yama; Yoshiki Miyachi; Kenji Kabashima

  Acta Dermato-Venereologica 93 (1) 118 - 119 0001-5555 2013 [Refereed]
  
• No Basophil Infiltration in Alopecia Areata Irrespective of the Intensity of Eosinophil Infiltration

  Sachiko Ono; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  ACTA DERMATO-VENEREOLOGICA ACTA DERMATO-VENEREOLOGICA 93 (2) 185 - 186 0001-5555 2013 [Refereed]
  
• Incomplete POEMS syndrome presenting for years solely with scleredema and hyperpigmentation

  Sachiko Ono; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  Journal of Dermatology 40 (1) 77 - 78 0385-2407 2013/01 [Refereed]
  
• Sarcoidosis of the scalp presenting as patchy alopecia; analysis of transforming growth factor-beta expression in the affected area by immunostaining

  Yumi Nonomura; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 23 (1) 115 - 116 1167-1122 2013/01 [Refereed]
  
• Subcorneal pustular dermatosis exhibiting a high serum TARC/CCL17 level

  Sachiko Ono; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  Case Reports in Dermatology 5 (1) 38 - 42 1662-6567 2013/01 [Refereed]
   

  Subcorneal pustular dermatosis (SPD) is a rare, relapsing, symmetric sterile pustular eruption that dominantly involves flexural areas. It is considered one form of neutrophilic dermatoses, which are associated with interleukin (IL)-17-producing T helper (Th) 17 cells that induce IL-8 production. We have previously reported that Th17 might be involved in the pathomechanism of Th2-dominant atopic dermatitis [Koga et al.: J Invest Dermatol 2008 128:2625-2630]. On the other hand, it has been a debate whether Th2 is involved in the etiology of neutrophilic dermatoses. Herein, we report a case of SPD that exhibited a high serum thymus and activation-regulated chemokine/chemokine (C-C motif) ligand 17 level, thereby raising the possibility of a Th2 association in its pathogenesis. Although it was limited to a single observation, our case raised the possibility that SPD may possess Th2 properties. © 2013 S. Karger AG, Basel.
• Evaluation of basophil infiltration into the skin lesions of tick bites

  Kyoko Nakahigashi; Atsushi Otsuka; Kaori Tomari; Yoshiki Miyachi; Kenji Kabashima

  Case Reports in Dermatology S. Karger AG 5 (1) 48 - 51 1662-6567 2013 [Refereed]
   

  Recently, it has been described that basophils play an essential role in antibody-mediated acquired immunity against ticks in mice. However, it is still unknown whether basophil infiltration has any significance in the infestation with ticks in humans. In this report, we have evaluated the infiltration of basophils into human skin lesions of tick bites.
• Evaluation of the effectiveness of antibiotics against eosinophilic pustular folliculitis

  Sachiko Ono; Yosuke Yamamoto; Atsushi Otsuka; Kenji Kabashima; Yoshiki Miyachi

  Case Reports in Dermatology S. Karger AG 5 (2) 144 - 147 1662-6567 2013 [Refereed]
   

  Eosinophilic pustular folliculitis (EPF) is a chronic intractable pruritic dermatosis. Although indomethacin is generally effective against EPF and considered as a first-line therapy, quite a few patients with indomethacin still suffer from the symptoms. Among other therapeutic options, some antibiotics have been reported to be effective however, there has been no epidemiological description regarding oral antibiotics use in patients with EPF. In this study, we investigated the frequency of antibiotics use and the effectiveness in patients with EPF.
• 好酸球性膿疱性毛包炎におけるロキシスロマイシンの臨床効果と作用機序の検討

  大塚 篤司; 中東 恭子; 山本 洋介; 小野 さち子; 椛島 健治; 宮地 良樹

  皮膚の科学 日本皮膚科学会-大阪地方会・京滋地方会 11 (Suppl.19) 27 - 30 1347-1813 2012/12 

  好酸球性膿疱性毛包炎(Eosinophilic pustular folliculitis:EPF)は,毛嚢一致性のそう痒性丘疹,無菌性膿疱が再燃寛解を繰り返す原因不明の慢性炎症疾患であり,病理組織学的に毛包脂腺系に多数の好酸球浸潤を伴う。EPF治療には,シクロオキシゲナーゼ阻害薬であるインドメタシンが第一選択として用いられ約7割の患者に奏効するとされている。一方,抗生剤が効果的である症例をしばしば経験するが,その実態は明らかでない。今回我々はアンケート調査を行い,EPFに対する抗生剤の効果を検討した。その結果,ロキシスロマイシンが効果的であることが示唆された。(著者抄録)
• Case of intractable ophiasis type of alopecia areata presumably improved by fexofenadine

  Yumi Nonomura; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 39 (12) 1063 - 1064 0385-2407 2012/12 [Refereed]
  
• Female pattern hair loss possibly caused by tamoxifen: Androgen receptor expression in the outer root sheath in the affected area

  Yumi Nonomura; Atsushi Otsuka; Shigeki Inui; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 39 (12) 1060 - 1061 0385-2407 2012/12 [Refereed]
  
• Efficacy of additional methotrexate as a maintenance treatment in a Japanese patient with psoriatic arthritis refractory to infliximab monotherapy

  Yumi Nonomura; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima; Miki Tanioka

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 39 (11) 954 - 955 0385-2407 2012/11 [Refereed]
  
• Nofilaggrin gene mutation in a patient with a combination of atopic dermatitis, alopecia areata and food allergy

  Sachiko Ono; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 22 (6) 785 - 786 1167-1122 2012/11 [Refereed]
  
• Sparganosis mansoni on abdominal skin, mimicking folliculitis and diagnosed by analysis of the mitochondrial cytochrome c oxidase subunit 1 gene, using polymerase chain reaction

  Yumi Nonomura; Atsushi Otsuka; Yuichiro Endo; Akihiro Fujisawa; Naoki Nakajima; Sachiko Minamiguchi; Aya Miyagawa-Hayashino; Minoru Yamada; Tatsuya Tegoshi; Hiroshi Yamasaki; Kenji Kabashima; Yoshiki Miyachi; Miki Tanioka

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 22 (6) 806 - 807 1167-1122 2012/11 [Refereed]
  
• Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis

  Takashi Sasaki; Hironori Niizeki; Atsushi Shimizu; Aiko Shiohama; Asami Hirakiyama; Torayuki Okuyama; Atsuhito Seki; Kenji Kabashima; Atsushi Otsuka; Akira Ishiko; Keiji Tanese; Shun-ichi Miyakawa; Jun-ichi Sakabe; Masamitsu Kuwahara; Masayuki Amagai; Hideyuki Okano; Makoto Suematsu; Jun Kudoh

  JOURNAL OF DERMATOLOGICAL SCIENCE ELSEVIER IRELAND LTD 68 (1) 36 - 44 0923-1811 2012/10 [Refereed]
   

  Background: Pachydermoperiostosis (PDP) is a rare genetic disorder characterized by 3 major symptoms: pachydermia including cutis verticis gyrata (CVG), periostosis, and finger clubbing. Recently, a homozygous mutation in the gene HPGD, which encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH), was found to be associated with PDP. However, mutations in HPGD have not been identified in Japanese PDP patients. Objective: We aimed to identify a novel responsible gene for PDP using whole exome sequencing by next-generation DNA sequencer (NGS). Methods: Five patients, including 2 patient-parent trios were enrolled in this study. Entire coding regions were sequenced by NGS to identify candidate mutations associated with PDP. The candidate mutations were subsequently sequenced using the Sanger method. To determine clinical characteristics, we analyzed histological samples, as well as serum and urinary prostaglandin E2 (PGE2) levels for each of the 5 PDP patients, and 1 additional patient with idiopathic CVG. Results: From initial analyses of whole exome sequencing data, we identified mutations in the solute carrier organic anion transporter family, member 2A1 (SLCO2A1) gene, encoding prostaglandin transporter, in 3 of the POP patients. Follow-up Sanger sequencing showed 5 different SLCO2A1 mutations (c.940+1G > A, p.E427_P430del, p.G104*, p.T3471, p.Q556H) in 4 unrelated PDP patients. In addition, the splice-site mutation c.940+1G > A identified in 3 of 4 PDP patients was determined to be founder mutation in the Japanese population. Furthermore, it is likely that the combination of these SLCO2A1 mutations in PDP patients is also associated with disease severity. Conclusion: We found that SLCO2A1 is a novel gene responsible for PDP. Although the SLCO2A1 gene is only the second gene discovered to be associated with PDP, it is likely to be a major cause of PDP in the Japanese population. (c) 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
• Extranodal NK/T-cell lymphoma, nasal type, presenting pseudoepitheliomatous hyperplasia mimicking squamous cell carcinoma

