中山 隆志 (ナカヤマ タカシ)

  • 薬学部 医療薬学科 教授
Last Updated :2024/02/13

コミュニケーション情報 byコメンテータガイド

  • コメント

    細胞遊走制御因子ケモカインはアレルギーなどの免疫疾患、感染症や癌の病態発症に重要な役割を果たすことが知られています。私達はケモカイン系を標的として免疫疾患、感染症や癌に対する新規創薬・ワクチンの開発を目指しています。

研究者情報

学位

  • 薬学修士(今本文男 教授)
  • 薬学博士(大阪大学薬学部、真弓忠範 教授)

ホームページURL

J-Global ID

研究キーワード

  • ケモカイン受容体   ケモカイン   Chemokine   

現在の研究分野(キーワード)

    細胞遊走制御因子ケモカインはアレルギーなどの免疫疾患、感染症や癌の病態発症に重要な役割を果たすことが知られています。私達はケモカイン系を標的として免疫疾患、感染症や癌に対する新規創薬・ワクチンの開発を目指しています。

研究分野

  • ライフサイエンス / 免疫学
  • ライフサイエンス / ウイルス学
  • ライフサイエンス / 分子生物学

経歴

  • 2012年 - 現在  近畿大学薬学部化学療法学研究室教授
  • 2004年 - 2012年  近畿大学医学部 講師Faculty of Medicine
  • 1999年 - 2003年  近畿大学医学部 助手Faculty of Medicine
  • 1994年 - 1998年  塩野義製薬医科学研究所 研究員

学歴

  •         - 2000年   大阪大学   薬学研究科(論文博士)
  •         - 2000年   大阪大学   Graduate School, Division of Pharmaceutical Sciences
  •         - 1992年   京都薬科大学   薬学部   生物薬学科
  •         - 1992年   京都薬科大学   Faculty of Pharmaceutical Science

所属学協会

  • 日本薬学会   日本癌学会   日本免疫学会   日本分子生物学会   

研究活動情報

論文

  • Yuta Hara; Tatsuma Honzawa; Moeka Kitagawa; Ritsuki Sano; Kazuhiko Matsuo; Takashi Nakayama
    Journal of Pharmacological Sciences 153 3 89 - 93 2023年11月
  • Nisha Rajeswari Dhanushkodi; Swayam Prakash; Afshana Quadiri; Latifa Zayou; Ruchi Srivastava; Jennifer Tran; Vivian Dang; Amin Mohammed Shaik; Amruth Chilukurri; Berfin Suzer; Phil De Vera; Miyo Sun; Pauline Nguyen; Ashley Lee; Amirah Salem; Joyce Loi; Mahmoud Singer; Takashi Nakayama; Hawa Vahed; Anthony B Nesburn; Lbachir BenMohamed
    Journal of immunology (Baltimore, Md. : 1950) 211 1 118 - 129 2023年07月 
    Four major mucosal-associated chemokines, CCL25, CCL28, CXCL14, and CXCL17, play an important role in protecting mucosal surfaces from infectious pathogens. However, their role in protection against genital herpes remains to be fully explored. The CCL28 is a chemoattractant for the CCR10 receptor-expressing immune cells and is produced homeostatically in the human vaginal mucosa (VM). In this study, we investigated the role of the CCL28/CCR10 chemokine axis in mobilizing protective antiviral B and T cell subsets into the VM site of herpes infection. We report a significant increase in the frequencies of HSV-specific memory CCR10+CD44+CD8+ T cells, expressing high levels of CCR10, in herpes-infected asymptomatic (ASYMP) women compared with symptomatic women. Similarly, a significant increase in the CCL28 chemokine (a ligand of CCR10), was detected in the VM of herpes-infected ASYMP C57BL/6 mice, associated with the mobilization of high frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+ TEM cells and memory CCR10+B220+CD27+ B cells in the VM of HSV-infected ASYMP mice. Inversely, compared with wild-type C57BL/6 mice, the CCL28 knockout (CCL28-/-) mice (1) appeared to be more susceptible to intravaginal infection and reinfection with HSV type 2, and (2) exhibited a significant decrease in the frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+ TEM cells and of memory CD27+B220+ B cells in the infected VM. These findings suggest a critical role of the CCL28/CCR10 chemokine axis in the mobilization of antiviral memory B and T cells within the VM to protect against genital herpes infection and disease.
  • Masako Sato; Kazuhiko Matsuo; Yoko Susami; Ayaka Yamashita; Haruko Hayasaka; Yuta Hara; Keiji Nishiwaki; Naoki Oiso; Akira Kawada; Atsushi Otsuka; Takashi Nakayama
    International Immunology 35 9 437 - 446 2023年06月 
    Abstract CCR4 is a major trafficking receptor for Th2 cells and Th17 cells and is considered as a potential therapeutic target for atopic dermatitis (AD). The CCR4 ligands CCL17 and CCL22 have been reported to be upregulated in the skin lesions of AD patients. Of note, Thymic stromal lymphopoietin (TSLP), a master regulator of the Th2 immune response, promotes the expression of CCL17 and CCL22 in AD skin lesions. Here, we investigated the role of CCR4 in an AD mouse model induced by MC903, a TSLP inducer. Topical application of MC903 to ear skin increased the expression of not only TSLP but also CCL17, CCL22, the Th2 cytokine IL-4, and the Th17 cytokine IL-17A. Consistently, MC903 induced AD-like skin lesions as shown by increased epidermal thickness; increased infiltration of eosinophils, mast cells, type 2 innate lymphoid cells, Th2 cells, and Th17 cells; and elevated serum levels of total IgE. We also found increased expansion of Th2 cells and Th17 cells in the regional lymph nodes (LNs) of AD mice. Compound 22, a CCR4 inhibitor, ameliorated AD-like skin lesions with reduction of Th2 cells and Th17 cells in the skin lesions and regional LNs. We further confirmed that compound 22 diminished the expansion of Th2 cells and Th17 cells in the coculture of CD11c + dendritic cells and CD4 + T cells derived from the regional LNs of AD mice. Collectively, CCR4 antagonists may exhibit anti-allergic effects by inhibiting both the recruitment and expansion of Th2 cells and Th17 cells in AD.
  • Tomonori Higuchi; Yumiko Hashida; Kazuhiko Matsuo; Kosuke Kitahata; Takako Ujihara; Ichiro Murakami; Takashi Nakayama; Masanori Daibata
    Cancer science 114 6 2622 - 2633 2023年03月 
    Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) develops in the setting of long-standing inflammation. This type of lymphoma may have specific expression profiles of chemokines involved in the pathogenesis of DLBCL-CI. EBV-positive pyothorax-associated lymphoma (PAL) is a prototype of DLBCL-CI and represents a valuable model for the study of this disease category. Using a panel of PAL cell lines, we found that PAL cells expressed and secreted C-X-C motif chemokine ligands 9 and 10 (CXCL9 and CXCL10), the ligands of CXCR3, in contrast to EBV-negative DLBCL cell lines, which did not. Culture supernatants from PAL cell lines attracted CXCR3-expressing CD4+ T cells, CD8+ T cells, and CD56+ natural killer cells from human peripheral blood mononuclear cells. PAL cells injected into mice also attracted CXCR3-positive cytotoxic lymphocytes that expressed interferon-γ. The expression of CXCL9 and CXCL10 was detected in PAL tumor biopsy samples from patients, and CXCR3-positive lymphocytes were abundant in the tissue samples. Collectively, these findings suggest that CXCL9 and CXCL10 are produced by PAL cells and can elicit cytotoxic responses via CXCR3. This chemokine system is also likely to contribute to tissue necrosis, which is a signature histological feature of DLBCL-CI. Further studies are warranted to determine whether the CXCL9-CXCL10/CXCR3 axis exerts antitumor effects in DLBCL-CI.
  • Elo Madissoon; Amanda J Oliver; Vitalii Kleshchevnikov; Anna Wilbrey-Clark; Krzysztof Polanski; Nathan Richoz; Ana Ribeiro Orsi; Lira Mamanova; Liam Bolt; Rasa Elmentaite; J Patrick Pett; Ni Huang; Chuan Xu; Peng He; Monika Dabrowska; Sophie Pritchard; Liz Tuck; Elena Prigmore; Shani Perera; Andrew Knights; Agnes Oszlanczi; Adam Hunter; Sara F Vieira; Minal Patel; Rik G H Lindeboom; Lia S Campos; Kazuhiko Matsuo; Takashi Nakayama; Masahiro Yoshida; Kaylee B Worlock; Marko Z Nikolić; Nikitas Georgakopoulos; Krishnaa T Mahbubani; Kourosh Saeb-Parsy; Omer Ali Bayraktar; Menna R Clatworthy; Oliver Stegle; Natsuhiko Kumasaka; Sarah A Teichmann; Kerstin B Meyer
    Nature genetics 55 1 66 - 77 2023年01月 
    Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org ). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new 'gland-associated immune niche' has implications for respiratory health.
  • Tatsuma Honzawa; Kazuhiko Matsuo; Shunya Hosokawa; Mayu Kamimura; Yuichiro Kaibori; Yuta Hara; Daisuke Nagakubo; Naoki Oiso; Akira Kawada; Atsushi Otsuka; Osamu Yoshie; Takashi Nakayama
    International immunology 34 12 635 - 642 2022年08月 
    Th17 cells express CCR4 and secrete cytokines such as IL-17A and GM-CSF, while dendritic cells (DCs) produce CCL22, a CCR4 ligand, upon stimulation with GM-CSF. Th17 cells are known to play a critical role in the pathogenesis of rheumatoid arthritis (RA). CCL22 has also been shown to be upregulated in the synovial tissues of RA patients. Here, we investigated the role of CCR4 in collagen-induced arthritis (CIA), a mouse model of RA. DBA/1J mice efficiently developed CIA as shown by erythema, paw swelling, joint rigidity, and joint destruction. Th17 cells were increased in the arthritic joints and regional lymph nodes (LNs) of CIA mice. A fraction of Th17 cells were also shown to produce GM-CSF. On the other hand, we observed no significant increases of Th2 cells or Treg cells, the T cell subsets also known to express CCR4, in these tissues. We further observed clusters of CCR4-expressing memory Th17 cells and CCL22-producing DCs in the regional LNs of CIA mice, supporting the role of the CCR4-CCL22 axis in the expansion of Th17 cells in the regional LNs. Compound 22, a CCR4 inhibitor, ameliorated the disease severity with reduction of Th17 cells in the arthritic joints and regional LNs and Th17-DC clusters in the regional LNs. We further confirmed that CCR4-deficient mice in the C57BL/6J background were highly resistant to CIA induction compared with wild-type mice. Collectively, CCR4 contributes to the pathogenesis of CIA and may thus represent a new therapeutic target for RA.
  • 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年04月 
    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.
  • Hiroyoshi Machida; Sumito Inoue; Akira Igarashi; Shinichi Saitoh; Keiko Yamauchi; Michiko Nishiwaki; Takako Nemoto; Yoichiro Otaki; Masamichi Sato; Kento Sato; Hiroshi Nakano; Sujeong Yang; Kodai Furuyama; Hiroaki Murano; Yu Ishibashi; Takahito Ota; Takashi Nakayama; Yoko Shibata; Masafumi Watanabe
    American journal of respiratory cell and molecular biology 66 4 428 - 438 2022年04月 
    Lung function deterioration is significantly associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). We previously reported that CC chemokine ligand 17/thymus and activation-regulated chemokine (CCL17/TARC) could be a predictive factor of lung function decline in patients with COPD. However, the role of CCL17 in the pathogenesis of COPD is unclear. Here we examined the role of CCL17 in lung inflammation using mouse COPD models. Exposure to cigarette smoking induced CCL17 production in bronchial epithelial cells and accumulation of alveolar macrophages in the lungs. Intranasal administration of recombinant CCL17 further enhanced cigarette smoke-induced macrophage accumulation and also aggravated elastase-induced pulmonary emphysema. We confirmed that cigarette smoke (CS) extract as well as hydrogen peroxide upregulated CCL17 in BAES-2B cells. Of note, macrophages of both M1 and M2 surface markers were accumulated by cigarette smoke. Both alveolar macrophage accumulation via exposure to cigarette smoking and emphysematous changes induced by elastase administration were significantly reduced in CCL17-deficient mice. We further demonstrated that CCL17 strongly induced the expression of CC chemokine ligand 2 (CCL2), a chemoattractant for macrophages, in RAW264.7 cells, and its production was inhibited by knockdown of CCR4, the receptor of CCL17. Collectively, the present results demonstrate that CCL17 is produced by lung epithelial cells upon CS exposure. Furthermore, CCL17 is involved in CS-induced accumulation of alveolar macrophages and development of elastase-induced pulmonary emphysema, possibly through CCL17-induced production of CCL2 by macrophages. Our findings may provide a new insight into the pathogenesis of COPD.
  • Kazuhiko Matsuo; Osamu Yoshie; Takashi Nakayama
    Cancers 13 23 2021年12月 
    Various immune cells are involved in host tumor immune responses. In particular, there are many T cell subsets with different roles in tumor immunity. T-helper (Th) 1 cells are involved in cellular immunity and thus play the major role in host anti-tumor immunity by inducing and activating cytotoxic T lymphocytes (CTLs). On the other hand, Th2 cells are involved in humoral immunity and suppressive to Th1 responses. Regulatory T (Treg) cells negatively regulate immune responses and contribute to immune evasion of tumor cells. Th17 cells are involved in inflammatory responses and may play a role in tumor progression. However, recent studies have also shown that Th17 cells are capable of directly inducting CTLs and thus may promote anti-tumor immunity. Besides these T cell subsets, there are many other innate immune cells such as dendritic cells (DCs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs) that are involved in host immune responses to cancer. The migratory properties of various immune cells are critical for their functions and largely regulated by the chemokine superfamily. Thus, chemokines and chemokine receptors play vital roles in the orchestration of host immune responses to cancer. In this review, we overview the various immune cells involved in host responses to cancer and their migratory properties regulated by the chemokine superfamily. Understanding the roles of chemokines and chemokine receptors in host immune responses to cancer may provide new therapeutic opportunities for cancer immunotherapy.
  • Kazuhiko Matsuo; Kosuke Kitahata; Yuichiro Kaibori; Yuka Arima; Arisa Iwama; Mana Ito; Yuta Hara; Daisuke Nagakubo; Ying-Shu Quan; Fumio Kamiyama; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama
    The Journal of investigative dermatology 141 8 1985 - 1994 2021年08月 
    Psoriasis is a chronic skin disease associated with T helper (Th)17-mediated inflammation. Because CCR4 is a major chemokine receptor expressed on Th17 cells, we investigated the role of CCR4 in a modified imiquimod-induced psoriasis model that showed enhanced skin infiltration of Th17 cells. CCR4-deficient mice had less severe skin disease than wild-type mice. Th17 cells were decreased in the skin lesions and regional lymph nodes of CCR4-deficient mice. In the regional lymph nodes of wild-type mice, CD44+ memory Th17 cells expressing CCR4 were found to be clustered with dendritic cells expressing CCL22, a ligand for CCR4. Such dendritic cell‒Th17 cell clusters were significantly decreased in CCR4-deficient mice. Similar results were obtained using the IL-23‒induced psoriasis model. In vitro, compound 22, a CCR4 antagonist, significantly reduced the expansion of Th17 cells in the coculture of CD11c+ dendritic cells and CD4+ T cells separately prepared from the regional lymph nodes of wild-type mice with psoriasis. In vivo, compound 22 ameliorated the psoriasis-like skin disease in wild-type mice with significant decreases of Th17 cells in the regional lymph nodes and skin lesions. Collectively, CCR4 is likely to play a role in the pathogenesis of psoriasis through the expansion of Th17 cells.
  • Kazuhiko Matsuo; Osamu Yoshie; Kosuke Kitahata; Momo Kamei; Yuta Hara; Takashi Nakayama
    Cancers 13 10 2021年05月 
    Cancer immunotherapy aims to treat cancer by enhancing cancer-specific host immune responses. Recently, cancer immunotherapy has been attracting much attention because of the successful clinical application of immune checkpoint inhibitors targeting the CTLA-4 and PD-1/PD-L1 pathways. However, although highly effective in some patients, immune checkpoint inhibitors are beneficial only in a limited fraction of patients, possibly because of the lack of enough cancer-specific immune cells, especially CD8+ cytotoxic T-lymphocytes (CTLs), in the host. On the other hand, studies on cancer vaccines, especially DC-based ones, have made significant progress in recent years. In particular, the identification and characterization of cross-presenting DCs have greatly advanced the strategy for the development of effective DC-based vaccines. In this review, we first summarize the surface markers and functional properties of the five major DC subsets. We then describe new approaches to induce antigen-specific CTLs by targeted delivery of antigens to cross-presenting DCs. In this context, the chemokine receptor XCR1 and its ligand XCL1, being selectively expressed by cross-presenting DCs and mainly produced by activated CD8+ T cells, respectively, provide highly promising molecular tools for this purpose. In the near future, CTL-inducing DC-based cancer vaccines may provide a new breakthrough in cancer immunotherapy alone or in combination with immune checkpoint inhibitors.
  • Ryota Sakai; Minako Ito; Kyoko Komai; Mana Iizuka-Koga; Kazuhiko Matsuo; Takashi Nakayama; Osamu Yoshie; Koichi Amano; Hiroshi Nishimasu; Osamu Nureki; Masato Kubo; Akihiko Yoshimura
    Cellular & molecular immunology 18 5 1249 - 1261 2021年05月 
    FoxP3+ regulatory T cells (Tregs) play crucial roles in peripheral immune tolerance. In addition, Tregs that reside or accumulate in nonlymphoid tissues, called tissue Tregs, exhibit tissue-specific functions and contribute to the maintenance of tissue homeostasis and repair. In an experimental mouse model of crescentic glomerulonephritis induced by an anti-glomerular basement membrane antibody, Tregs started to accumulate in the kidney on day 10 of disease onset and remained at high levels (~30-35% of CD4+ T cells) during the late stage (days 21-90), which correlated with stable disease control. Treg depletion on day 21 resulted in the relapse of renal dysfunction and an increase in Th1 cells, suggesting that Tregs are essential for disease control during the convalescence stage. The Tregs that accumulated in the kidney showed tissue Treg phenotypes, including high expression of GATA3, ST2 (the IL33 receptor subunit), amphiregulin (Areg), and PPARγ. Although T-bet+ Tregs and RORγt+ Tregs were observed in the kidney, GATA3+ Tregs were predominant during the convalescence stage, and a PPARγ agonist enhanced the accumulation of GATA3+ Tregs in the kidney. To understand the function of specific genes in kidney Tregs, we developed a novel T cell transfer system to T cell-deficient mice. This experiment demonstrates that ST2, Areg, and CCR4 in Tregs play important roles in the accumulation of GATA3+ Tregs in the kidney and in the amelioration of renal injury. Our data suggest that GATA3 is important for the recruitment of Tregs into the kidney, which is necessary for convalescence after renal tissue destruction.
  • Junko Okano; Yuki Nakae; Takahiko Nakagawa; Miwako Katagi; Tomoya Terashima; Daisuke Nagakubo; Takashi Nakayama; Osamu Yoshie; Yoshihisa Suzuki; Hideto Kojima
    Scientific reports 11 1 5653 - 5653 2021年03月 
    Exposure to moderate doses of ionizing radiation (IR), which is sufficient for causing skin injury, can occur during radiation therapy as well as in radiation accidents. Radiation-induced skin injury occasionally recovers, although its underlying mechanism remains unclear. Moderate-dose IR is frequently utilized for bone marrow transplantation in mice; therefore, this mouse model can help understand the mechanism. We had previously reported that bone marrow-derived cells (BMDCs) migrate to the epidermis-dermis junction in response to IR, although their role remains unknown. Here, we investigated the role of BMDCs in radiation-induced skin injury in BMT mice and observed that BMDCs contributed to skin recovery after IR-induced barrier dysfunction. One of the important mechanisms involved the action of CCL17 secreted by BMDCs on irradiated basal cells, leading to accelerated proliferation and recovery of apoptosis caused by IR. Our findings suggest that BMDCs are key players in IR-induced skin injury recovery.
  • Shinya Yamamoto; Kazuhiko Matsuo; Sho Sakai; Itsuki Mishima; Yuta Hara; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama
    International immunology 33 1 49 - 55 2021年01月 
    Extracellular ATP is known to promote Th17 cell differentiation in the intestinal lamina propria by stimulating CD70+CD11clow dendritic cells (DCs) via P2X receptors (P2XRs). Recent studies have also shown that Th17 cells enhance antitumor immunity by directly promoting proliferation of cytotoxic T lymphocytes (CTLs). These finding led us to test a P2XR agonist, αβ-methylene ATP (αβ-ATP), as a mucosal vaccine adjuvant to promote CTL responses through Th17 induction. We demonstrated that (i) CD70+CD11clow DCs were present in the nasal lamina propria and expressed P2X1R, P2X2R and P2X4R; (ii) CD70+CD11clow DCs isolated from the nasal lamina propria enhanced Th17 cell differentiation of cocultured splenic CD4+ T cells upon stimulation with αβ-ATP; (iii) mice intranasally immunized with ovalbumin (OVA) and αβ-ATP had increased OVA-specific Th17 cells and CTLs in the nasal lamina propria and regional lymph nodes; (iv) mice intranasally immunized with OVA and αβ-ATP also had elevated resistance to E.G7-OVA tumor growth compared with those intranasally immunized with OVA alone; (v) suramin, a broad-range inhibitor of P2 receptors, suppressed the increases of OVA-specific Th17 cells and CTLs in mice intranasally immunized with OVA and αβ-ATP; and (vi) suramin also abrogated the enhanced antitumor immunity of mice intranasally immunized with OVA and αβ-ATP against E.G7-OVA. Collectively, αβ-ATP may be a promising mucosal adjuvant that promotes antigen-specific CTL responses via CD70+CD11clow DC-mediated Th17 induction.
  • Momo Kamei; Kazuhiko Matsuo; Haruka Imanishi; Yuta Hara; Ying-Shu Quen; Fumio Kamiyama; Naoki Oiso; Akira Kawada; Naoki Okada; Takashi Nakayama
    Journal of pharmacological sciences 143 3 182 - 187 2020年07月 [査読有り]
     