  Yumi Nonomura; Atsushi Otsuka; Yuichiro Endo; Akihiro Fujisawa; Aya Miyagawa-Hayashino; Shinji Sumiyoshi; Kenji Kabashima; Yoshiki Miyachi; Miki Tanioka

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 22 (5) 688 - 689 1167-1122 2012/09 [Refereed]
  
• Treatment of intractable oral lichen planus with intravenous immunoglobulin therapy

  Chisa Nakashima; Atsushi Otsuka; Hiroko Sonobe; Akihiko Kitoh; Mayumi Kato; Satoshi Kore-Eda; Yoshiki Miyachi; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 22 (5) 693 - 693 1167-1122 2012/09 [Refereed]
  
• Improvement of anti-TNF alpha antibody-induced pustular psoriasis by azathioprine

  Tomoko Kayama; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 22 (4) 565 - 566 1167-1122 2012/07 [Refereed]
  
• 乳癌ホルモン療法に伴う男型脱毛症の2例

  野々村 優美; 大塚 篤司; 松村 由美; 藤澤 章弘; 谷岡 未樹; 椛島 健治; 宮地 良樹

  日本皮膚科学会雑誌 (公社)日本皮膚科学会 122 (7) 1800 - 1800 0021-499X 2012/06
• Fixed drug eruption induced by cyclophosphamide

  Kenji Sakurai; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 22 (3) 401 - 402 1167-1122 2012/05 [Refereed]
  
• Suspected Nagashima-type palmoplantar keratosis with atypical hyperkeratotic lesions on the ears

  Yumi Nonomura; Atsushi Otsuka; Yoshiki Miyachi; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 22 (3) 392 - 393 1167-1122 2012/05 [Refereed]
  
• Clostridium difficile Colitis and Neutropenic Fever Associated with Docetaxel Chemotherapy in a Patient with Advanced Extramammary Paget's Disease.

  Yumi Nonomura; Atsushi Otsuka; Yuichiro Endo; Akihiro Fujisawa; Miki Tanioka; Kenji Kabashima; Yoshiki Miyachi

  Case reports in dermatology 4 (2) 177 - 80 2012/05 [Refereed]
   

  Extramammary Paget's disease is a rare cutaneous malignant neoplasm. Previous studies indicated the efficacy of docetaxel in advanced cases. The common side effects of docetaxel are usually tolerable and seldom life-threatening. We experienced a case of severe pseudomembranous colitis and neutropenic fever that developed just after the first cycle of docetaxel chemotherapy. To the best of our knowledge, there are few reports of pseudomembranous colitis associated with docetaxel administration for skin cancers. The patient showed complete resolution of her symptoms within 2 weeks with an oral metronidazole therapy. During the second and third cycles, the patient received docetaxel safely with lower doses. The present case indicated that pseudomembranous colitis should be included in the differential diagnosis when assessing patients who develop severe diarrhea during systemic chemotherapy with docetaxel.
• Improvement of anti-TNF-α antibody-induced palmoplantar pustular psoriasis using a 308-nm excimer light

  Natsuko Iga; Atsushi Otsuka; Miki Tanioka; Yoshiki Miyachi; Kenji Kabashima

  Case Reports in Dermatology S. Karger AG 4 (3) 261 - 264 1662-6567 2012/04 [Refereed]
   

  Anti-tumor necrosis factor (TNF)-α antibody is utilized in the treatment of a variety of chronic inflammatory conditions, including psoriasis. However, it can induce paradoxical development and/or exacerbation of psoriasis in the course of anti-TNF-α antibody treatment, which is sometimes refractory to conventional treatments. Herein, we report a case of refractory palmoplantar pustular psoriasis induced by anti-TNF-α antibody treatment, which was improved by treatment with a 308-nm excimer light. The 308-nm excimer light has less long-term risks than narrow-band UVB. The 308-nm excimer light may be a good therapeutic option for refractory psoriatic skin lesions induced by anti-TNF-α antibody therapy because of localized side effects without systemic problems, short length of treatment and low cumulative dosages of UV light.
• Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling

  Saeko Nakajima; Botond Z. Igyarto; Tetsuya Honda; Gyohei Egawa; Atsushi Otsuka; Mariko Hara-Chikuma; Norihiko Watanabe; Steven F. Ziegler; Michio Tomura; Kayo Inaba; Yoshiki Miyachi; Daniel H. Kaplan; Kenji Kabashima

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY MOSBY-ELSEVIER 129 (4) 1048 - U564 0091-6749 2012/04 [Refereed]
   

  Background: The clarification of cutaneous dendritic cell subset and the role of thymic stromal lymphopoietin (TSLP) signaling in epicutaneous sensitization with protein antigens, as in the development of atopic dermatitis, is a crucial issue. Objectives: Because TSLP is highly expressed in the vicinity of Langerhans cells (LCs), we sought to clarify our hypothesis that LCs play an essential role in epicutaneous sensitization with protein antigens through TSLP signaling. Methods: By using Langerin-diphtheria toxin receptor knock-in mice and human Langerin-diphtheria toxin A transgenic mice, we prepared mice deficient in LCs. We also prepared mice deficient in TSLP receptors in LCs by using TSLP receptor-deficient mice with bone marrow chimeric technique. We applied these mice to an ovalbumin (OVA)-induced epicutaneous sensitization model. Results: Upon the epicutaneous application of OVA, conditional LC depletion attenuated the development of clinical manifestations as well as serum OVA-specific IgE increase, OVA-specific T-cell proliferation, and IL-4 mRNA expression in the draining lymph nodes. Consistently, even in the steady state, permanent LC depletion resulted in decreased serum IgE levels, suggesting that LCs mediate the T(H)2 local environment. In addition, mice deficient in TSLP receptors on LCs abrogated the induction of OVA-specific IgE levels upon epicutaneous OVA sensitization. Conclusion: LCs initiate epicutaneous sensitization with protein antigens and induce T(H)2-type immune responses via TSLP signaling. (J Allergy Clin Immunol 2012;129:1048-55.)
• PGD(2) induces eotaxin-3 via PPAR gamma from sebocytes: A possible pathogenesis of eosinophilic pustular folliculitis

  Kyoko Nakahigashi; Hiromi Doi; Atsushi Otsuka; Tetsuya Hirabayashi; Makoto Murakami; Yoshihiro Urade; Hideaki Tanizaki; Gyohei Egawa; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY MOSBY-ELSEVIER 129 (2) 536 - 543 0091-6749 2012/02 [Refereed]
   

  Background: Eosinophilic pustular folliculitis (EPF) is a chronic intractable pruritic dermatosis characterized by massive eosinophil infiltrates involving the pilosebaceous units. Recently, EPF has been regarded as an important clinical marker of HIV infection, and its prevalence is increasing in number. The precise mechanism by which eosinophils infiltrate into the pilosebaceous units remains largely unknown. Given that indomethacin, a COX inhibitor, can be successfully used to treat patients with EPF, we can assume that COX metabolites such as prostaglandins (PGs) are involved in the etiology of EPF. Objective: To determine the involvement of PGs in the pathogenesis of EPF. Methods: We performed immunostaining for PG synthases in EPF skin lesions. We examined the effect of PGD(2) on induction of eotaxin, a chemoattractant for eosinophils, in human keratinocytes, fibroblasts, and sebocytes and sought to identify its responsible receptor. Results: Hematopoietic PGD synthase was detected mainly in infiltrating inflammatory cells in EPF lesions, implying that PGD(2) was produced in the lesions. In addition, PGD(2) and its immediate metabolite 15-deoxy-Delta 12,14-PGJ(2) (15d-PGJ(2)) induced sebocytes to produce eotaxin-3 via peroxisome proliferator-activated receptor gamma. Consistent with the above findings, eotaxin-3 expression was immunohistochemically intensified in sebaceous glands of the EPF lesions. Conclusion: The PG Delta(2)/PGJ(2)-peroxisome proliferator-activated receptor gamma pathway induces eotaxin production from sebocytes, which may explain the massive eosinophil infiltrates observed around pilosebaceous units in EPF. (J Allergy Clin Immunol 2012;129:536-43.)
• The effect of roxithromycin on eosinophilic pustular folliculitis

  A. Otsuka; K. Nakahigashi; S. Ono; K. Kabashima; Y. Miyachi; Y. Yamamoto

  Skin Research 11 (SUPPL. 19) 27 - 30 2012 [Refereed]
  
• Comparison of basophil infiltration into the skin between eosinophilic pustular folliculitis and neutrophilic folliculitis

  OTSUKA A.

  J Eur Acad Dermatol Venereol 26 (4) 527 - 9 2012 [Refereed]
  
• Effects of cyclosporine on pruritus and serum IL-31 levels in patients with atopic dermatitis

  Atsushi Otsuka; Miki Tanioka; Yujin Nakagawa; Tetsuya Honda; Akihiko Ikoma; Yoshiki Miyachi; Kenji Kabashima

  EUROPEAN JOURNAL OF DERMATOLOGY JOHN LIBBEY EUROTEXT LTD 21 (5) 816 - 817 1167-1122 2011/09 [Refereed]
  
• Requirement of Interaction between Mast Cells and Skin Dendritic Cells to Establish Contact Hypersensitivity

  Atsushi Otsuka; Masato Kubo; Tetsuya Honda; Gyohei Egawa; Saeko Nakajima; Hideaki Tanizaki; Bongju Kim; Satoshi Matsuoka; Takeshi Watanabe; Susumu Nakae; Yoshiki Miyachi; Kenji Kabashima

  PLOS ONE PUBLIC LIBRARY SCIENCE 6 (9) e25538  1932-6203 2011/09 [Refereed]
   

  The role of mast cells (MCs) in contact hypersensitivity (CHS) remains controversial. This is due in part to the use of the MC-deficient Kit(W/Wv) mouse model, since Kit(W/Wv) mice congenitally lack other types of cells as a result of a point mutation in c-kit. A recent study indicated that the intronic enhancer (IE) for Il4 gene transcription is essential for MCs but not in other cell types. The aim of this study is to re-evaluate the roles of MCs in CHS using mice in which MCs can be conditionally and specifically depleted. Transgenic Mas-TRECK mice in which MCs are depleted conditionally were newly generated using cell-type specific gene regulation by IE. Using this mouse, CHS and FITC-induced cutaneous DC migration were analyzed. Chemotaxis assay and cytoplasmic Ca(2+) imaging were performed by co-culture of bone marrow-derived MCs (BMMCs) and bone marrow-derived dendritic cells (BMDCs). In Mas-TRECK mice, CHS was attenuated when MCs were depleted during the sensitization phase. In addition, both maturation and migration of skin DCs were abrogated by MC depletion. Consistently, BMMCs enhanced maturation and chemotaxis of BMDC in ICAM-1 and TNF-alpha dependent manners Furthermore, stimulated BMDCs increased intracellular Ca(2+) of MC upon direct interaction and up-regulated membrane-bound TNF-alpha on BMMCs. These results suggest that MCs enhance DC functions by interacting with DCs in the skin to establish the sensitization phase of CHS.
• Enhanced murine contact hypersensitivity by depletion of endogenous regulatory T cells in the sensitization phase

  Tetsuya Honda; Atsushi Otsuka; Hideaki Tanizaki; Yusuke Minegaki; Keisuke Nagao; Herman Waldmann; Michio Tomura; Shohei Hori; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF DERMATOLOGICAL SCIENCE ELSEVIER IRELAND LTD 61 (2) 144 - 147 0923-1811 2011/02 [Refereed]
  
• S13-4 皮膚免疫反応における好塩基球の新たな役割(S13 マスト細胞・好塩基球欠損マウスを用いたアレルギー疾患の病態解明,シンポジウム,第61回日本アレルギー学会秋季学術大会)

  椛島 健治; 大塚 篤司; 久保 允人; 宮地 良樹

  アレルギー 一般社団法人 日本アレルギー学会 60 (9) 1236 - 1236 2011
• An H1-histamine receptor antagonist decreases serum interleukin-31 levels in patients with atopic dermatitis

  A. Otsuka; T. Honda; H. Doi; Y. Miyachi; K. Kabashima

  British Journal of Dermatology 164 (2) 455 - 456 2011 [Refereed]
  
• A case with significant proteinuria caused by secreted protein from urothelial carcinoma.

  Masanori Sakakima; Yoshihide Fujigaki; Hideo Yasuda; Akashi Togawa; Tomoyuki Fujikura; Atsushi Otsuka; Seiichiro Ozono; Akira Hishida

  Case reports in nephrology 2011 373480 - 373480 2090-6641 2011 [Refereed]
   

  58-year-old female was admitted to our hospital complaining isolated proteinuria of 1.7 g/day. Abdominal echography showed right-sided unilateral hydronephrosis, and computed tomography pointed out a tumor of the right renal pelvis, suggesting cancer of renal pelvis. The right nephroureterectomy was carried out. Pathological diagnosis was urothelial carcinoma. Renal tissue revealed no apparent glomerulopathy with tubular atrophy, interstitial fibrosis, and mildly-to-moderately interstitial mononuclear cell infiltration. Immunofluorescence study showed no deposition of immunoreactanct, and electron microscopy showed almost normal glomerulus without electron dense deposit. Proteinuria disappeared within 6 days after the operation. Moderate amount of proteinuria in our patient was probably caused by secreted protein from urothelial carcinoma. This condition is rare but should be taken into account in patients with even moderate amount of proteinuria.
• Rho-mDia1 pathway is required for adhesion, migration, and T-cell stimulation in dendritic cells

  Hideaki Tanizaki; Gyohei Egawa; Kayo Inaba; Tetsuya Honda; Saeko Nakajima; Catharina Sagita Moniaga; Atsushi Otsuka; Toshimasa Ishizaki; Michio Tomura; Takeshi Watanabe; Yoshiki Miyachi; Shuh Narumiya; Takaharu Okada; Kenji Kabashima

  BLOOD AMER SOC HEMATOLOGY 116 (26) 5875 - 5884 0006-4971 2010/12 [Refereed]
   

  Dendritic cells (DCs) are essential for the initiation of acquired immune responses through antigen acquisition, migration, maturation, and T-cell stimulation. One of the critical mechanisms in this response is the process actin nucleation and polymerization, which is mediated by several groups of proteins, including mammalian Diaphanous-related formins (mDia). However, the role of mDia in DCs remains unknown. Herein, we examined the role of mDia1 (one of the isoforms of mDia) in DCs. Although the proliferation and maturation of bone marrow-derived DCs were comparable between control C57BL/6 and mDia1-deficient (mDia1(-/-)) mice, adhesion and spreading to cellular matrix were impaired in mDia1(-/-) bone marrow-derived DCs. In addition, fluorescein isothiocyanate-induced cutaneous DC migration to draining lymph nodes in vivo and invasive migration and directional migration to CCL21 in vitro were suppressed in mDia1(-/-) DCs. Moreover, sustained T-cell interaction and T-cell stimulation in lymph nodes were impaired by mDia1 deficiency. Consistent with this, the DC-dependent delayed hypersensitivity response was attenuated by mDia1-deficient DCs. These results suggest that actin polymerization, which is mediated by mDia1, is essential for several aspects of DC-initiated acquired immune responses. (Blood. 2010;116(26):5875-5884)
• Fluctuation of blood and skin plasmacytoid dendritic cells in drug-induced hypersensitivity syndrome

  Kazunari Sugita; Mikiko Tohyama; Hideaki Watanabe; Atsushi Otsuka; Saeko Nakajima; Masafumi Iijima; Koji Hashimoto; Yoshiki Tokura; Yoshiki Miyachi; Kenji Kabashima

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY MOSBY-ELSEVIER 126 (2) 408 - 410 0091-6749 2010/08 [Refereed]
  
• Flaky Tail Mouse Denotes Human Atopic Dermatitis in the Steady State and by Topical Application with Dermatophagoides pteronyssinus Extract