    Memory CD8+ cytotoxic T-lymphocytes (CTLs) play a key role in protective immunity against infection and cancer. However, the induction of memory CTLs with currently available vaccines remains difficult. The chemokine receptor XCR1 is predominantly expressed on CD103+ cross-presenting dendritic cells (DCs). Recently, we have demonstrated that a high activity form of murine lymphotactin/XCL1 (mXCL1-V21C/A59C), a ligand of XCR1, can induce antigen-specific memory CTLs by increasing the accumulation of CD103+ DCs in the vaccination site and the regional lymph nodes. Here, we combined a hydrophilic gel patch as a transcutaneous delivery device and mXCL1-V21C/A59C as an adjuvant to further enhance memory CTL responses. The transcutaneous delivery of ovalbumin (OVA) and mXCL1-V21C/A59C by the hydrophilic gel patch increased CD103+ DCs in the vaccination site and the regional lymph nodes for a prolonged period of time compared with the intradermal injection of OVA and mXCL1-V21C/A59C. Furthermore, the hydrophilic gel patch containing OVA and mXCL1-V21C/A59C strongly induced OVA-specific memory CTLs and efficiently inhibited the growth of OVA-expressing tumors more than the intradermal injection of OVA and mXCL1-V21C/A59C. Collectively, this type of hydrophilic gel patch and a high activity form of XCL1 may provide a useful tool for the induction of memory CTL responses.
  • 松尾 一彦; 中山 隆志
    ファルマシア 56 4 335_2 - 335_2 公益社団法人 日本薬学会 2020年 
    免疫細胞は,生体内を循環することで異物侵入に対して全身をパトロールしているが,いざ異物が侵入してくると,その侵入部位へ即座に動員される.このような免疫細胞の細胞遊走には,方向性を持たないランダムな運動(chemokinesis)と細胞遊走因子の濃度勾配にしたがった方向性を持った運動(chemotaxis)に分けられる.Chemotaxis反応では,標的部位におけるケモカインの発現と免疫細胞におけるケモカイン受容体の選択的発現によって,免疫細胞の体内動態は緻密に制御されている.また細胞が,細胞外マトリックスに結合した細胞遊走因子と接触することで引き起こされる運動(haptotaxis)もある.
  • 松尾 一彦; 中山 隆志
    ファルマシア 56 4 335_3 - 335_3 公益社団法人 日本薬学会 2020年 
    免疫系の主役となるリンパ球は,血管系とリンパ系を絶えず循環し,外界からの異物侵入に対してパトロール役として機能する.骨髄や胸腺などの一次リンパ組織で産生されたリンパ球は,二次リンパ組織に流入し,さらにその場を離れて全身を巡り,再び特定の二次リンパ組織に戻ってくる.この現象をリンパ球ホーミングという.この特定の組織への流入を制御する分子メカニズムには,リンパ球上に発現する接着分子やケモカイン受容体と標的組織の血管に発現するケモカインの組み合わせが重要である.例えば,リンパ節ホーミングには,接着分子L-セレクチンおよびケモカイン受容体CCR7が重要な役割を果たすことが明らかにされている.
  • Shiki Takamura; Shigeki Kato; Chihiro Motozono; Takeshi Shimaoka; Satoshi Ueha; Kazuhiko Matsuo; Kosuke Miyauchi; Tomoko Masumoto; Asami Katsushima; Takashi Nakayama; Michio Tomura; Kouji Matsushima; Masato Kubo; Masaaki Miyazawa
    The Journal of experimental medicine 216 12 2736 - 2747 2019年12月 [査読有り]
     
    Populations of CD8+ lung-resident memory T (TRM) cells persist in the interstitium and epithelium (airways) following recovery from respiratory virus infections. While it is clear that CD8+ TRM cells in the airways are dynamically maintained via the continuous recruitment of new cells, there is a vigorous debate about whether tissue-circulating effector memory T (TEM) cells are the source of these newly recruited cells. Here we definitively demonstrate that CD8+ TRM cells in the lung airways are not derived from TEM cells in the circulation, but are seeded continuously by TRM cells from the lung interstitium. This process is driven by CXCR6 that is expressed uniquely on TRM cells but not TEM cells. We further demonstrate that the lung interstitium CD8+ TRM cell population is also maintained independently of TEM cells via a homeostatic proliferation mechanism. Taken together, these data show that lung memory CD8+ TRM cells in the lung interstitium and airways are compartmentally separated from TEM cells and clarify the mechanisms underlying their maintenance.
  • Jamie C Fox; Monica A Thomas; Acacia F Dishman; Olav Larsen; Takashi Nakayama; Osamu Yoshie; Mette Marie Rosenkilde; Brian F Volkman
    Science signaling 12 597 2019年09月 
    Chemokines interact with their G protein-coupled receptors (GPCRs) through a two-step, two-site mechanism and, through this interaction, mediate various homeostatic and immune response mechanisms. Upon initial recognition of the chemokine by the receptor, the amino terminus of the chemokine inserts into the orthosteric pocket of the GPCR, causing conformational changes that trigger intracellular signaling. There is considerable structural and functional evidence to suggest that the amino acid composition and length of the chemokine amino terminus is critical for GPCR activation, complementing the size and amino acid composition of the orthosteric pocket. However, very few structures of a native chemokine-receptor complex have been solved. Here, we used a hybrid approach that combines structure-function data with Rosetta modeling to describe key contacts within a chemokine-GPCR interface. We found that the extreme amino-terminal residues of the chemokine XCL1 (Val1, Gly2, Ser3, and Glu4) contribute a large fraction of the binding energy to its receptor XCR1, whereas residues near the disulfide bond-forming residue Cys11 modulate XCR1 activation. Alterations in the XCL1 amino terminus changed XCR1 activation, as determined by assessing inositol triphosphate accumulation, intracellular calcium release, and directed cell migration. Computational analysis of XCL1-XCR1 interactions revealed functional contacts involving Glu4 of XCL1 and Tyr117 and Arg273 of XCR1. Subsequent mutation of Tyr117 and Arg273 led to diminished binding and activation of XCR1 by XCL1. These findings demonstrate the utility of a hybrid approach, using biological data and homology modeling, to study chemokine-GPCR interactions.
  • Tomonori Higuchi; Kazuhiko Matsuo; Yumiko Hashida; Kosuke Kitahata; Takako Ujihara; Ayuko Taniguchi; Osamu Yoshie; Takashi Nakayama; Masanori Daibata
    Cancer letters 453 184 - 192 2019年07月 [査読有り]
     
    Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas associated with chronic inflammation (DLBCL-CI) develop in patients with chronic inflammation but without any predisposing immunodeficiency. Given the expression of the EBV latent genes, DLBCL-CI should have mechanisms for evasion of host antitumor immunity. EBV-positive pyothorax-associated lymphoma (PAL) is a prototype of DLBCL-CI and may provide a valuable model for the study of immune evasion by DLBCL-CI. This study demonstrates that PAL cell lines express and secrete CCL17 and/or CCL22 chemokines, the ligands of C-C motif chemokine receptor 4 (CCR4), in contrast to EBV-negative DLBCL cell lines. Accordingly, culture supernatants of PAL cell lines efficiently attracted CCR4-positive regulatory T (Treg) cells in human peripheral blood mononuclear cells. PAL cells injected into mice also attracted CCR4-expressing Treg cells. Furthermore, this study confirmed that CCR4-expressing Treg cells were abundantly present in primary PAL tissues. Collectively, these findings provide new insight into the mechanisms of immune evasion by PAL, and further studies are warranted on whether such mechanisms eventually lead to the development of DLBCL-CI.
  • Kazuhiko Matsuo; Shota Hatanaka; Yuta Kimura; Yuta Hara; Keiji Nishiwaki; Ying-Shu Quan; Fumio Kamiyama; Naoki Oiso; Akira Kawada; Kenji Kabashima; Takashi Nakayama
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 109 1437 - 1444 2019年01月 [査読有り]
     
    CCR4 is a chemokine receptor highly expressed by Th2 cells, and regarded as a potential therapeutic target for atopic dermatitis (AD). CCL17 and CCL22 are the CCR4 ligands, and thymic stromal lymphopoietin (TSLP) is shown to promote the expression of CCL17 and CCL22 by dendritic cells. Here, by using dibutyl phthalate (DBP), a TSLP inducer, and a hydrogel patch as a transcutaneous delivery device for ovalbumin, we developed a novel murine AD model and investigated the effect of Compound 22, a CCR4 antagonist. We first found that the mRNA expression of TSLP together with CCL17 and CCL22 was increased in the skins treated with DBP. Furthermore, the topical application of ovalbumin and DBP efficiently and rapidly induced AD-like skin lesions in BALB/c mice, which were characterized by ear swelling accompanied by infiltration of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions, and elevated total IgE levels in the sera. Using this AD model, we demonstrated that cutaneous administration of Compound 22 inhibited Th2 cell infiltration and ameliorated the AD-like skin lesions. These results suggest that our AD model could be useful for studying new therapeutic strategies. Collectively, CCR4 antagonists may be a promising approach for treating AD.
  • Minako Ito; Kyoko Komai; Setsuko Mise-Omata; Mana Iizuka-Koga; Yoshiko Noguchi; Taisuke Kondo; Ryota Sakai; Kazuhiko Matsuo; Takashi Nakayama; Osamu Yoshie; Hiroko Nakatsukasa; Shunsuke Chikuma; Takashi Shichita; Akihiko Yoshimura
    Nature 565 7738 246 - 250 2019年01月 [査読有り]
     
    In addition to maintaining immune tolerance, FOXP3+ regulatory T (Treg) cells perform specialized functions in tissue homeostasis and remodelling1,2. However, the characteristics and functions of brain Treg cells are not well understood because there is a low number of Treg cells in the brain under normal conditions. Here we show that there is massive accumulation of Treg cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain Treg cells are similar to Treg cells in other tissues such as visceral adipose tissue and muscle3-5, they are apparently distinct and express unique genes related to the nervous system including Htr7, which encodes the serotonin receptor 5-HT7. The amplification of brain Treg cells is dependent on interleukin (IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration into the brain is driven by the chemokines CCL1 and CCL20. Brain Treg cells suppress neurotoxic astrogliosis by producing amphiregulin, a low-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is a leading cause of neurological disability, and there are currently few effective recovery methods other than rehabilitation during the chronic phase. Our findings suggest that Treg cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases.
  • Kosuke Kitahata; Kazuhiko Matsuo; Yuta Hara; Takanori Naganuma; Naoki Oiso; Akira Kawada; Takashi Nakayama
    Journal of pharmacological sciences 138 4 284 - 288 2018年12月 [査読有り]
     
    Psoriasis is a chronic inflammatory skin disease in which inflammatory cytokines play a major role in its pathogenesis. Because DDH-1, a novel amphipathic ascorbic acid derivative, has been recently shown to reduce inflammatory cytokine expression in human keratinocytes in vitro, we investigated its effect on imiquimod-induced psoriasis-like skin lesions in C57BL/6 mice. We first found that IL-1β and TNF-α mRNA expression was significantly decreased in the skin lesions treated with DDH-1. Furthermore, cutaneous administration of DDH-1 ameliorated psoriasis-like skin lesions. These results suggest that DDH-1 may be effective in the prevention and supplemental treatment of psoriasis.
  • Kazuhiko Matsuo; Daisuke Nagakubo; Yuhei Komori; Shun Fujisato; Natsumi Takeda; Mizuki Kitamatsu; Keiji Nishiwaki; Ying-Shu Quan; Fumio Kamiyama; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama
    The Journal of investigative dermatology 138 8 1764 - 1773 2018年08月 [査読有り]
     
    Atopic dermatitis is a chronic inflammatory skin disease involving T-helper (Th) 2 cells, eosinophils, and mast cells. Although CCR4 is a major chemokine receptor expressed on Th2 cells and regarded as a potential therapeutic target for allergic diseases, its role in atopic dermatitis remains unclear. Here, by using a hydrogel patch as a transcutaneous delivery device for ovalbumin (an antigen) and Staphylococcus aureus δ-toxin (a mast cell activator), we efficiently induced acute atopic dermatitis-like skin lesions in BALB/c mice, a strain prone to Th2 responses, which were characterized by increased numbers of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions; elevated levels of total and ovalbumin-specific IgE in the sera; and increased expression of IL-4, IL-17A, IL-22, CCL17, CCL22, and CCR4 in the skin lesions. Of note, the same model was less efficient in C57BL/6 mice, a strain prone to Th1 responses. Using this atopic dermatitis model in BALB/c mice, we demonstrated that CCR4-deficiency or a CCR4 antagonist ameliorated the allergic responses. Collectively, these results demonstrate that CCR4 plays a pivotal role in skin allergic inflammation of BALB/c mice by recruiting CCR4-expressing Th2 cells and Th17 cells.
  • Shinya Yamamoto; Kazuhiko Matsuo; Daisuke Nagakubo; Shintaro Higashiyama; Keiji Nishiwaki; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama
    Journal of pharmacological sciences 136 3 165 - 171 2018年03月 [査読有り]
     
    CCR4 is a major chemokine receptor expressed by Treg cells that downregulate immune responses. Here, we investigated the role of CCR4-mediated Treg cell recruitment in antigen-specific immune responses. CCR4-deficient mice immunized intramuscularly with ovalbumin (OVA) showed enhanced OVA-specific IgG responses. Furthermore, intramuscular administration of OVA induced the expression of MDC/CCL22, a ligand for CCR4, in macrophages of the muscle tissues, and enhanced the recruitment of CCR4+ Treg cells in wild-type mice, whereas this recruitment of Treg cells was severely impaired in CCR4-deficient mice. Furthermore, OVA-loaded dendritic cells (DCs) derived from the muscle injection site of CCR4-deficient mice had an upregulated expression of the DC activation marker CD40 and 86, and the lymphoid organ homing receptor CCR7 resulting in an increased number of migratory DCs in the regional lymph node. Compound 22, a CCR4 antagonist, also inhibited the recruitment of Treg cells to the muscle tissue, and further enhanced DC activation and homing to the regional lymph node. Consequently, Compound 22 enhanced OVA-specific IgG responses, and the expression levels of IL-4 and IFN-γ in CD4+ T cells and the levels of IFN-γ in CD8+ T cells. Finally, intramuscular administration of OVA and Compound 22 significantly inhibited the growth of OVA-expressing tumors. Collectively, CCR4 plays a pivotal role in Treg cell recruitment to the muscle tissue, and intramuscular administration of CCR4 antagonists may be a promising approach for enhancing vaccine efficacy.
  • Kazuhiko Matsuo; Daisuke Nagakubo; Shinya Yamamoto; Akiko Shigeta; Shuta Tomida; Mitsugu Fujita; Takako Hirata; Ikuo Tsunoda; Takashi Nakayama; Osamu Yoshie
    Journal of immunology (Baltimore, Md. : 1950) 200 2 800 - 809 2018年01月 [査読有り]
     
    CCL28 induces the migration of IgA Ab-secreting cells (ASCs) via CCR10 and also displays a potent antimicrobial activity in vitro. To explore the role of CCL28 in vivo, we generated CCL28-deficient mice. The mice exhibited a significant reduction and abnormal distribution of IgA ASCs in the lamina propria of the colon. The concentrations of total and Ag-specific IgA in the fecal extracts of CCL28-deficient mice were also drastically reduced. The average amount of IgA secreted by a single IgA ASC derived from the colon was also substantially reduced in CCL28-deficient mice. Furthermore, CCL28 was found to significantly increase the average amount of IgA secreted by a single IgA ASC derived from the colon in vitro. In contrast, the generation of IgA ASCs in Peyer's and cecal patches was not significantly impaired in CCL28-deficient mice. We also found a relative increase in the Class Bacilli in the fecal extracts of CCL28-deficient mice and demonstrated a potent antimicrobial activity of CCL28 against Bacillus cereus and Enterococcus faecalis, both of which belong to Class Bacilli. Thus, CCL28 may also suppress the outgrowth of some bacterial species by its direct antimicrobial activity. Finally, CCL28-deficient mice exhibited a highly aggravated dextran sodium sulfate-induced colitis that was ameliorated by pretreatment with antibiotics. Collectively, CCL28 plays a pivotal role in the homing, distribution, and function of IgA ASCs in the colon and may also affect the intestinal microbiota through its direct antimicrobial activity.
  • Kazuhiko Matsuo; Kosuke Kitahata; Fumika Kawabata; Momo Kamei; Yuta Hara; Shiki Takamura; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama
    Frontiers in immunology 9 2775 - 2775 2018年 [査読有り]
     
    The chemokine receptor XCR1 is known to be selectively expressed by cross-presenting dendritic cells (DCs), while its ligand XCL1/lymphotactin is mainly produced by activated CD8+ T cells and natural killer cells. Recent studies have shown that XCL1-antigen fusion proteins efficiently induce CD8+ T cell responses by preferentially delivering antigens to XCR1+ DCs. However, XCL1 per se was found to be a poor adjuvant for induction of CD8+ T cell responses. XCL1 is unique because of its lack of one of the two disulfide bonds commonly conserved in all other chemokines and thus has an unstable structure with a relatively weak chemokine activity. In the present study, we generated a variant form of murine XCL1 termed mXCL1-V21C/A59C that contained a second disulfide bond to stabilize its chemokine structure. We confirmed that mXCL1-V21C/A59C had much more potent chemotactic and calcium mobilization activities than the wild type XCL1 (mXCL1-WT). Intradermal injection of mXCL1-V21C/A59C, but not that of mXCL1-WT, significantly increased the accumulation of XCR1+CD103+ DCs in the injection site, and most of the accumulated XCR1+CD103+ DCs were found to take up co-injected ovalbumin (OVA). Furthermore, recruited XCR1+CD103+ DCs efficiently migrated to the draining lymph nodes and stayed for a prolonged period of time. Consequently, mXCL1-V21C/A59C strongly induced OVA-specific CD8+ T cells. The combination of OVA and mXCL1-V21C/A59C well protected mice from E.G7-OVA tumor growth in both prophylactic and therapeutic protocols. Finally, memory CTL responses were efficiently induced in mice immunized with OVA and mXCL1-V21C/A59C. Although intradermal injection of OVA and polyinosinic-polycytidylic acid (poly(I:C)) as an adjuvant also induced CD8+ T cell responses to OVA, poly (I:C) poorly recruited XCR1+CD103+ DCs in the injection site and failed to induce significant memory CTL responses to OVA. Collectively, our findings demonstrate that a highly active form of XCL1 is a promising vaccine adjuvant for cross-presenting DCs to induce antigen-specific effector and memory CD8+ T cells.
  • Rana Mashud; Akira Nomachi; Akihide Hayakawa; Koji Kubouchi; Sally Danno; Takako Hirata; Kazuhiko Matsuo; Takashi Nakayama; Ryosuke Satoh; Reiko Sugiura; Manabu Abe; Kenji Sakimura; Shigeharu Wakana; Hiroyuki Ohsaki; Shingo Kamoshida; Hideyuki Mukai
    SCIENTIFIC REPORTS 7 1 7663  2017年08月 [査読有り]
     