  Catharina Sagita Moniaga; Gyohei Egawa; Hiroshi Kawasaki; Mariko Hara-Chikuma; Tetsuya Honda; Hideaki Tanizaki; Saeko Nakajima; Atsushi Otsuka; Hiroyuki Matsuoka; Akiharu Kubo; Jun-ichi Sakabe; Yoshiki Tokura; Yoshiki Miyachi; Masayuki Amagai; Kenji Kabashima

  AMERICAN JOURNAL OF PATHOLOGY ELSEVIER SCIENCE INC 176 (5) 2385 - 2393 0002-9440 2010/05 [Refereed]
   

  The barrier abnormality, a loss-of-function mutation In the gene encoding filaggrin (FLG), which is linked to the incidence of atopic dermatitis (AD), is a recently discovered but important factor in the pathogenesis of AD. Flaky tail (Flg(ft)) mice, essentially deficient in filaggrin, have been used to investigate the role of filaggrin on AD. However, the relevancy of Flg(ft) mice to human AD needs to be determined further. In this study, we observed the clinical manifestations of Flg(ft) mice in the steady state and their cutaneous immune responses against external stimuli, favoring human AD. Under specific pathogen-free conditions, the majority of Flg(ft) mice developed clinical and histological eczematous skin lesions similar to human AD with outside-to-inside skin barrier dysfunction evaluated by newly devised methods. In addition, cutaneous hapten-induced contact hypersensitivity as a model of acquired immune response and a mite extract-induced dermatitis model physiologically relevant to a human AD were enhanced in Flg(ft) mice. These results suggest that the Flg(ft) mouse genotype has potential as an animal model of AD corresponding with filaggrin mutation in human AD. (Am J Pathol 2010, 176:2385-2393; DOI: 10.2353/ajpath.2010.090957)
• Prostaglandin I-2-IP Signaling Promotes Th1 Differentiation in a Mouse Model of Contact Hypersensitivity

  Saeko Nakajima; Tetsuya Honda; Daiji Sakata; Gyohei Egawa; Hideaki Tanizaki; Atsushi Otsuka; Catharina Sagita Moniaga; Takeshi Watanabe; Yoshiki Miyachi; Shuh Narumiya; Kenji Kabashima

  JOURNAL OF IMMUNOLOGY AMER ASSOC IMMUNOLOGISTS 184 (10) 5595 - 5603 0022-1767 2010/05 [Refereed]
   

  PGI(2), which exerts its actions via its specific Gs-coupled I prostanoid receptor (IP), is known to be present in the lymph nodes, but its roles in acquired cutaneous immune responses remain unclear. To investigate the role of PGI(2) IP signaling in cutaneous immune responses, we applied IP-deficient (Ptgir(-/-)) mice to contact hypersensitivity as a model of acquired immune response and found that Ptgir(-/-) mice exhibited a significantly decreased contact hypersensitivity response. Lymph node cells from sensitized Ptgir(-/-) mice exhibited decreased IFN-gamma production and a smaller T-bet(+) subset compared with control mice. PGI synthase and IP expression were detected in dendritic cells and T cells, respectively, by quantitative real-time PCR analysis, suggesting that PGI(2) produced by dendritic cells acts on IP in T cells. In fact, in vitro Th1 differentiation was enhanced by an IP agonist, and this enhancement was nullified by protein kinase A inhibitor. These results suggest that PGI(2) IP signaling promotes Th1 differentiation through a cAMP-protein kinase A pathway and thereby initiates acquired cutaneous immune responses. The Journal of Immunology, 2010, 184: 5595-5603.
• Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice

  Michio Tomura; Tetsuya Honda; Hideaki Tanizaki; Atsushi Otsuka; Gyohei Egawa; Yoshiki Tokura; Herman Waldmann; Shohei Hori; Jason G. Cyster; Takeshi Watanabe; Yoshiki Miyachi; Osami Kanagawa; Kenji Kabashima

  JOURNAL OF CLINICAL INVESTIGATION AMER SOC CLINICAL INVESTIGATION INC 120 (3) 883 - 893 0021-9738 2010/03 [Refereed]
   

  Tregs play an important role in protecting the skin from autoimmune attack. However, the extent of Treg trafficking between the skin and draining lymph nodes (DLNs) is unknown. We set out to investigate this using mice engineered to express the photoconvertible fluorescence protein Kaede, which changes from green to red when exposed to violet light. By exposing the skin of Kaede-transgenic mice to violet light, we were able to label T cells in the periphery under physiological conditions with Kaede-red and demonstrated that both memory phenotype CD4(+)Foxp(3-) non-Tregs and CD4(+)Foxp3(+)Tregs migrated from the skin to DLNs in the steady state. During cutaneous immune responses, Tregs constituted the major emigrants and inhibited immune responses more robustly than did LN-resident Tregs. We consistently observed that cutaneous immune responses were prolonged by depletion of endogenous Tregs in vivo. In addition, the circulating Tregs specifically included activated CD25(hi) Tregs that demonstrated a strong inhibitory function. Together, our results suggest that Tregs in circulation infiltrate the periphery, traffic to DLNs, and then recirculate back to the skin, contributing to the downregulation of cutaneous immune responses.
• Treatment of eosinophilic pustular folliculitis with ciclosporin: Suppression of mRNA expression of IL-4 and IL-13

  A. Otsuka; H. Doi; Y. Miyachi; K. Kabashima

  Journal of the European Academy of Dermatology and Venereology 24 (12) 1489 - 1491 2010 [Refereed]
  
• Trehalose Dimycolate Elicits Eosinophilic Skin Hypersensitivity in Mycobacteria-Infected Guinea Pigs

  Atsushi Otsuka; Isamu Matsunaga; Takaya Komori; Kadusa Tomita; Yoshinobu Toda; Toshiaki Manabe; Yoshiki Miyachi; Masahiko Sugita

  JOURNAL OF IMMUNOLOGY AMER ASSOC IMMUNOLOGISTS 181 (12) 8528 - 8533 0022-1767 2008/12 [Refereed]
   

  Delayed-type hypersensitivity represents high levels of protein Ag-specific adaptive immunity induced by mycobacterial infection, and can be monitored in the Ag-challenged skin. Besides protein Ags, recent evidence has suggested that a substantial immunity directed against glycolipid Ags is also elicited in response to mycobacterial infection, but skin hypersensitivity to this class of Ags has not been fully assessed. To address this issue directly, glycolipid-specific skin reactions were evaluated in guinea pigs infected with Mycobacterium avium complex (MAC). Significant skin induration was observed in MAC-infected, but not mock-infected, guinea pigs, following intradermal administration of a mixture of MAC-derived glycolipids. Surprisingly, this glycolipid-specific skin response involved up-regulated expression of IL-5 mRNA in situ and marked local infiltration of eosinophils. Challenge experiments with individual glycolipid components detected an outstanding capability for trehalose dimycolate (TDM), but not a structurally related glycolipid, glucose monomycolate, to elicit the skin response. T lymphocytes derived from the spleen of MAC-infected, but not uninfected, guinea pigs specifically responded to TDM in vitro by up-regulating IL-5 transcription, and this response was not blocked by Abs that reacted to the known guinea pig group 1 CD1 proteins. Finally, the eosinophilic skin hypersensitivity to TDM was also elicited in guinea pigs vaccinated with bacillus Calmette-Guerin, which contrasted sharply with the classical delayed-type hypersensitivity response to the purified protein derivative. Therefore, the TDM-elicited eosinophilic response defines a new form of hypersensitivity in mycobacterial infection, which may account for local infiltration of eosinophils often observed at the site of infection. The Journal of Immunology, 2008, 181: 8528-8533.
• Mycolyltransferase-mediated Glycolipid Exchange in Mycobacteria

  Isamu Matsunaga; Takashi Naka; Rahul S. Talekar; Matthew J. McConnell; Kumiko Katoh; Hitomi Nakao; Atsushi Otsuka; Samuel M. Behar; Ikuya Yano; D. Branch Moody; Masahiko Sugita

  JOURNAL OF BIOLOGICAL CHEMISTRY AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC 283 (43) 28835 - 28841 0021-9258 2008/10 [Refereed]
   

  Trehalose dimycolate (TDM), also known as cord factor, is a major surface glycolipid of the cell wall of mycobacteria. Because of its potent biological functions in models of infection, adjuvancy, and immunotherapy, it is important to determine how its biosynthesis is regulated. Here we show that glucose, a host-derived product that is not readily available in the environment, causes Mycobacterium avium to down-regulate TDM expression while up-regulating production of another major glycolipid with immunological roles in T cell activation, glucose monomycolate (GMM). In vitro, the mechanism of reciprocal regulation of TDM and GMM involves competitive substrate selection by antigen 85A. The switch from TDM to GMM biosynthesis occurs near the physiological concentration of glucose present in mammalian hosts. We further demonstrate that GMM is produced in vivo by mycobacteria growing in mouse lung. These results establish an enzymatic pathway for GMM production. More generally, these observations provide a specific enzymatic mechanism for dynamic alterations of cell wall glycolipid remodeling in response to the transition from noncellular to cellular growth environments, including factors that are monitored by the host immune system.
• Induction of allergic contact dermatitis by astigmatid mite-derived monoterpene, alpha-acaridial

  Toshio Sasai; Yunosuke Hirano; Sayaka Maeda; Isamu Matsunaga; Atsushi Otsuka; Daisuke Morita; Ritsuo Nishida; Hideo Nakayama; Yasumasa Kuwahara; Masahiko Sugita; Naoki Mori

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ACADEMIC PRESS INC ELSEVIER SCIENCE 375 (3) 336 - 340 0006-291X 2008/10 [Refereed]
   

  alpha-Acaridial [2(E)-(4-methyl-3-pentenyl)butenedial] is a novel monoterpene secreted from the house dust mites. Because of its molecular nature of a highly reactive, small lipidic compound, we addressed whether alpha-acaridial might function as a haptenic allergen that induced allergic contact dermatitis. Mice sensitized with alpha-acaridial were challenged by the same antigen on the ear skin. After 2 days, significant ear swelling with a prominent infiltration of CD4(+) T lymphocytes was observed. In vitro, alpha-acaridial exhibited an outstanding ability to quickly interact with and chemically modify a reference protein. Virtually all cysteine residues and a sizable fraction of lysine residues Were found to be selectively modified, suggesting that alpha-acaridial could potentially interact with any proteins. Previously, numerous mite-derived proteinaceous allergens have been associated with contact dermatitis. Our study now emphasizes that small lipidic compounds released from mites comprise a new class of mite allergens, and therefore, is of significant medical implications. (C) 2008 Elsevier Inc. All rights reserved.
• Allergic contact dermatitis with mite-derived lidpids

  N. MORI; I .MATSUNAGA; A. OTSUKA; D. MORITA; M. SUGITA

  (1) Graduate School of Agriculture, Kyoto University Biiochem. Biophys. Res. Commun. 375:336, 2008 2008 [Refereed]
  
• A case of acute generalized exanthematous pustulosis caused by lincomycin

  A Otsuka; H Tanizaki; N Okamoto; K Takagaki

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 32 (11) 929 - 930 0385-2407 2005/11 [Refereed]
  
• A case of Merkel cell carcinoma successfully treated with radiotherapy

  OTSUKA Atsushi; OKUNAKA Makiko; KAMBE Naotomo; KOREEDA Satoshi; TACHIBANA Takao; MIYACHI Yoshiki

  Skin Cancer The Japanese Skin Cancer Society 20 (1) 84 - 88 0915-3535 2005/05 

  We report a case of recurring Merkel cell carcinoma on the nose of a 90-year-old man. A radical operation was performed on the red nodule on his nose. However, 1 month later a red nodule 30×30mm in diameter was found on his nose and another red nodule 6×7mm in diameter appeared on his right cheek. The biopsy specimen revealed cytokeratin20-positive tumor cells localized in the dermis to subcutaneous fatty tissue. We chose radiotherapy treatment of (5MeV) for both lesions. When the total amount of irradiation reached 66 Gy, the tumor completely disappeared. We reviewed 21 reported cases of radiotherapy treated Merkel cell carcinoma and found a 24% rate of local recurrence. The recurrence cases with prophylactic lymph node radiation were observed only in 10%, whereas the recurrence rate without radiotherapy revealed 45.5%. Local recurrence and lymph node involvement are important prognostic factors. We suggest that adjuvant radiotherapy is very effective for Merkel cell carcinoma. [Skin Cancer (Japan) 2005; 20: 84-88]
• Amphiphysin1 inhibits vitronectin-mediated cell adhesion, spreading, and migration in vitro

  A Otsuka; K Hirose; MW Kilimann; T Kamata

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ACADEMIC PRESS INC ELSEVIER SCIENCE 301 (3) 769 - 775 0006-291X 2003/02 [Refereed]
   

  To investigate the regulatory mechanism of cell adhesion, we have searched for cellular inhibitory factors which prevent cell adhesion. The brain cytosol was found to inhibit the adhesion of various transformed cells to the substratum. An inhibitory 120-kDa protein was purified by sequential column chromatography. Peptide sequencing revealed that the protein is identical to amphiphysin 1. GST-amphiphysin 1 suppressed the attachment of HeLa cells to the plate when cells were cultured in the serum-containing medium. Vitronectin, a major cell-adhesive protein in serum and a ligand to alphanubeta3 integrin, was responsible for this cell attachment, and the vitronectin action was blocked by GST-amphiphysin 1. GST-amphiphysin 1 also inhibited the vitronectin-mediated spreading and migration of malignant melanoma cells. Furthermore, GST-amphiphysin 1 bound directly to vitronectin. These findings point to the interesting possibility that amphiphysin 1 could be a useful tool to inhibit cell-adhesive vitronectin. (C) 2003 Elsevier Science (USA). All rights reserved.
• Amphiphysin1 inhibits vitronectin-mediated cell adhesion, spreading, and migration in vitro

  A Otsuka; K Hirose; MW Kilimann; T Kamata

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ACADEMIC PRESS INC ELSEVIER SCIENCE 301 (3) 769 - 775 0006-291X 2003/02 [Refereed]
   

  To investigate the regulatory mechanism of cell adhesion, we have searched for cellular inhibitory factors which prevent cell adhesion. The brain cytosol was found to inhibit the adhesion of various transformed cells to the substratum. An inhibitory 120-kDa protein was purified by sequential column chromatography. Peptide sequencing revealed that the protein is identical to amphiphysin 1. GST-amphiphysin 1 suppressed the attachment of HeLa cells to the plate when cells were cultured in the serum-containing medium. Vitronectin, a major cell-adhesive protein in serum and a ligand to alphanubeta3 integrin, was responsible for this cell attachment, and the vitronectin action was blocked by GST-amphiphysin 1. GST-amphiphysin 1 also inhibited the vitronectin-mediated spreading and migration of malignant melanoma cells. Furthermore, GST-amphiphysin 1 bound directly to vitronectin. These findings point to the interesting possibility that amphiphysin 1 could be a useful tool to inhibit cell-adhesive vitronectin. (C) 2003 Elsevier Science (USA). All rights reserved.
• Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis

  Sakurai K; Dainichi T; Garcet S; Tsuchiya S; Yamamoto Y; Kitoh A; Honda T; Nomura T; Egawa G; Otsuka A; Nakajima S; Matsumoto R; Nakano Y; Otsuka M; Iwakura Y; Grinberg-Bleyer Y; Ghosh S; Sugimoto Y; Guttman-Yassky E; Krueger J.G; Kabashima K

  Journal of Allergy and Clinical Immunology 144 (4) 1036 - 1049 [Refereed]
  

MISC

• 進行期末端黒子型黒色腫に対する抗PD-1抗体治療増悪後二次治療の有効性-JAMP neo study副次解析

  中村泰大; 並川健二郎; 木庭幸子; 加藤裕史; 山崎修; 吉川周佐; 前川武雄; 竹之内辰也; 松下茂人; 中井康雄; 猪爪隆史; 福島聡; 大塚篤司; 齋藤晋太郎; 藤本徳毅; 爲政大幾; 馬場夏希; 松谷泰祐; 田中了; 金子高英; 大西正純; 鍬塚大; 永瀬浩太郎; 大沼毅紘  西日本皮膚科  84-  (6)  2022
• 末端黒子型黒色腫に対するPD1抗体治療増悪後二次治療の有効性:JAMP-neo study副次解析

  森龍彦; 並川健二郎; 木庭幸子; 加藤裕史; 山崎修; 吉川周佐; 前川武雄; 竹之内辰也; 松下茂人; 中井康雄; 猪爪隆史; 福島聡; 大塚篤司; 齋藤晋太郎; 中村泰大  日本癌治療学会学術集会(Web)  60th-  2022
• A Case of Steven-Johnson Syndrome Induced by Nivolumab