    Knock-in mice lacking PKN1 kinase activity were generated by introducing a T778A point mutation in the catalytic domain. PKN1[T778A] mutant mice developed to adulthood without apparent external abnormalities, but exhibited lower T and B lymphocyte counts in the peripheral blood than those of wild-type (WT) mice. T and B cell development proceeded in an apparently normal fashion in bone marrow and thymus of PKN1[T778A] mice, however, the number of T and B cell counts were significantly higher in the lymph nodes and spleen of mutant mice in those of WT mice. After transfusion into WT recipients, EGFP-labelled PKN1[T778A] donor lymphocytes were significantly less abundant in the peripheral circulation and more abundant in the spleen and lymph nodes of recipient mice compared with EGFP-labelled WT donor lymphocytes, likely reflecting lymphocyte sequestration in the spleen and lymph nodes in a cell-autonomous fashion. PKN1[T778A] lymphocytes showed significantly lower chemotaxis towards chemokines and sphingosine 1-phosphate (S1P) than WT cells in vitro. The biggest migration defect was observed in response to S1P, which is essential for lymphocyte egress from secondary lymphoid organs. These results reveal a novel role of PKN1 in lymphocyte migration and localization.
  • Masanobu Tsubaki; Tomoya Takeda; Toshiki Kino; Kazuko Sakai; Tatsuki Itoh; Motohiro Imano; Takashi Nakayama; Kazuto Nishio; Takao Satou; Shozo Nishida
    Oncotarget 8 24 38717 - 38730 2017年06月 [査読有り]
     
    Resistance to the breakpoint cluster region-abelson 1 (BCR-ABL1) tyrosine kinase inhibitor (TKI) imatinib poses a major problem when treating chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, in the absence of a mutation in BCR-ABL1, the basis of BCR-ABL1-independent resistance must be elucidated. To gain insight into the mechanisms of BCR-ABL1-independent imatinib resistance, we performed an array-based comparative genomic hybridization. We identified various resistance-related genes, and focused on MET. Treatment with a MET inhibitor resensitized K562/IR cells to BCR-ABL1 TKIs. Combined treatment of K562/IR cells with imatinib and a MET inhibitor suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) activation, but did not affect AKT activation. Our findings implicate the MET/ERK and MET/JNK pathways in conferring resistance to imatinib, providing new insights into the mechanisms of BCR-ABL1 TKI resistance in CML.
  • がんゲノム医療の実装と遺伝性疾患の責任遺伝子探索・創薬から予防までのトータルケアー
    西尾 和人; 田村 和朗; 西郷 和真; 杉浦 麗子; 中山 隆志; 奥野 清隆; 菰池 佳史; 万代 昌紀; 竹村 司; 伊藤 彰彦; 大磯 直毅; 浮田 真沙世; 坂井 和子
    日本遺伝カウンセリング学会誌 38 2 35 - 36 日本遺伝カウンセリング学会 2017年05月
  • Kazuhiko Matsuo; Tatsuki Itoh; Atsushi Koyama; Reira Imamura; Shiori Kawai; Keiji Nishiwaki; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama
    Cancer letters 378 1 16 - 22 2016年08月 [査読有り]
     
    CCR4 is a major chemokine receptor expressed by Treg cells and Th17 cells. While Treg cells are known to suppress antitumor immunity, Th17 cells have recently been shown to enhance the induction of antitumor cytotoxic T lymphocytes. Here, CCR4-deficient mice displayed enhanced tumor growth upon intradermal inoculation of B16-F10 melanoma cells. In CCR4-deficient mice, while IFN-γ+CD8+ effector T cells were decreased in tumor sites, IFN-γ+CD8+ T cells and Th17 cells were decreased in regional lymph nodes. In wild-type mice, CD4+IL-17A+ cells, which were identified as CCR4+CD44+ memory Th17, were found to be clustered around dendritic cells expressing MDC/CCL22, a ligand for CCR4, in regional lymph nodes. Compound 22, a CCR4 antagonist, also enhanced tumor growth and decreased Th17 cells in regional lymph nodes in tumor-bearing mice treated with Dacarbazine. In contrast, CCR6 deficiency did not affect the tumor growth and the numbers of Th17 cells in regional lymph nodes. These findings indicate that CCR4 is critically involved in regional lymph node DC-Th17 cell interactions that are necessary for Th17 cell-mediated induction of antitumor CD8+ effector T cells in mice bearing B16 melanoma.
  • Toshio Morikawa; Ikuko Hachiman; Kazuhiko Matsuo; Eriko Nishida; Kiyofumi Ninomiya; Takao Hayakawa; Osamu Yoshie; Osamu Muraoka; Takashi Nakayama
    JOURNAL OF NATURAL PRODUCTS 79 8 2005 - 2013 2016年08月 [査読有り]
     
    CC chemokine receptor 3 (CCR3) is expressed selectively in eosinophils, basophils, and some Th2 cells and plays a major role in allergic diseases. A methanol extract from the arils of Myristica fragrans inhibited CC chemokine ligand 11-induced chemotaxis in CCR3-expressing L1.2 cells at 100 mu g/mL. From this extract, eight new neolignans, maceneolignans A-H (1-8), were isolated, and their stereostructures were elucidated from their spectroscopic values and chemical properties. Of those constituents, compounds 1, 4, 6, and 8 and (+)-erythro-(7S,8R)-Delta(8)'-7-hydroxy-3,4-methylenedioxy-3,5'-dimethoxy-8-O-4'-neolignan (11), (-)- (8R)-Delta(8,)-3,4-methylene dioxy-3',5-dimethoxy-8-O-4'-neolignan (17), (+)-licarin A (20), nectandrin B (25), verrucosin (26), and myristicin (27) inhibited CCR3-mediated chemotaxis at, a concentration of 1 mu M. Among them, 1 (EC50 1.6 mu M), 6 (1.5 mu M), and 8 (1.4 mu M) showed relatively strong activities, which were comparable to that of a synthetic CCR3 selective antagonist, SB328437 (0.78 mu M).
  • Matsuo K; Nishiuma S; Hasegawa Y; Kawabata F; Kitahata K; Nakayama T
    Biological & pharmaceutical bulletin 39 6 1073 - 1076 2016年06月 [査読有り]
     
    Adjuvants are required to enhance antigen-specific immune responses by vaccines. Extracellular ATP serves as a danger signal to alert the immune system of tissue damage by acting on P2X and P2Y receptors and triggers the activation of dendritic cells (DCs). Here we investigated the in vivo adjuvant efficacy of alpha,beta-methylene-ATP (alpha beta-ATP), a non-hydrolysable form of ATP. We found that intradermal injection of ovalbumin (OVA), as a model antigen, combined with alpha beta-ATP, as the adjuvant, enhanced OVA-specific immune responses more than OVA alone. Additionally, DCs in the skin of mice injected with OVA and alpha beta-ATP had increased expression of major histocompatibility complex class II and co-stimulator molecules, CD40, CD80, and CD86, suggesting that alpha beta-ATP activated DC. These findings indicate that alpha beta-ATP functions as a potent vaccine adjuvant.
  • Kota Moriguchi; Katsuichi Miyamoto; Noriko Tanaka; Rino Ueno; Takashi Nakayama; Osamu Yoshie; Susumu Kusunoki
    JOURNAL OF NEUROIMMUNOLOGY 291 54 - 58 2016年02月 [査読有り]
     
    Chemokines and chemokine receptors play important roles in the immune response. We previously reported the pathogenic role of C-C chemokine receptor type 4 (CCR4) in experimental autoimmune encephalomyelitis (EAE). Here, we examined whether CCR4 antagonism modulates the disease course of EAE. Wild-type and CCR4-knockout mice were induced EAE and were administered Compound 22, an antagonist of CCR4. Compound 22 significantly ameliorated the severity of EAE in wild-type mice, but not in the CCR4-knockout mice. Compound 22 inhibited Th1 and Th17 polarization of antigen-induced T-cell responses. Therefore, CCR4 antagonists might be potential therapeutic agents for multiple sclerosis. (C) 2015 Elsevier B.V. All rights reserved.
  • Kazuhiko Matsuo; Keiichi Koizumi; Mitsugu Fujita; Toshio Morikawa; Michiko Jo; Naotoshi Shibahara; Ikuo Saiki; Osamu Yoshie; Takashi Nakayama
    Frontiers in cell and developmental biology 4 54 - 54 2016年 [査読有り]
     
    Chemokine receptors CCR3 and CCR4 are preferentially expressed by TH2 cells, mast cells, and/or eosinophils, all of which are involved in the pathogenesis of allergic diseases. Therefore, CCR3 and CCR4 have long been highlighted as potent therapeutic targets for allergic diseases. Japanese traditional herbal medicine Kampo consists of multiple crude drugs/herbs, which further consist of numerous chemical substances. Recent studies have demonstrated that such chemical substances appear to promising sources in the development of novel therapeutic agents. Based on these findings, we hypothesize that Kampo-related crude drugs/herbs would contain chemical substances that inhibit the cell migration mediated by CCR3 and/or CCR4. To test this hypothesis, we screened 80 crude drugs/herbs to identify candidate substances using chemotaxis assay. Among those tested, Ephedra Herb inhibited the chemotaxis mediated by both CCR3 and CCR4, Cornus Fruit inhibited that mediated by CCR3, and Rhubarb inhibited that mediated by CCR4. Furthermore, Ephedra Herb specifically inhibited the chemotaxis mediated by not only CCR3 and CCR4 but CCR8, all of which are selectively expressed by TH2 cells. This result led us to speculate that ephedrine, a major component of Ephedra Herb, would play a central role in the inhibitory effects on the chemotaxis mediated by CCR3, CCR4, and CCR8. However, ephedrine exhibited little effects on the chemotaxis. Therefore, we fractionated Ephedra Herb into four subfractions and examined the inhibitory effects of each subfraction. As the results, ethyl acetate-insoluble fraction exhibited the inhibitory effects on chemotaxis and calcium mobilization mediated by CCR3 and CCR4 most significantly. In contrast, chloroform-soluble fraction exhibited a weak inhibitory effect on the chemotaxis mediated by CCR8. Furthermore, maoto, one of the Kampo formulations containing Ephedra Herb, exhibited the inhibitory effects on the chemotaxis mediated by CCR3, CCR4, and CCR8. Taken together, our data suggest that these crude drugs/herbs might be useful sources to develop new drugs targeting TH2-mediated allergic diseases.
  • Akinori Wada; Aya Ito; Hirofumi Iitsuka; Koichi Tsuneyama; Takayoshi Miyazono; Jun Murakami; Naotoshi Shibahara; Hiroaki Sakurai; Ikuo Saiki; Takashi Nakayama; Osamu Yoshie; Keiichi Koizumi; Toshiro Sugiyama
    ONCOLOGY REPORTS 33 6 2935 - 2939 2015年06月 [査読有り]
     
    Several chemokines/chemokine receptors such as CXCL12, CCL3, CXCR4 and CCR1 attract multiple myelomas to specific microenvironments. In the present study, we investigated whether the CX3CL1/CX3CR1 axis is involved in the interaction of the multiple myeloma cells with their microenvironment. The expression of CX3CR1 (also known as fractalkine) was detected in three of the seven human myeloma cell lines. CX3CL1-induced phosphorylation of Akt and ERK1/2 was detected in the CX3CR1-positive cell lines, but not in the CX3CR1-negative cell lines. In addition, CX3CL1-induced cell adhesion to fibronectin and vascular cell adhesion molecule-1 (VCAM-1) in the human myeloma RPMI-8226 cell line. We also investigated whether a relationship existed between myeloma cells and osteoclasts that may function via the CX3CL1/CX3CR1 axis. Conditioned medium from CX3CL1-stimulated RPMI-8226 cells drastically increased the osteoclast differentiation. Collectively, the results from the present study support the concept of the CX3CL1-mediated activation of the progression of the multiple myeloma via CX3CR1. Thus, CX3CR1 may represent a potential therapeutic target for the treatment of multiple myeloma in a bone microenvironment.
  • Jamie C. Fox; Takashi Nakayama; Robert C. Tyler; Tara L. Sander; Osamu Yoshie; Brian F. Volkman
    CYTOKINE 71 2 302 - 311 2015年02月 [査読有り]
     
    Known for its unusual metamorphic native state structure, XCL1 has been the focus of most efforts to elucidate the structural, functional, and physiological properties of chemokines in the C subfamily. By comparison, its closely related paralog XCL2 remains virtually uncharacterized. Based on the importance of the chemokine N-terminus in receptor activation, it was hypothesized that two amino acid differences in XCL2 would alter its agonist activity relative to XCL1 for their shared receptor XCR1. This present study reveals several properties of XCL2 that were unexamined until now. Structurally, XCL1 and XCL2 are very similar, exchanging between the monomeric chemokine fold and an unrelated dimeric state under physiological NaCl and temperature conditions. Ca2+ flux, chemotaxis, and heparin binding assays showed that the monomer form of XCL2 is responsible for G protein-coupled receptor activation while the dimeric form is important for GAG binding. Despite their high structural similarity, XCL2 displays a slightly higher affinity for heparin than XCL1. Because their in vitro functional profiles are virtually identical, distinct physiological roles for XCL1 and XCL2 are probably encoded at the level of expression. (C) 2014 Elsevier Ltd. All rights reserved.
  • Kee JY; Ito A; Hojo S; Hashimoto I; Igarashi Y; Tsuneyama K; Tsukada K; Irimura T; Shibahara N; Takasaki I; Inujima A; Nakayama T; Yoshie O; Sakurai H; Saiki I; Koizumi K
    BMC cancer 14 949 - 949 2014年12月 [査読有り]
     
    Background: Inhibition of metastasis through upregulation of immune surveillance is a major purpose of chemokine gene therapy. In this study, we focused on a membrane-bound chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients. Methods: We generated a CXCL16-expressing metastatic CRC cell line and identified changes in TNF and apoptosis-related factors. To investigate the effect of CXCL16 on colorectal liver metastasis, we injected SL4-Cont and SL4-CXCL16 cells into intraportal vein in C57BL/6 mice and evaluated the metastasis. Moreover, we analyzed metastatic liver tissues using flow cytometry whether CXCL16 expression regulates the infiltration of M1 macrophages. Results: CXCL16 expression enhanced TNF-alpha-induced apoptosis through activation of PARP and the caspase-3-mediated apoptotic pathway and through inactivation of the NF-kappa B-mediated survival pathway. Several genes were changed by CXCL16 expression, but we focused on IRF8, which is a regulator of apoptosis and the metastatic phenotype. We confirmed CXCL16 expression in SL4-CXCL16 cells and the correlation between CXCL16 and IRF8. Silencing of IRF8 significantly decreased TNF-alpha-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-alpha-induced apoptosis through the induction of M1 macrophages, which released TNF-alpha. Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis. Conclusions: Collectively, this study revealed that CXCL16 regulates immune surveillance and cell signaling. Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule.
  • Masataka Matsumoto; Takashi Nakayama; Daiki Inoue; Kazufumi Takamatsu; Ryo Itotani; Manabu Ishitoko; Shinko Suzuki; Minoru Sakuramoto; Yoshiaki Yuba; Osamu Yoshie; Masaya Takemura; Motonari Fukui
    BMC CANCER 14 588 - 588 2014年08月 [査読有り]
     
    Background: Lung cancer cells have been reported to produce cytokines, resulting in systemic reactions. There have been few reports showing that these cytokines induced the formation of an inflammatory mass around lung cancers. Case presentation: We encountered a patient with a pleomorphic carcinoma of the lung. This tumor produced interleukin (IL)-8, granulocyte colony-stimulating factor and IL-6, which in turn recruited inflammatory cells, such as CD8 positive lymphocytes, around the tumor, resulting in a rapidly growing tumor shadow. Conclusion: 18 F-fluoro-deoxy-glucose positron emission tomography, in addition to a conventional radiological approach such as computed tomography, may detect immunological responses around a tumor.
  • Maiko Kato; Naoki Oiso; Tatsuki Itoh; Masako Sato; Kazuhiko Matsuo; Takashi Nakayama; Takao Satou; Akira Kawada
    JOURNAL OF DERMATOLOGY 41 5 459 - 461 2014年05月 [査読有り]
  • Tatsuki Itoh; Masaki Tabuchi; Nobuyuki Mizuguchi; Motohiro Imano; Masahiro Tsubaki; Shozo Nishida; Shigeo Hashimoto; Kazuhiko Matsuo; Takashi Nakayama; Akihiko Ito; Hiroshi Munakata; Takao Satou
    JOURNAL OF NEURAL TRANSMISSION 120 5 767 - 783 2013年05月 [査読有り]
     
    Our previous study indicated that consuming (-)-epigallocatechin gallate (EGCG) before or after traumatic brain injury (TBI) eliminated free radical generation in rats, resulting in inhibition of neuronal degeneration and apoptotic death, and improvement of cognitive impairment. Here we investigated the effects of administering EGCG at various times pre- and post-TBI on cerebral function and morphology. Wistar rats were divided into five groups and were allowed access to (1) normal drinking water, (2) EGCG pre-TBI, (3) EGCG pre- and post-TBI, (4) EGCG post-TBI, and (5) sham-operated group with access to normal drinking water. TBI was induced with a pneumatic controlled injury device at 10 weeks of age. Immunohistochemistry and lipid peroxidation studies revealed that at 1, 3, and 7 days post-TBI, the number of 8-Hydroxy-2'-deoxyguanosine-, 4-Hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells, and levels of malondialdehyde around the damaged area were significantly decreased in all EGCG treatment groups compared with the water group (P < 0.05). Although there was a significant increase in the number of surviving neurons after TBI in each EGCG treatment group compared with the water group (P < 0.05), significant improvement of cognitive impairment after TBI was only observed in the groups with continuous and post-TBI access to EGCG (P < 0.05). These results indicate that EGCG inhibits free radical-induced neuronal degeneration and apoptotic death around the area damaged by TBI. Importantly, continuous and post-TBI access to EGCG improved cerebral function following TBI. In summary, consumption of green tea may be an effective therapy for TBI patients.
  • Tomonori Higuchi; Takashi Nakayama; Tokuzo Arao; Kazuto Nishio; Osamu Yoshie
    BLOOD 121 18 3640 - 3649 2013年05月 [査読有り]
     
    Previously, we have shown that an AP-1 family member, FRA-2, is constitutively expressed in adult T-cell leukemia/lymphoma (ATL) and, together with JUND, upregulates CCR4 and promotes ATL cell growth. Among the identified potential target genes of FRA-2/JUND was SOX4. Here, we examine the expression and function of SOX4 in ATL. SOX4 was indeed consistently expressed in primary ATL cells. FRA-2/JUND efficiently activated the SOX4 promoter via an AP-1 site. Knockdown of SOX4 expression by small interfering RNA (siRNA) strongly suppressed cell growth of ATL cell lines. Microarray analyses revealed that SOX4 knockdown reduced the expression of genes such as germinal center kinase related (GCKR), NAK-associated protein 1 (NAP1), and histone deacetylase 8 (HDAC8). We confirmed consistent expression of GCKR, NAP1, and HDAC8 in primary ATL cells. We also showed direct activation of the HDAC8 promoter by SOX4. Furthermore, siRNA knockdown of GCKR, NAP1, and HDAC8 each significantly suppressed cell growth of ATL cell lines. Taken together, we have revealed an important oncogenic cascade involving FRA-2/JUND and SOX4 in ATL, which leads to the expression of genes such as GCKR, NAP1, and HDAC8.
  • Tatsuki Itoh; Motohiro Imano; Shozo Nishida; Masahiro Tsubaki; Takashi Nakayama; Nobuyuki Mizuguchi; Shigeaki Yamanaka; Masaki Tabuchi; Hiroshi Munakata; Shigeo Hashimoto; Akihiko Ito; Takao Satou
    JOURNAL OF NEURAL TRANSMISSION 120 3 361 - 374 2013年03月 [査読有り]
     
    We have previously reported free radical production after traumatic brain injury (TBI), which induces neural stem cell (NSC) degeneration and death. However, the effects of aging on NSC proliferation around the damaged area following TBI have not been investigated. Therefore, in this study, we used 10-week (young group) and 24-month-old (aged group) rat TBI models to investigate the effects of aging on NSC proliferation around damaged tissue using immunohistochemical and ex vivo techniques. Young and aged rats received TBI. At 1, 3 and 7 days after TBI, immunohistochemical and lipid peroxidation studies were performed. Immunohistochemistry revealed that the number of nestin-positive cells around the damaged area after TBI in the aged group decreased significantly when compared with those in the young group (P < 0.01). However, the number of 8-hydroxy-2'-deoxyguanosine-, 4-hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells and the level of peroxidation around the damaged area after TBI significantly increased in the aged group, compared with those in the young group (P < 0.01). Furthermore, almost all ssDNA-positive cells in young and aged groups co-localized with NeuN and nestin staining. Ex vivo studies revealed that neurospheres, which differentiated into neurons and glia in culture, could only be isolated from injured brain tissue in young and aged groups at 3 days after TBI. These results indicate that, although there were fewer NSCs that have the potential to differentiate into neurons and glia, these NSCs escaped free radical-induced degeneration around the damaged area after TBI in the aged rat brain.
  • Ji-Ye Kee; Aya Ito; Shozo Hojo; Isaya Hashimoto; Yoshiko Igarashi; Kazuhiro Tsukada; Tatsuro Irimura; Naotoshi Shibahara; Takashi Nakayama; Osamu Yoshie; Hiroaki Sakurai; Ikuo Saiki; Keiichi Koizumi
    Oncology Reports 29 3 975 - 982 2013年03月 [査読有り]
     
    Colorectal cancer (CRC) is a typical lifestyle-related disease, and it metastasizes mostly to the liver. It is important to understand the molecular mechanisms of CRC metastasis in order to design new and effective treatments for CRC patients. Chemokines are known to have antitumor effects as their chemoattractant properties stimulate the accumulation of infiltrating immune cells (TILs) in tumors. Chemokine (C-X-C motif) ligand 16 (CXCL16), also known as SR-PSOX, is a unique membrane-bound chemokine that induces the expression of its specific receptor CXCR6. We previously reported that the expression of CXCL16 by cancer cells enhances the recruitment of TILs, thereby improving the prognosis of CRC. It has since been reported that CXCL16/CXCR6 expression is involved in the metastasis of various types of cancer. However, there is no report of the association between CXCL16 expression and liver metastasis in CRC. In this study, we investigated the role of cancer-derived CXCL16 and the possibility of gene therapy using CXCL16. Therefore, we examined the metastasis of colon 38 SL4 cells to the liver in an experimental model. Following injection of cancer cells into the intraportal vein, CXCL16-expressing CRC cells drastically inhibited liver metastasis. We also found that CD8 T cells and natural killer T (NKT) cells, known as CXCR6-expressing cells, increased in CXCL16-expressing metastatic tissue. Collectively, the inhibitory effect on metastasis to the liver by CXCL16 was observed in NKT cell-depleted mice but not in CD8 T cell-depleted mice. These results demonstrate the inhibitory effect of CXCL16 on liver metastasis via NKT cells in CRC.
  • Takashi Nakayama; Tomonori Higuchi; Naoki Oiso; Akira Kawada; Osamu Yoshie
    ANTICANCER RESEARCH 32 4 1367 - 1373 2012年04月 [査読有り]
     
    Adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphomas (CTCLs) are known to frequently express CC chemokine receptor 4 (CCR4). Previously, we investigated the transcriptional control of CCR4 expression in ATLL and have found that an activating protein 1 (AP1) family member, FBJ murine osteosarcoma viral oncogene homolog (FOS)-related antigen 2 (FRA2), is consistently expressed at high levels in ATLL and, together with v-JUN avian sarcoma virus 17 oncogene homolog D (JUND), up-regulates the expression of CCR4 as well as that of several proto-oncogenes such as v-MYB myeloblastosis viral oncogene homolog (MYB), murine double minute 2 homolog (MDM2), and B-cell lymphoma 6 (BCL6). Here, we examined the expression of these genes in clinical samples of CTCLs. We detected the transcripts of FRA2, JUND, CCR4, MYB, MDM2, and BCL6 at high levels in CTCL skin lesions. Except for BCL6, we confirmed protein expression of FRA2, JUND, CCR4, MYB, and MDM2 in CTCL skin lesions. Furthermore, siRNA-mediated knockdown of FRA2 or JUND suppressed cell growth and the expression of CCR4, MYB, MDM2, and BCL6 in CTCL cell lines. Our results, thus, demonstrate the presence of a common oncogenic cascade initiated by FRA2/JUND in CCR4-expressing mature T-cell malignancies such as ATLL and CTCLs.
  • Haruo Ohtani; Takashi Nakayama; Osamu Yoshie
    PATHOLOGY INTERNATIONAL 61 11 645 - 651 2011年11月 [査読有り]
     
    Lymphocyte-rich gastric cancer (Ly-rich GC) is characterized by lymphoid stroma. To understand its formation, we studied the expression of a chemokine ligand (CCL)20 and its receptor CCR6 in 36 and 37 cases of Ly-rich- and conventional GC, respectively. Lymphoid tissues in the alimentary tract were studied in parallel. By quantitative polymerase chain reaction, Ly-rich GC contained CCL20 and CCR6 mRNAs at higher levels than conventional GC. By immunohistochemistry, CCL20 was expressed by cancer cells more frequently in Ly-rich GC than in conventional GC. This was comparable with its expression in epithelial cells of the alimentary tract lymphoid tissues. CCR6 was mostly expressed by dendritic cells (DC) and B cells in Ly-rich GC, which was also comparable with its expression in the alimentary tract lymphoid tissues. Cancer cells also expressed CCR6. However, its expression did not differ between Ly-rich- and conventional GC, nor was it related to the stage of cancer. Given that the CCL20-CCR6 axis is involved in the formation of alimentary tract lymphoid tissue, the similarity between the lymphoid stroma of Ly-rich GC and the alimentary tract lymphoid tissues supports the notion that it plays a significant role in the formation of lymphoid stroma in Ly-rich GC.
  • Takashi Nakayama; Yoshiko Watanabe; Naoki Oiso; Tomonori Higuchi; Akiko Shigeta; Nobuyuki Mizuguchi; Fuminori Katou; Kenji Hashimoto; Akira Kawada; Osamu Yoshie
    JOURNAL OF IMMUNOLOGY 185 11 6472 - 6479 2010年12月 [査読有り]
     