  廣田菜々子; 鈴木緑; 加藤麻衣子; 柳原茂人; 遠藤英樹; 大磯直毅; 川田暁; 大塚篤司; 田中薫; 藤田岳  皮膚の科学  21-  (1)  2022
• 好酸球と好塩基球の活性化メカニズム 蕁麻疹の活動期に見られる好塩基球減少に関する動物モデルからの検証

  岸本 泉; 馬 尼; 谷崎 英昭; 中嶋 千紗; 大塚 篤司; 三宅 健介; 烏山 一; 神戸 直智  アレルギー  70-  (6-7)  799  -799  2021/08
• Identification of CD49a+ CD8+ resident memory T cells in vitiligo-like lesions associated with nivolumab treatment for melanoma

  C. Nakashima; Y. Ishida; K. Nakagawa; H. Irie; M. Hirata; T. Kataoka; A. Otsuka; K. Kabashima  Journal of the European Academy of Dermatology and Venereology  34-  (2)  e79  -e82  2020/02
• 進行期悪性黒色腫の抗PD1抗体治療における効果予測システムの開発

  藤村 卓; 佐藤 遥太; 谷田 佳世; 神林 由美; 大塚 篤司; 藤澤 康弘; 吉野 公二; 松下 茂人; 日高 高徳; 相場 節也  日本皮膚科学会雑誌  129-  (5)  1176  -1176  2019/05
• Real-world efficacy of anti-PD-1 antibodies in advanced acral melanoma patients: A retrospective, multicenter study (JAMP study).

  Yasuhiro Nakamura; Kenjiro Namikawa; Koji Yoshino; Shusuke Yoshikawa; Hiroshi Uchi; Katsunobu Goto; Yoshiyuki Nakamura; Satoshi Fukushima; Yukiko Kiniwa; Tatsuya Takenouchi; Hisashi Uhara; Toru Kawai; Naohito Hatta; Takeru Funakoshi; Yukiko Teramoto; Atsushi Otsuka; Haruki Doi; Dai Ogata; Shigeto Matsushita; Naoya Yamazaki  JOURNAL OF CLINICAL ONCOLOGY  37-  (15)  2019/05
• ニボルマブ術後補助療法にて3臓器に内分泌系有害事象を発現した口腔粘膜悪性黒色腫の1例

  山村 健太郎; 大塚 篤司; 野村 基雄; 椛島 健治  日本皮膚悪性腫瘍学会学術大会プログラム・抄録集  35回-  164  -164  2019/04
• 血清因子による抗PD1抗体治療効果予測法の開発

  藤村 卓; 佐藤 遥太; 谷田 佳世; 神林 由美; 大塚 篤司; 藤澤 康弘; 吉野 公二; 松下 茂人; 日高 高徳; 相場 節也  日本皮膚悪性腫瘍学会学術大会プログラム・抄録集  35回-  160  -160  2019/04
• Evaluation of efficacy and safety of retreatment or concurrent immunoradiotherapy after progression in metastatic melanoma patients previously treated with nivolumab

  Yumi Nonomura; Motoo Nomura; Atsushi Otsuka; Michio Yoshimura; Tomohiro Kondo; Hiroki Nagai; Yo Kaku; Shigemi Matsumoto; Manabu Muto; Mitchell Levesque; Reinhard Dummer  JOURNAL OF TRANSLATIONAL MEDICINE  17-  2019/01
• Retrospective study on the correlation between 18-fluorodeoxyglucose uptake in positron emission tomography–computer tomography and tumour volume, cytological activity as assessed with Ki-67 and GLUT-1 staining in 10 cases of Merkel cell carcinoma

  S. Kitamura; T. Yanagi; Y. Inamura-Takashima; K. Imafuku; H. Hata; J. Uehara; Y. Ishida; A. Otsuka; K. Hirata; H. Shimizu  Journal of the European Academy of Dermatology and Venereology  32-  (7)  e285  -e287  2018/07
• Baseline neutrophil to lymphocyte ratio combined with serum lactate dehydrogenase level associated with outcome of nivolumab immunotherapy in a Japanese advanced melanoma population

  Fujisawa Y; Yoshino K; Otsuka A; Funakoshi T; Fujimura T; Yamamoto Y; Hata H; Tanaka R; Yamaguchi K; Nonomura Y; Hirai I; Furudate S; Okuhira H; Imafuku K; Aoki M; Matsushita S  British Journal of Dermatology  179-  (1)  213  -215  2018/07
• ニボルマブ治療後にイピリムマブ治療を受けた進行期悪性黒色腫症例60例の後ろ向き臨床研究

  吉野 公二; 藤澤 康弘; 大塚 篤司; 舩越 建; 内 博史; 藤村 卓; 松下 茂人; 秦 洋郎; 山本 有紀; Japan Skin Cancer Network; JSCa  日本皮膚科学会雑誌  128-  (5)  1231  -1231  2018/05
• 投与前の好中球/リンパ球比と血清LDH値はニボルマブによる治療結果と相関する

  藤澤 康弘; 吉野 公二; 大塚 篤司; 舩越 建; 藤村 卓; 山本 有紀; 秦 洋郎; 松下 茂人  日本皮膚科学会雑誌  128-  (5)  1231  -1231  2018/05
• 免疫チェックポイント阻害薬による免疫関連副作用の予測システムの開発

  藤村 卓; 佐藤 遥太; 谷田 佳世; 神林 由美; 大塚 篤司; 藤澤 康弘; 吉野 公二; 松下 茂人; 舩越 建; 相場 節也  日本皮膚科学会雑誌  128-  (5)  1231  -1231  2018/05
• Three cases of facial erythema with dryness and pruritus in psoriasis patients during treatment with IL-17 inhibitors

  T. Oiwa; T. Honda; A. Otsuka; K. Kabashima  Journal of the European Academy of Dermatology and Venereology  32-  (4)  e122  -e123  2018/04
• Skin findings of 21st-century movie characters

  Y. Ishida; E. Lin; A. Otsuka; K. Kabashima  Journal of the European Academy of Dermatology and Venereology  32-  (3)  e98  -e100  2018/03
• Barrier dysfunction of atopic dermatitis and atopic march

  大塚 篤司; 椛島 健治  臨床免疫・アレルギー科 = Clinical immunology & allergology  68-  (5)  496  -501  2017/11
• ニボルマブ抵抗性悪性黒色腫に対するイピリムマブの効果

  内 博史; 藤澤 康弘; 吉野 公二; 大塚 篤司; 舩越 建; 藤村 卓; 松下 茂人; 山本 有紀; 秦 洋郎  日本癌治療学会学術集会抄録集  55回-  P122  -5  2017/10
• Peripheral nerves promote basophil infiltration via TLR2 in murine atopic-dermatitis-like inflammation

  C. Nakashima; A. Otsuka; K. Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  137-  (10)  S251  -S251  2017/10
• Decrease in serum IL-32 level in patients with atopic dermatitis after cyclosporine treatment

  N. Kitayama; A. Otsuka; Y. Nonomura; C. Nakashima; T. Honda; K. Kabashima  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  31-  (10)  E449  -E450  2017/10
• Acantholytic dyskeratotic acanthoma: a possible skin adverse event of vemurafenib treatment

  T. Komori; A. Otsuka; Y. Kaku; T. Honda; K. Kabashima  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  31-  (10)  E474  -E475  2017/10
• Nilotinib-induced panniculitis in a patient with chronic myelogenous leukaemia

  N. Kitayama; A. Otsuka; C. Hamamoto; Y. Kaku; H. Shiragami; Y. Okumura; K. Tsujioka  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  31-  (9)  2017/09
• A case of chilblain lupus erythematosus with lupus erythematosus/lichen planus overlap syndrome

  T. Komori; A. Otsuka; T. Honda; Y. Kaku; K. Kabashima  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  31-  (9)  2017/09
• Multiple erosive lichen planus preceded by solitary lichen planus after combination therapy with nivolumab and radiation

  T. Komori; T. Honda; H. Irie; A. Otsuka; K. Kabashima  Journal of the European Academy of Dermatology and Venereology  31-  (8)  e382  -e384  2017/08
• 左下肢の多発in-transit転移にnivolumabが完全奏効した悪性黒色腫の1例