    Eotaxin-3/CCL26 is a functional ligand for CCR3 and abundantly produced by IL-4-/IL-13-stimulated vascular endothelial cells. CCL26 also functions as a natural antagonist for CCR1, CCR2, and CCR5. In this study, we report that CCL26 is yet a functional ligand for CX3CR1, the receptor for fractalkine/CX3CL1, which is expressed by CD16(+) NK cells, cytotoxic effector CD8(+) T cells, and CD14(low)CD16(high) monocytes. Albeit at relatively high concentrations, CCL26 induced calcium flux and chemotaxis in mouse L1.2 cells expressing human CX3CR1 but not mouse CX3CR1 and competed with CX3CL1 for binding to CX3CR1. In chemotaxis assays using human PBMCs, CCL26 attracted not only eosinophils but also CD16(+) NK cells, CD45RA(+)CD27(-)CD8(+) T cells, and CD14(low)CD16(high) monocytes. Intraperitoneal injection of CCL26 into mice rapidly recruited mouse eosinophils and intravenously transferred human CD16(+) NK cells into the peritoneal cavity. IL-4-stimulated HUVECs produced CCL26 and efficiently induced adhesion of cells expressing CX3CR1. Real-time PCR showed that skin lesions of psoriasis consistently contained CX3CL1 mRNA but not CCL26 mRNA, whereas those of atopic dermatitis contained CCL26 mRNA in all samples but CX3CL1 mRNA in only about half of the samples. Nevertheless, the skin lesions from both diseases consistently contained CX3CR1 mRNA at high levels. Thus, CCL26 may be partly responsible for the recruitment of cells expressing CX3CR1 in atopic dermatitis particularly when the expression of CX3CL1 is low. Collectively, CCL26 is another agonist for CX3CR1 and may play a dual role in allergic diseases by attracting eosinophils via CCR3 and killer lymphocytes and resident monocytes via CX3CR1. The Journal of Immunology, 2010, 185: 6472-6479.
  • Yoshiko Watanabe; Fuminori Katou; Haruo Ohtani; Takashi Nakayama; Osamu Yoshie; Kenji Hashimoto
    ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTOLOGY 109 5 744 - 752 2010年05月 [査読有り]
     
    Objective. The objective of this study was to clarify the prognostic significance of tumor-infiltrating lymphocytes (TILs) in oral squamous cell carcinoma (OSCC); the present study analyzed various TIL-related parameters. Study design. Immunohistochemistry was performed in 87 patients with OSCC for the following TIL-related parameters: nest-CD8(+) T cells, stromal CD8(+) T cells, CD4(+) T cells, total regulatory T cells (Tregs), CCR4(+) Tregs, ratio of nest CD8(+) T cells/CCR4(+) Tregs, and ratio of stromal CD8(+) T cells/CCR4(+) Tregs. Results. In univariate analyses, the following parameters were associated with decreased survival: few nest-and stromal CD8(+) T cells and more stromal CCR4(+) Tregs, but not total Tregs. Low ratios of nest and stromal CD8(+) T cell/CCR4(+) Treg were associated with worse survival. In multivariate analysis, the stromal CD8(+) T cell/CCR4(+) Treg ratio was an independent prognostic factor. Conclusion. Host immune responses in the stroma of OSCC affect the survival of the patients. The in situ balance between effector T cells and regulatory T cells is the most important factor predicting survival. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109: 744-752)
  • Keiichi Koizumi; Yurika Saitoh; Takayuki Minami; Nobuhiro Takeno; Koichi Tsuneyama; Tatsuro Miyahara; Takashi Nakayama; Hiroaki Sakurai; Yasuo Takano; Miyuki Nishimura; Toshio Imai; Osamu Yoshie; Ikuo Saiki
    JOURNAL OF IMMUNOLOGY 183 12 7825 - 7831 2009年12月 [査読有り]
     
    The recruitment of osteoclast precursors toward osteoblasts and subsequent cell-cell interactions are critical for osteoclast differentiation. Chemokines are known to regulate cell migration and adhesion. CX3CL1 (also called fractalkine) is a unique membrane-bound chemokine, that has dual functions for cells expressing its receptor CX3CR1: a potent chemotactic factor in its soluble form and a type of efficient cell adhesion molecule in its membrane-bound form. In this paper, we demonstrate a novel role of CX3CL1 in osteoblast-induced osteoclast differentiation. We found that osteoclast precursors selectively expressed CX3CR1, whereas CX3CL1 is expressed by osteoblasts. We confirmed that soluble CX3CL1 induced migration of bone marrow cells containing osteoclast precursors, whereas immobilized CX3CL1 mediated firm adhesion of osteoclast precursors. Furthermore, a blocking mAb against CX3CL1 efficiently inhibited osteoclast differentiation in mouse bone marrow cells cocultured with osteoblasts. Anti-CX3CL1 also significantly suppressed bone resorption in neonatal mice by reducing the number of bone-resorbing mature osteoclasts. Collectively, CX3CL1 expressed by osteoblasts plays an important role in osteoclast differentiation, possibly through its dual functions as a chemotactic factor and adhesion molecule for osteoclast precursors expressing CX3CR1. The CX3CL1-CX3CR1 axis may be a novel target for the therapeutic intervention of bone resorbing diseases such as rheumatoid arthritis, osteoporosis, and cancer bone metastasis. The Journal of Immunology, 2009, 183: 7825-7831.
  • Zhe Jin; Daisuke Nagakubo; Aiko-Konno Shirakawa; Takashi Nakayama; Akiko Shigeta; Kunio Hieshima; Yasuaki Yamada; Osamu Yoshie
    INTERNATIONAL JOURNAL OF CANCER 125 9 2229 - 2235 2009年11月 [査読有り]
     
    Human T-lymphotropic virus type 1 (HTLV-1), the etiological agent of adult T-cell leukemia (ATL), encodes the potent transcriptional activator Tax, which is required for HTLV-1-induced immortalization of T cells. CXCR7 is an atypical chemokine receptor frequently expressed by tumor cells and known to promote cell growth and survival. We found that HTLV-1-immortalized T cells expressing Tax consistently expressed CXCR7. Induction of Tax in JPX-9 upregulated CXCR7. Wild-type Tax efficiently activated the CXCR7 promoter via a proximal NF-kappa B site, while a mutant Tax selectively defective in NF-kappa B activation did not. CCX754, a synthetic CXCR7 antagonist, inhibited cell growth and increased apoptosis of HTLV-1-immortalized T cells. Knockdown of CXCR7 by small interfering RNA also reduced cell growth. Stable expression of CXCR7 in a CXCR7-negative ATL cell line promoted cell growth and survival. Taken together, CXCR7 is inducible by Tax and may play an important role in HTLV-1-induced immortalization of T cells by promoting growth and survival of HTLV-1-infected T cells. (C) 2009 UICC
  • T. Nakayama; K. Hieshima; T. Arao; Z. Jin; D. Nagakubo; A. K. Shirakawa; Y. Yamada; M. Fujii; N. Oiso; A. Kawada; K. Nishio; O. Yoshie
    Oncogene 27 23 3221 - 3232 2008年05月 
    Adult T-cell leukemia (ATL) is a mature CD4+ T-cell malignancy etiologically associated with human T-cell leukemia virus type 1 (HTLV-1). Primary ATL cells frequently express CCR4 at high levels. Since HTLV-1 Tax does not induce CCR4 expression, transcription factor(s) constitutively active in ATL may be responsible for its strong expression. We identified an activator protein-1 (AP-1) site in the CCR4 promoter as the major positive regulatory element in ATL cells. Among the AP-1 family members, Fra-2, JunB and JunD are highly expressed in fresh primary ATL cells. Consistently, the Fra-2/JunB and Fra-2/JunD heterodimers strongly activated the CCR4 promoter in Jurkat cells. Furthermore, Fra-2 small interfering RNA (siRNA) or JunD siRNA, but not JunB siRNA, effectively reduced CCR4 expression and cell growth in ATL cells. Conversely, Fra-2 or JunD overexpression promoted cell growth in Jurkat cells. We identified 49 genes, including c-Myb, BCL-6 and MDM2, which were downregulated by Fra-2 siRNA in ATL cells. c-Myb, BCL-6 and MDM2 were also downregulated by JunD siRNA. As Fra-2, these proto-oncogenes were highly expressed in primary ATL cells but not in normal CD4+ T cells. Collectively, aberrantly expressed Fra-2 in association with JunD may play a major role in CCR4 expression and oncogenesis in ATL. © 2008 Nature Publishing Group All rights reserved.
  • Emma Poole; Elizabeth Atkins; Takashi Nakayama; Osamu Yoshie; Ian Groves; Antonio Alcami; John Sinclair
    JOURNAL OF VIROLOGY 82 9 4250 - 4256 2008年05月 [査読有り]
     
    The product of the human cytomegalovirus (HCMV) gene UL144, expressed at early times postinfection, is located in the UL/b' region of the viral genome and is related to members of the tumor necrosis factor receptor superfamily, but it does not bind tumor necrosis factor superfamily ligands. However, UL144 does activate NF-kappa B, resulting in NF-kappa B-mediated activation of the cellular chemokine CCL22. Consistent with this finding, isolates of HCW lacking the UL/b' region show no such activation of CCL22. Recently, it has been suggested that activation of NF-kappa B is repressed by the product of the viral gene IE86: IE86 appears to block NF-kappa B binding to DNA but not nuclear translocation of NF-kappa B. Intriguingly, IE86 is detectable throughout an infection with the virus, so how UL144 is able to activate NF-kappa B in the presence of continued IE86 expression is unclear. Here we show that although IE86 does repress the UL144-mediated activation of a synthetic NF-kappa B promoter, it is unable to block UL144-mediated activation of the CCL22 promoter, and this lack of responsiveness to IE86 appears to be regulated by binding of the CREB transcription factor.
  • Shinji Kagami; Hidehisa Saeki; Yuichiro Tsunemi; Koichiro Nakamura; Yoshihiro Kuwano; Mayumi Komine; Takashi Nakayama; Osamu Yoshie; Kunihiko Tamaki
    EUROPEAN JOURNAL OF IMMUNOLOGY 38 3 647 - 657 2008年03月 [査読有り]
     
    CCL27 is one of the CC chemokines produced by epidermal keratinocytes and is suggested to be involved in the pathogenesis of inflammatory skin diseases. To clarify the contribution of CCL27 in skin inflammation, we created transgenic C57BL/6 mice that constitutively produce CCL27 in epidermal keratinocytes. These mice had high serum CCL27 levels and did not show any phenotypical change. Thus we stimulated these mice with various reagents by single and repeated application. Interestingly, only contact hypersensitivity to repeated application with fluorescein isothiocyanate was significantly enhanced in transgenic mice compared to non-transgenic mice. Under this condition, the numbers of inflammatory cells, CCR10-positive cells, CCR4-positive cells and cutaneous lymphocyte-associated antigen-positive cells were increased, and IL-4 mRNA expression was higher in the lesional skin of transgenic mice. Increased number of mast cells and higher serum IgE levels, which were similar to atopic dermatitis, were also observed. These results indicated that CCL27 modified inflammation by attracting CCR10-positive and CCR4-positive cells into the lesional skin, and may participate in the pathogenesis of Th2-shifted skin diseases such as atopic dermatitis.
  • Aiko-Konno Shirakawa; Daisuke Nagakubo; Kunio Hieshima; Takashi Nakayama; Zhe Jin; Osamu Yoshie
    JOURNAL OF IMMUNOLOGY 180 5 2786 - 2795 2008年03月 [査読有り]
     
    In the B cell lineage, CCR10 is known to be selectively expressed by plasma cells, especially those secreting IgA. In this study, we examined the regulation of CCR10 expression in terminally differentiating human B cells. As reported previously, IL-21 efficiently induced the differentiation of activated human CD19(+) B cells into IgD(-)CD38(+) plasma cells in vitro. A minor proportion of the resulting CD19(+)IgD(-)CD38(+) cells expressed CCR10 at low levels. 1,25-Dihydroxyvitamin D-3 (1,25-(OH)(2)D-3), the active metabolite of vitamine D-3, dramatically increased the proportion of CD19(+)IgD(-)CD38(+) cells expressing high levels of CCR10. The 1,25(OH)2D3 also increased the number of CCR10(+) cells expressing surface IgA, although the majority of CCR10(+) cells remained negative for surface IgA. Thus, 1,25-(OH)(2)D-3 alone may not be sufficient for the induction of IgA expression in terminally differentiating human B cells. To further determine whether 1,25-(OH)(2)D-3 directly induces CCR10 expression in terminally differentiating B cells, we next performed the analysis on the human CCR10 promoter. We identified a proximal Ets-1 site and an upstream potential vitamin D response element to be critical for the inducible expression of CCR10 by 1,25-(OH)(2)D-3. We confirmed the specific binding of Ets-1 and 1,25-(OH)(2)D-3-activated vitamin D receptor to the respective sites. In conclusion, 1,25-(OH)(2)D-3 efficiently induces CCR10 expression in terminally differentiating human B cells in vitro. Furthermore, the human CCR10 promoter is cooperatively activated by Ets-1 and vitamin D receptor in the presence of 1,25-(OH)(2)D-3.
  • Sumio Takegawa; Zhe Jin; Takashi Nakayama; Takashi Oyama; Kunio Hieshima; Daisuke Nagakubo; Aiko-Konno Shirakawa; Toyonori Tsuzuki; Shigeo Nakamura; Osamu Yoshie
    CANCER SCIENCE 99 2 296 - 302 2008年02月 [査読有り]
     
    Age-related Epstein-Barr virus-positive (EBV+) B-cell lymphoproliferative disorder (ALPD) is a disease entity identified from a large-scale re-survey of cases diagnosed as diffuse large B-cell lymphoma. ALPD is a group of EBV+ polymorphic B-cell lymphoma typically seen in elderly patients. An age-associated decline in host immunity against EBV might be partly responsible for the pathogenesis of ALPD. Histologically, ALPD is often characterized by a minor proportion of EBV-encoded RNA-positive tumor cells in a background of extensive cellular infiltration, similar to that of classical Hodgkin's lymphoma. In contrast to Hodgkin and Reed-Sternberg cells, ALPD tumor cells are clearly positive for B cell markers CD20 and/or CD79a. Hodgkin and Reed-Sternberg cells produce various chemokines, including CCL17 and CCL22, that attract chemokine receptor CCR4-expressing Th2 cells and regulatory T cells. Previously, we have shown that EBV-immortalized B cells also produce CCL17 and CCL22 through latent membrane protein 1 (LMP1)-mediated activation of nuclear factor kappa B. Here we examined expression of CCL17 and CCL22 in ALPD. ALPD tumor cells were often heterogeneous in size in accordance with the differential expression of EBV latent genes at the single cell level. LMP1-expressing tumor cells were typically large in size and selectively positive for CCL17 and CCL22. CCR4(+) cells and forkhead box protein 3(+) regulatory T cells were abundantly present, and the majority of forkhead box protein 3(+) cells were CCR4(+). Collectively, our data show production of CCL17 and CCL22 by LMP1(+) large-sized tumor cells and accumulation of CCR4-expressing cells including regulatory T cells in ALPD.
  • Kunio Hieshima; Daisuke Nagakubo; Takashi Nakayama; Aiko-Konno Shirakawa; Zhe Jin; Osamu Yoshie
    JOURNAL OF IMMUNOLOGY 180 2 931 - 939 2008年01月 [査読有り]
     
    Adult T cell leukemia is a mature CD4(+) T cell malignancy which predominantly expresses CCR4 and is etiologically associated with human T cell leukemia virus type 1 (HTLV-1). Because HTLV-1 transmission depends on close cell-cell contacts, HTLV-1-infected T cells may preferentially interact with CCR4(+)CD4(+) T cells for efficient viral transmission. In terms of gene expression and protein secretion, we found a strong correlation between HTLV-1 Tax oncoprotein and CCL22, a CCR4 ligand, in HTLV-1-infected T cells. Transient Tax expression in an HTLV-1-negative T cell line activated the CCL22 promoter and induced CCL22. Additionally, tax gene knockdown by small interference RNA reduced CCL22 expression in the infected T cells. These findings indicate that CCL22 is a cellular target gene of Tax. In chemotaxis assays, the culture supernatants of HTLV-1-infected T cells selectively attracted CCR4(+)CD4(+) T cells in PBMCs. This was blocked by pretreating the supernatants with anti-CCL22 Ab or PBMCs with a synthetic CCR4 antagonist. In coculture experiments, primary CCR4(+)CD4(+) T cells significantly adhered to Tax-expressing cells. This adhesion was blocked by the CCR4 antagonist or pertussis toxin. Interestingly, CCR4 was redistributed to the contact region, and in some cases, this was accompanied by a polarized microtubule-organizing center, which is an indicator of virological synapse formation, in the infected T cells. Finally, anti-CCL22 Ab treatment also blocked HTLV-1 transmission to primary CD4(+) T cells in coculture experiments with HTLV-1 producer cells. Thus, HTLV-1-infected T cells produce CCL22 through Tax and selectively interact with CCR4(+)CD4(+) T cells, resulting in preferential transmission of HTLV-1 to CCR4(+)CD4(+) T cells.
  • Fuminori Katou; Haruo Ohtani; Yoshiko Watanabe; Takashi Nakayama; Osamu Yoshie; Kenji Hashimoto
    CANCER RESEARCH 67 23 11195 - 11201 2007年12月 [査読有り]
     
    The significance of tumor-infiltrating lymphocytes (TIL) has attracted much attention in relation to the prognosis of patients. We herein examined the activation status of the TILs in relation to the tumor microenvironment. By using frozen sections of human early-stage tongue cancers (n = 22), the TILs in the cancer nests and those in the cancer stroma were compared for the expression of PD-1, NKG2A, NKG2D, CD69, and Ki-67. The lymphocytes in oral lichen planus, an active immune response-mediated mucosal disease, were also analyzed for comparison purposes. All of the cancer specimens were abundantly infiltrated by CD8(+) T cells and CD56(+) natural killer (NK) cells in the stroma, as well as in the tumor nest. The tumor nest-infiltrating (intraepith,elial) CD8(+) T cells frequently expressed PD-1, an inhibitory receptor, in sharp contrast to those in the stroma or in the lichen planus. Conversely, the intraepithelial CD8(+) T cells only infrequently expressed NKG2D), an activating receptor, in contrast to those in the stroma or in the lichen planus. No intraepithelial CD8(+) T cells expressed Ki-67, a proliferation-associated marker, whereas those in the stroma frequently expressed it. Furthermore, the intraepithelial NK cells expressed NKG2A, an inhibitory receptor, more frequently than those in the stroma or the lichen planus. Collectively, the intraepithelial CD8(+) T cells and NK cells are phenotypically inactivated, whereas stromal counterparts are phenotypically just as active as those in the lichen planus. These results suggest the first-step occurrence of an immune evasion mechanism in the tumor nest of oral squamous cell carcinoma.
  • Shozo Hojo; Keiichi Koizumi; Koichi Tsuneyama; Yoshihisa Arita; Zhengguo Cui; Kanna Shinohara; Takayuki Minami; Isaya Hashimoto; Takashi Nakayama; Hiroaki Sakurai; Yasuo Takano; Osamu Yoshie; Kazuhiro Tsukada; Ikuo Saiki
    CANCER RESEARCH 67 10 4725 - 4731 2007年05月 [査読有り]
     
    CXCL16 is a new member of the chemokine superfamily, which exists in a transmembrane as well as a soluble form. Its receptor CXCR6 is detected on CD4(+) T cells, CD8(+) T cells, and natural killer T cells. Here, we report a significant correlation of CXCL16 expression by tumor cells with the infiltration of T cells and prognosis in colorectal cancer (CRC). We first found that CXCL16 expression was consistently up-regulated more in tumor tissues than in normal mucosa derived from the same CRC patients. Four human CRC cell lines also expressed CXCL16 mRNA and secreted soluble CXCL16. We next examined the expression of CXCL16 and infiltration of lymphocytes in CRC specimens (n = 58) by immunohistochemistry. CRC patients with high levels of CXCL16 expression (n = 43) had higher levels of CD4(+) and CD8(+) tumor-infiltrating lymphocytes (TIL; P < 0.01) than those with tow levels of CXCL16 expression (n = 15). Furthermore, the high CXCL16 expression group showed significantly better prognosis than the low CXCL16 expression group (P < 0.05). Collectively, our data suggest that the expression of CXCL16 by tumor cells enhances the recruitment of TILs, thereby bringing about a better prognosis in CRC. Thus, CXCL16 is a new prognostic biomarker and may be useful for the development of a more effective therapeutic strategy for CRC.
  • Daisuke Nagakubo; Zhe Jin; Kunio Hieshima; Takashi Nakayama; Aiko-Konno Shirakawa; Yuetsu Tanaka; Hitoshi Hasegawa; Tomayoshi Hayashi; Kunihiro Tsukasaki; Yasuaki Yamada; Osamu Yoshie
    INTERNATIONAL JOURNAL OF CANCER 120 7 1591 - 1597 2007年04月 [査読有り]
     
    Adult T-cell leukemia (ATL) is a highly aggressive mature CD4(+) T-cell malignancy that is etiologically associated with human T-lymphotropic virus Type I (HTLV-1). ATL is characterized by frequent infiltration of lymph nodes, spleen, liver, skin and gut. Previously, we and others have shown that the majority of ATL cases are strongly positive for CCR4, which may explain the frequent skin invasion of ATL. Here, we examined whether ATL cells express CCR9, which is involved in T-cell homing to the gastrointestinal tract. Human T cell lines carrying HTLV-1 consistently expressed CCR9 together with the HTLV-1-encoded transcriptional activator Tax. Although ATL cells freshly isolated from peripheral blood hardly expressed CCR9, ATL cells cultured for I day consistently expressed CCR9 in parallel with the upregulation of Tax. Induction of Tax by Cd2+ in JPX-9, a subline of Jurkat human T cell line carrying Tax under the control of metallothionein promoter, led to upregulation of CCR9. A luciferase reporter gene under the control of the CCR9 promoter was expressed by cotransfection of an expression vector for Tax or in Cd2+-treated JPX-9 cells. Furthermore, immunohistochemical staining demonstrated that ATL cells infiltrating gastrointestinal tract were frequently positive for CCR9. Collectively, CCR9 is inducible in ATL cells expressing Tax and may play a role in the gastrointestinal involvement of ATL. (c) 2007 Wiley-Liss, Inc.
  • 単純ヘルペスウイルス1型に対するケモカインの抗ウイルス活性の検討
    白根 授美; 中山 隆志; 義江 修; 三島 弘; 下村 嘉一
    日本眼科学会雑誌 111 臨増 157 - 157 (公財)日本眼科学会 2007年03月
  • Hitomi Harasawa; Yasuaki Yamada; Kunio Hieshima; Zhe Jin; Takashi Nakayama; Osamu Yoshie; Kazuhiro Shimizu; Hiroo Hasegawa; Tomayoshi Hayashi; Yoshitaka Imaizumi; Shuichi Ikeda; Hiroshi Soda; Hisashi Soda; Sunao Atogami; Yumi Takasaki; Kunihiro Tsukasaki; Masao Tomonaga; Ken Murata; Kazuyuki Sugahara; Kazuto Tsuruda; Shimeru Kamihira
    LEUKEMIA & LYMPHOMA 47 10 2163 - 2173 2006年10月 [査読有り]
     
    Adult T-cell leukemia/lymphoma (ATLL) is a malignancy of mature T-cell origin with multi-organ involvement. Because the chemokine receptors play crucial roles in tissue-specific homing of mature lymphocytes, particular chemokine receptors expressed on ATLL cells may be involved in their tissue infiltration. We thus performed a comprehensive survey on the chemokine receptor expression in ATLL. ATLL cells expressed transcripts of CCR1, CCR4, CCR7, CCR8, CCR10 and CXCR4 but hardly expressed those of CCR2, CCR3, CCR5, CCR6, CCR9, CXCR1, CXCR2, CXCR3 and CXCR5. These results were confirmed at the protein level by flow cytometric analysis. Notably, patients who have skin lesions showed significantly higher levels of CCR10 mRNA expression than patients without skin lesions. ATLL cells migrated efficiently to the CCR4 ligand, CCL22, and moderately to the CCR10 ligands, CCL27 and CCL28. Moreover, ATLL skin lesions consistently contained transcripts of CCR10 and its ligands CCL27 and CCL28 besides those of CCR4 and its ligands CCL17 and CCL22 that have been reported previously. Collectively, the frequent co-expression of CCR4 and CCR10, the known pair of skin-homing chemokine receptors, may play an important role in ATLL invasion into the skin.
  • Yuichiro Tsunemi; Hidehisa Saeki; Koichiro Nakamura; Daisuke Nagakubo; Takashi Nakayama; Osamu Yoshie; Shinji Kagami; Kiyo Shimazu; Takafumi Kadono; Makoto Sugaya; Mayumi Komine; Koji Matsushima; Kunihiko Tamaki
    EUROPEAN JOURNAL OF IMMUNOLOGY 36 8 2116 - 2127 2006年08月 [査読有り]
     
    CC chemokine ligand (CCL)17 is implicated in the pathogenesis of atopic dermatitis (AD). To study the effect of CCL17 produced by keratinocytes (KC) during inflammation, we created transgenic (Tg) mice in which CCL17 is overexpressed in KC. Th2-type contact hypersensitivity (CHS) was enhanced and Th1-type CHS was suppressed in these mice. Increased numbers of CC chemokine receptor (CCR)4(+) cells and mast cells infiltrated in Tg mice. Levels of IL-4 mRNA were higher and those of IFN-gamma mRNA were lower in both acute and chronic CHS. Higher levels of serum IgE were observed after CHS. Numbers of CCR4(+) cells among PBMC were increased in Tg mice challenged acutely on the trunk. Chronic irritation with croton oil induced dermatitis and an elevation of serum IgE levels. Tg mice showed enhanced ear swelling after tape stripping. CCL17 was thought to modify the inflammation caused by sensitizing reagents as well as irritant reagents by attracting CCR4(+) cells into the lesional skin and creating a Th2-dominant condition. AD-like conditions such as increased number of mast cells and elevated levels of serum IgE were observed. Thus, CCL17 may participate in the pathogenesis of skin diseases such as AD by regulating both allergic and irritant inflammation.
  • T Nakayama; J Shirane; K Hieshima; M Shibano; M Watanabe; Z Jin; D Nagakubo; T Salto; Y Shimomura; O Yoshie
    VIROLOGY 350 2 484 - 492 2006年07月 [査読有り]
     