  野々山 翔子; 加来 洋; 堀口 亜有未; 遠藤 雄一郎; 大塚 篤司; 椛島 健治; 北口 紘子  皮膚の科学  16-  (4)  287  -287  2017/08
• CCR4 and CCR5 expression in a case of subcutaneous panniculitis-like T-cell lymphoma

  Naomi Kitayama; Atsushi Otsuka; Yuki Honda; Yumi Matsumura; Tetsuya Honda; Kenji Kabashima  EUROPEAN JOURNAL OF DERMATOLOGY  27-  (4)  414  -415  2017/07
• 円形脱毛症に対するステロイドパルス療法―京都大学皮膚科105例の統計解析―

  藤井弘子; 遠藤雄一郎; 大塚篤司; 藤澤章弘; 谷岡未樹; 大日輝記; 宮地良樹; 椛島健治  日本皮膚科学会雑誌  127-  (5)  1164  -1164  2017/05
• Possible involvement of interleukin-33 and basophils in the pathophysiology of human atopic dermatitis via ST2 receptor

  Y. Nonomura; A. Otsuka; J. A. Seidel; C. Nakashima; K. Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  137-  (5)  S107  -S107  2017/05
• Infiltration of PD-1+cells is a poor prognostic factor in invasive extramammary Paget disease

  N. Iga; A. Otsuka; K. Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  137-  (5)  S64  -S64  2017/05
• PD-L1 expression is a positive prognostic factor in cutaneous angiosarcoma

  A. Otsuka; Y. Honda; S. Ono; K. Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  137-  (5)  S49  -S49  2017/05
• A novel role of sensory nerves to establish contact hypersensitivity by promoting cutaneous dendritic cell functions via PACAP

  Y. Yamamoto; A. Otsuka; Y. Nonomura; C. Nakashima; N. Konishi; M. Hayashi; K. Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  137-  (5)  S3  -S3  2017/05
• 円形脱毛症に対するステロイドパルス療法 京都大学皮膚科105例の統計解析

  藤井 弘子; 遠藤 雄一郎; 大塚 篤司; 藤澤 章弘; 谷岡 未樹; 大日 輝記; 宮地 良樹; 椛島 健治  日本皮膚科学会雑誌  127-  (5)  1164  -1164  2017/05
• 環状の皮疹より始まった毛孔性紅色粃糠疹の1例

  北山尚美; 辻岡馨; 加来洋; 中溝聡; 遠藤雄一郎; 藤澤章弘; 大塚篤司; 椛島健治  角化症研究会記録集  31st-  124‐126  -126  2017/03
• ADAMTSL5 is upregulated in melanoma tissues in patients with idiopathic psoriasis vulgaris induced by nivolumab

  Y. Nonomura; A. Otsuka; M. Ohtsuka; T. Yamamoto; R. Dummer; K. Kabashima  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  31-  (2)  E100  -E101  2017/02
• MEFV gene mutation in two cases of pyoderma gangrenosum with aseptic arthritis

  Y. Honda; A. Otsuka; K. Yamashita; A. Takaori-Kondo; K. Kabashima  Journal of the European Academy of Dermatology and Venereology  30-  (12)  e183  -e184  2016/12
• Upregulation of granzyme B and interferon-gamma mRNA in responding lesions by treatment with nivolumab for metastatic melanoma: a case report

  H. Anegawa; A. Otsuka; Y. Kaku; Y. Nonomura; A. Fujisawa; Y. Endo; K. Kabashima  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  30-  (12)  E231  -E232  2016/12
• Immunological analysis of metastatic melanoma patients treated with nivolumab; is Th9 cell subset a possible biomarker of treatment efficacy?

  Y. Nonomura; A. Otsuka; C. Nakashima; J. Seidel; K. Kabashima  EXPERIMENTAL DERMATOLOGY  25-  24  -24  2016/11
• Langerhans cells can infiltrate primary cutaneous melanomas and display a tolerogenic phenotype

  J. Seidel; A. Otsuka; K. Kabashima  EXPERIMENTAL DERMATOLOGY  25-  23  -24  2016/11
• 京大病院におけるチーム医療の取り組みと安全性対策 免疫チェックポイント阻害剤を安全に使用するために

  永井 宏樹; 金 永学; 大塚 篤司; 寺尾 真琴; 池見 泰明; 黒田 貴子; 浜辺 陽子; 安田 有斗; 船造 智子; 野溝 岳; 辻 貴宏; 八木 由生; 吉田 博徳; 阪森 優一; 小笹 裕晃; 松本 繁巳; 武藤 学  肺癌  56-  (6)  601  -601  2016/11
• Pneumocephalus as a fatal complication of scalp angiosarcoma

  Y. Honda; A. Otsuka; Y. Endo; A. Fujisawa; Y. Miyachi; K. Kabashima  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  30-  (10)  E40  -E42  2016/10
• Exacerbation of psoriasis vulgaris during nivolumab for oral mucosal melanoma

  Y. Kato; A. Otsuka; Y. Miyachi; K. Kabashima  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  30-  (10)  E89  -E91  2016/10
• Diminution of Langerhans cells in keratitis, ichthyosis and deafness (KID) syndrome patient with recalcitrant cutaneous candidiasis

  P. Rerknimitr; H. Tanizaki; A. Otsuka; Y. Miyachi; K. Kabashima  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  30-  (10)  E47  -E49  2016/10
• A possible primary carcinoid (neuroendocrine) tumour of the skin with multiple metastases

  H. Otake; H. Tanizaki; Y. Kaku; A. Otsuka; T. Sakurai; Y. Miyachi; K. Kabashima  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  30-  (10)  E49  -E50  2016/10
• Experiences of treating melanoma with vemurafenib at our institution and a discussion of its adverse effects

  YAMASHITA Chisato; OTSUKA Atsushi; KAKU Yo; ENDO Yuichiro; KABASHIMA Kenji  Skin Cancer  31-  (2)  123  -127  2016/10
• Eosinophilic annular erythema limited on the palms and the soles and possibly associated with thymoma

  N. Iga; A. Otsuka; Y. Kaku; Y. Miyachi; K. Kabashima  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  30-  (7)  1213  -1214  2016/07
• Hypokalaemia and QT Prolongation in BRAF (V600) Mutated Melanoma Treated with Vemurafenib: Two Case Reports

  Anegawa Hiroko; Otsuka Atsushi; Yamamura Kentaro; Kaku Yo; Nakamizo Satoshi; Endo Yuichiro; Kabashima Kenji  The Japanese Journal of Dermatology  126-  (8)  1459  -1463  2016/07
• The effect of janus kinase inhibitor on pruritus in an atopic dermatitis murine model

  Y. Yamamoto; A. Otsuka; C. Nakashima; W. Amano; A. Tanimoto; M. Hayashi; K. Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  136-  (5)  S92  -S92  2016/05
• 当院において悪性黒色腫に対しVemurafenibを投与した5例の検討

  山下千聡; 大塚篤司; 加来洋; 遠藤雄一郎; 大日輝記; 椛島健治  日本皮膚悪性腫瘍学会学術大会プログラム・抄録集  32回-  151  -151  2016/05
• Idiopathic thrombocytopenic purpura induced by nivolumab in a metastatic melanoma patient with elevated PD-1 expression on B cells

  S. Kanameishi; A. Otsuka; Y. Nonomura; A. Fujisawa; Y. Endo; K. Kabashima  ANNALS OF ONCOLOGY  27-  (3)  546  -547  2016/03
• 右半身のみ厚い鱗屑の付着を認めた成人男性の1例

  北山尚美; 大塚篤司; 加来洋; 松村由美; 遠藤雄一郎; 藤澤章弘; 椛島健治; 下村裕  角化症研究会記録集  30-  136  -138  2016/03
• 抗PD‐1抗体(ニボルマブ)投与により生じた特発性血小板減少性紫斑病の1例

  要石就斗; 加来洋; 遠藤雄一郎; 藤澤章弘; 大塚篤司; 椛島健治  日本皮膚科学会雑誌  126-  (1)  40  -40  2016/01
• Atopic dermatitis and skin care

  大塚 篤司  医学のあゆみ  256-  (1)  101  -106  2016/01
• Epidermal hyperinnervation is mediated by VEGF-A in an imiquimod-induced itchy psoriasiform model

  L. Wong; A. Otsuka; Y. Yamamoto; K. Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  135-  S43  -S43  2015/09
• インフリキシマブとメトトレキサートが著効した関節リウマチに合併した脂肪萎縮症の1例

  北山尚美; 大塚篤司; 遠藤雄一郎; 藤澤章弘; 椛島健治; 藤井隆夫  皮膚の科学  14-  (4)  199  -199  2015/08
• Interaction of disruption of skin barrier function and allergy

  大塚 篤司; 椛島 健治  臨床免疫・アレルギー科 = Clinical immunology & allergology  64-  (1)  33  -38  2015/07
• Re: Natural Killer T Cells Are Essential for the Development of Contact Hypersensitivity in BALB/c Mice Response

  Chihiro Shimizuhira; Atsushi Otsuka; Yosuke Yamamoto; Kenji Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  135-  (6)  1687  -1687  2015/06
• Mast cells and basophils in cutaneous immune responses

  A. Otsuka; K. Kabashima  ALLERGY  70-  (2)  131  -140  2015/02
• The role of basophils during cutaneous disease

  大塚 篤司; 椛島 健治  医学のあゆみ  250-  (12)  1091  -1095  2014/09
• 皮膚バリア機能を向上させる"フィラグリン"のメカニズムと化粧品・医薬品への応用

  大塚 篤司; 椛島 健治  Cosmetic stage  8-  (5)  29  -34  2014/06
• PGD(2) induces eotaxin-3 via PPAR gamma from sebocytes: A possible pathogenesis of eosinophilic pustular folliculitis (vol 129, pg 536, 2012)

  K. Nakahigashi; H. Doi; A. Otsuka; T. Hirabayashi; M. Murakami; Y. Urade; C. C. Zouboulis; H. Tanizaki; G. Egawa; Y. Miyachi; K. Kabashima  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY  133-  (2)  604  -604  2014/02
• Hapten repeated application elicit Th2 immune reaction

  大塚 篤司; 椛島 健治  臨床免疫・アレルギー科  60-  (4)  419  -427  2013/10
• Interplay between basophils and eosinophils is essential in the development of skin inflammation

  C. Nakashima; A. Otsuka; K. Kabashima; Y. Miyachi  JOURNAL OF INVESTIGATIVE DERMATOLOGY  133-  S197  -S197  2013/05
• Narrowband ultraviolet B phototherapy decreased the serum IL-17E level in a patient with psoriasis vulgaris

  A. Otsuka; Y. Miyachi; K. Kabashima  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  26-  (11)  1455  -1456  2012/11
• Regulatory T cells suppress basophils-induced IgE-mediated chronic allergic inflammation

  K. Sugita; Y. Minegaki; S. Nakamizo; A. Otsuka; T. Nomura; M. Nakamura; Y. Miyachi; K. Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  132-  S1  -S1  2012/09
• Benign Atypical Junctional Melanocytic Hyperplasia Associated with Intradermal Nevusの一例

  野々村 優美; 遠藤 雄一郎; 大塚 篤司; 藤澤 章弘; 谷岡 未樹; 椛島 健治; 宮地 良樹; 宮川 文  日本皮膚科学会雑誌  122-  (4)  1236  -1236  2012/04
• 放射線照射が誘因と思われるStevens‐Johnson症候群の1例

  野々村優美; 遠藤雄一郎; 中島沙恵子; 大塚篤司; 藤澤章弘; 谷岡未樹; 椛島健治; 宮地良樹  皮膚の科学  11-  (1)  109  -109  2012/02
• Role of mast cells in contact hypersensitivity

  大塚 篤司; 椛島 健治  臨床免疫・アレルギー科  56-  (6)  628  -635  2011/12
• PGD2 acts on sebocytes to induce eotaxin-3/CCL26 through PPAR gamma: a possible involvement of the pathogenesis of eosinophilic pustular folliculitis

  Kyoko Nakahigashi; Atsushi Otsuka; Hiromi Doi; Yoshiki Miyachi; Kenji Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  131-  S34  -S34  2011/09
• Role of mast cells in contact dermatitis

  大塚 篤司; 椛島 健治  Clinical immunology & allergology  55-  (5)  559  -565  2011/05
• The role of basophils in skin Th2 response using newly generated basophil-specific conditional depletion model

  Atsushi Otsuka; Masato Kubo; Yoshiki Miyachi; Kenji Kabashima  JOURNAL OF IMMUNOLOGY  186-  2011/04
• Narrowband ultraviolet B phototherapy decreased CCR4+CD8+T cells in a patient with palmoplantar pustulosis

  A. Otsuka; Y. Miyachi; K. Kabashima  JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY  25-  (4)  495  -496  2011/04
• A Case of Pustular Eruption and Alopecia Areata following TNF-α Inhibitor Treatment for Psoriasis Vulgaris

  KAKU Nobuko; TANIZAKI Hideaki; OTSUKA Atsushi; ARAKAWA Akiko; KABASHIMA Kenji; TANIOKA Miki; MIYACHI Yoshiki  Journal of environmental dermatology and cutaneous allergology  5-  (1)  39  -45  2011/01
• The role of basophils in skin Th2 response using newly generated basophil specific conditional depletion model

  Atsushi Otsuka; Yusuke Minegaki; Chisa Nakashima; Masato Kubo; Yoshiki Miyachi; Kenji Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  130-  S35  -S35  2010/09
• Mast cells are essential to establish contact hypersensitivity by stimulating cutaneous dendritic cells revealed by a newly generated mast cell-specific conditional depletion model

  A. Otsuka; M. Kubo; Y. Miyachi; K. Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  130-  S114  -S114  2010/04
• The role of mast cells in contact hypersensitivity using newly-generated mast cell-specific conditional depletion model

  A. Otsuka; Y. Miyachi; K. Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  129-  S2  -S2  2009/09
• Characterization of functions and egress mechanism on skin regulatory T cell using Kaede-transgenic mice

  T. Honda; M. Tomura; A. Otsuka; H. Tanizaki; O. Kanagawa; Y. Miyachi; K. Kabashima  JOURNAL OF INVESTIGATIVE DERMATOLOGY  129-  S88  -S88  2009/09
• Eosinophilic skin reactions to glycolipids define a novel form of hypersensitivity in mycobacterial infection.

  Otsuka A; Matsunaga l; Miyachi Y; Sugita M  第38 回日本免疫学会  2008  [Refereed]
  
• Eosinophilic DTH を標的とした新しい皮 アレルギー応答

  大塚篤司; 松永勇; 小森崇矢; 冨田和沙; 戸田好信; 真 俊明; 宮地 樹; 杉田昌彦  第１１回京 免 疫ワークショップ、平成20 年3 月22 日  2008  [Refereed]
  
• Dermoscopy Findings in Japanese Spotted Fever

  OTSUKA Atsushi; TAKAGAKI Kenji; TANIZAKI Hideaki; OKAMOTO Natsuko; TABARA Kenji  日本皮膚科学会雑誌 = THE JAPANESE JOURNAL OF DERMATOLOGY  116-  (12)  1771  -1775  2006/11
• 症例報告 歯科治療後に著明に改善した汎発性脱毛症の1例

  大塚 篤司; 江川 形平; 谷崎 英昭  臨床皮膚科  60-  (2)  159  -161  2006/02
• 症例報告 被髮頭部に生じた有茎性基底細胞癌の1例

  大塚 篤司; 谷崎 英昭; 今岡 千治  臨床皮膚科  60-  (1)  68  -70  2006/01
• 当科における皮膚潰瘍治療

  大西 里佳; 石田 智子; 大塚 篤司; 高井 美穂; 玉城 裕妃子; 佐々木 弘真; 藤澤 章弘; 松村 由美; 是枝 哲; 立花 隆夫; 宮地 良樹  皮膚の科学  3-  (2)  251  -251  2004/04
• 仙骨部褥瘡の2例 特にその手術適応について

  山本 洋介; 大塚 篤司; 平 貴文; 藤澤 章弘; 是枝 哲; 立花 隆夫; 宮地 良樹; 三富 陽子  Skin Surgery  13-  (1)  24  -24  2004/01
• 褥瘡の手術適応例

  山本 洋介; 大塚 篤司; 平 貴文; 荒木 絵里; 藤澤 章弘; 是枝 哲; 立花 隆夫; 宮地 良樹; 三富 陽子  皮膚の科学  2-  (5)  477  -477  2003/10

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