    Antimicrobial peptides are a diverse family of small, mostly cationic polypeptides that kill bacteria, fungi and even some enveloped viruses, while chemokines are a group of mostly cationic small proteins that induce directed migration of leukocytes through interactions with a group of seven transmembrane G protein-coupled receptors. Recent studies have shown that antimicrobial peptides and chemokines have substantially overlapping functions. Thus, while some antimicrobial peptides are chemotactic for leukocytes, some chemokines can kill a wide range of bacteria and fungi. Here, we examined a possible direct antiviral activity of chemokines against an enveloped virus HSV-1. Among 22 human chemokines examined, chemokines such as MIP-1 alpha/CCL3,MIP-1 beta/CCL4 and RANTES/CCL5 showed a significant direct antiviral activity against HSV-1. It is intriguing that these chemokines are mostly known to be highly expressed by effector CD8(+) T cells. The chemokines with a significant anti-HSV-1 activity commonly bound to HSV-1 virions via envelope glycoprotein gB. Electron microscopy revealed that the chemokines with a significant anti-HSV-1 activity were commonly capable of generating pores in the envelope of HSV-1. Thus, some chemokines have a significant direct antiviral activity against HSV-1 in vitro and may have a potential role in host defense against HSV-1 as a direct antiviral agent. (c) 2006 Elsevier Inc. All rights reserved.
  • H Hasegawa; A Inoue; M Kohno; M Muraoka; T Miyazaki; M Terada; T Nakayama; O Yoshie; M Nose; M Yasukawa
    ARTHRITIS AND RHEUMATISM 54 4 1174 - 1183 2006年04月 [査読有り]
     
    Objective. Mononuclear cell infiltration of the salivary glands is a major feature of Sjogren's syndrome (SS) and its animal model. Local generation of chemokines and the presence of chemokine receptors on the infiltrating cells may be involved in this process. We undertook the present study to investigate the expression of chemokines during the development of autoimmune sialadenitis in MRL/lpr mice and the therapeutic effect of chemokine antagonists on sialadenitis. Methods. NH2-terminal-truncated interferon-inducible protein 10 (IP-10)/CXCL10 analogs were transfected into a nonmetastatic fibroblastoid cell line, MRL/N-1, and injected subcutaneously into MRL/lpr mice, and the effects on sialadenitis were monitored. Results. IP-10 analogs truncated by 5 or more amino acid residues from the N-terminal failed to induce chemotaxis and calcium influx by CXCR3-expressing cells. Of these, the most potent antagonist (AT) (IP-10-AT) was a molecule with methionine added after removal of the 5 N-terminal amino acid residues. Significantly increased expression of the Th1-associated chemokines IP-10, monokine induced by interferon-gamma/ CXCL9, and interferon-inducible T cell chemo-attractant/CXCL11 was induced in the ductal epithelium by interferon-gamma produced in the salivary glands, whereas expression of the Th2-associated chemokines thymus and activation-regulated chemokine (TARC)/ CCL17 and monocyte-derived chemokine/CCL22 was almost undetectable during sialadenitis. Inoculation of IP-10-AT into MRL/lpr mice during the early stage of sialadenitis significantly reduced periductal mononuclear cell infiltration and parenchymal destruction compared with these features in control and TARC-AT-bearing mice. This was due to a significant reduction in infiltration of CXCR3+ T cells, predominantly Th1 cells, resulting in decreased interferon-gamma production. Conclusion. We prepared a novel potent IP-10 antagonist and demonstrated its ability to ameliorate the progression of autoimmune sialadenitis. This agent may provide a new therapeutic approach to SS.
  • Eliane Shizuka Nakamura; Keiichi Koizumi; Mitsuo Kobayashi; Yurika Saitoh; Yoshihisa Arita; Takashi Nakayama; Hiroaki Sakurai; Osamu Yoshie; Ikuo Saiki
    CLINICAL & EXPERIMENTAL METASTASIS 23 1 9 - 18 2006年03月 [査読有り]
     
    Chemokines are now known to play an important role in cancer growth and metastasis. Here we report that differentiating osteoclasts constitutively produce CCL22 (also called macrophage-derived chemokine) and potentially promote bone metastasis of lung cancer expressing its receptor CCR4. We first examined expression of chemokines by differentiating osteoclasts. CCL22 was selectively upregulated in osteoclast-like cells derived from RAW264.7 cells and mouse bone marrow cells upon stimulation with RANKL (receptor activator of nuclear factor-kappa B ligand). In addition, a human lung cancer cell line SBC-5 that efficiently metastasized to bone when intravenously injected into NK cell-depleted SCID mice was found to express CCR4. Stimulation of SBC-5 cells with CCL22 induced cell migration and also enhanced phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase (ERK). Furthermore, immunohistochemical analysis of bone metastasis lesions demonstrated close co-localization of tartrate-resistant alkaline phosphatase (TRAP)-positive osteoclasts expressing CCL22 and SBC-5 cells expressing CCR4. Collectively, these results suggest that osteoclasts may promote bone metastasis of cancer cells expressing CCR4 in the bone marrow by producing its ligand CCL22.
  • K Yasumoto; K Koizumi; A Kawashima; Y Saitoh; Y Arita; K Shinohara; T Minami; T Nakayama; H Sakurai; Y Takahashi; O Yoshie; Saiki, I
    CANCER RESEARCH 66 4 2181 - 2187 2006年02月 [査読有り]
     
    Peritoneal carcinomatosis is a frequent cause of death in patients with advanced gastric carcinoma. Because chemokines are now considered to play an important role in the metastasis of various malignancies, we hypothesized that they may be involved in the development of peritoneal carcinomatosis by gastric carcinoma. Human gastric carcinoma cell lines, which were all highly efficient in generating malignant ascites in nude mice upon i.p. inoculation, selectively expressed CXCR4 mRNA and protein. In particular, NUGC4 cells expressed CXCR4 mRNA at high levels and showed vigorous migratory responses to its ligand CXCL12. CXCL12 enhanced proliferation and rapid increases in phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase of NUGC4 cells. We also showed that AMD3100 (a specific CXCR4 antagonist) effectively reduced tumor growth and ascitic fluid formation in nude mice inoculated with NUGC4 cells. Additionally, we examined human clinical samples. Malignant ascitic fluids from patients with peritoneal carcinomatosis contained high concentrations of CXCL12 (4.67 ng/mL). Moreover, immunohistochemical analysis showed that 22 of 33 primary gastric tumors with peritoneal metastasis were positive for CXCR4 expression (67%), whereas only 4 of 16,with other distant metastasis were positive (25%). Notably, 22 of 26 CXCR4-expressing primary tumors developed peritoneal metastases (85%). CXCR4 positivity of primary gastric carcinomas significantly correlated with the development of peritoneal carcinomatosis (P < 0.001). Collectively, our results strongly suggest that the CXCR4/CXC12 axis plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. Thus, CXCR4 may be a potential therapeutic target for peritoneal carcinomatosis of gastric carcinoma.
  • Y Watanabe; T Nakayama; D Nagakubo; K Hieshima; Z Jin; F Katou; K Hashimoto; O Yoshie
    JOURNAL OF IMMUNOLOGY 176 2 848 - 856 2006年01月 [査読有り]
     
    The nervous systems affect immune functions by releasing neurohormones and neurotransmitters. A neurotransmitter dopamine signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. The secondary lymphoid tissues are highly innervated by sympathetic nerve fibers that store dopamine at high contents. Lymphocytes also produce dopamine. In this study, we examined expression and function of dopamine receptors in lymphocytes. We found that D3 was the predominant subtype of dopamine receptors in the secondary lymphoid tissues and selectively expressed by naive CD8(+) T cells of both humans and mice. Dopamine induced calcium flux and chemotaxis in mouse L1.2 cells stably expressing human D3. These responses were almost completely inhibited by pertussis toxin, indicating that D3 was coupled with the G alpha i class of G proteins. Consistently, dopamine selectively induced chemotactic responses in naive CD8(+) T cells of both humans and mice in a manner sensitive to pertussis toxin and D3 antagonists. Dopamine was highly synergistic with CCL19, CCL21, and CXCL12 in induction of chemotaxis in naive CD8(+) T cells. Dopamine selectively induced adhesion of naive CD8(+) T cells to fibronectin and ICAM-1 through activation of integrins. Intraperitoneal injection of mice with dopamine selectively attracted naive CD8(+) T cells into the peritoneal cavity. Treatment of mice with a D3 antagonist U-99194A selectively reduced homing of naive CD8(+) T cells into lymph nodes. Collectively, naive CD8(+) T cells selectively express D3 in both humans and mice, and dopamine plays a significant role in migration and homing of naive CD8(+) T cells via D3.
  • H Musha; H Ohtani; T Mizoi; M Kinouchi; T Nakayama; K Shiiba; K Miyagawa; H Nagura; O Yoshie; Sasaki, I
    INTERNATIONAL JOURNAL OF CANCER 116 6 949 - 956 2005年10月 [査読有り]
     
    T cell infiltration in colorectal cancer is associated with a favorable prognosis, suggesting an occurrence of a certain degree of anti-tumor immunity. T helper type 1 (Th1) and Th2 cells are now known to selectively express CC-chemokine receptor 5 (CCR5)/CXC-chemokine receptor 3 (CXCR3) and CCR4, respectively. To clarify the mechanism of T cell infiltration, we examined in situ expression of these chemokine receptors and their respective chemokine ligands in 40 cases of human colorectal cancer. Immunohistochemistry showed a predominant accumulation of T cells expressing CCR5 and CXCR3 mainly along the invasive margin, whereas those expressing CCR4 were rare. Flow cytometric analysis showed that more than half of CD8(+) T cells and a fraction of CD4(+) cells isolated from fresh tumor tissues co-expressed CCR5 and CXCR3, and CD8(+) T cells and CD4+ cells predominantly produced interferon-gamma (IFN-gamma) over interleukin-4 (IL-4) after in vitro stimulation. RANTES/CCL5, a ligand of CCR5, was localized within infiltrating CD8+ T cells in a granular pattern, whereas IP-10/CXCL10, a ligand of CXCR3, was localized in cancer cells and macrophages along the invasive margin. These data were consistent with an active recruitment of T cells expressing CCR5 or CXCR3 into the invasive margin of colorectal cancer. With the previous clinicopathological studies showing a favorable prognostic impact of T cell infiltration in colorectal cancer, our study supports the occurrence of a certain level of Th1-shifted cellular immune responses in human colorectal cancer. (C) 2005 Wiley-Liss, Inc.
  • JQ Gao; T Sugita; N Kanagawa; K Iida; N Okada; H Mizuguchi; T Nakayama; T Hayakawa; O Yoshie; Y Tsutsumi; T Mayumi; S Nakagawa
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 28 6 1066 - 1070 2005年06月 [査読有り]
     
    Considerable attention has recently been paid to the application of chemokines to cancer immunotherapy because of their chemotactic affinity for a variety of immune cells and because several chemokines are strongly angiostatic. In the present study, the recombinant adenovirus vectors encoding chemokine CCL19 or XCL1 in an El cassette (AdRGD-mCCL19 and AdRGD-mXCL1) were developed. The constructed fiber-mutant adenovirus vector, which contained the integrin-targeting Arg-Gly-Asp (RGD) sequence in the fiber knob, notably enhanced the transfection efficiency to OV-HM ovarian carcinoma cells compared to that induced by conventional adenovirus vector. The results of an in vitro chemotaxis assay for chemokine-encoding vector demonstrated that both AdRGD-mCCL19 and AdRGD-mXCL1 could induce the migration of cells expressing specific chemokine receptors. Of the two chemokine-en coding vectors evaluated in vivo, AdRGD-mCCL19 showed significant tumor-suppressive activity in R6C3F1 mice via transduction into OV-HM cells, whereas XCL1 did not exhibit any notable anti-tumor effects, suggesting that CCL19 may be a candidate for cancer immunotherapy.
  • N. Okada; 義江 修; 中山 隆志; N. Mori; R. Koretomo T; Fujita A. Yamamoto; Y. Okada; H. Mizuguchi; T. Hayakawa; S. Nakagawa; T. Mayumi
    Gene Therapy 12 2 129 - 139 2005年01月
  • K Hieshima; Y Kawasaki; H Hanamoto; T Nakayama; D Nagakubo; A Kanamaru; O Yoshie
    JOURNAL OF IMMUNOLOGY 173 6 3668 - 3675 2004年09月 [査読有り]
     
    CCL25 (also known as thymus-expressed chemokine) and CCL28 (also known as mucosae-associated epithelial chemokine) play important roles in mucosal immunity by recruiting IgA Ab-secreting cells (ASCs) into mucosal lamina propria. However, their exact roles in vivo still remain to be defined. In this study, we first demonstrated in mice that IgA ASCs in small intestine expressed CCR9, CCR10, and CXCR4 on the cell surface and migrated to their respective ligands CCL25, CCL28, and CXCL12 (also known as stromal cell-derived factor 1), whereas IgA ASCs in colon mainly expressed CCR10 and CXCR4 and migrated to CCL28 and CXCL12. Reciprocally, the epithelial cells of small intestine were immunologically positive for CCL25 and CCL28, whereas those of colon were positive for CCL28 and CXCL12. Furthermore, the venular endothelial cells in small intestine were positive for CCL25 and CCL28, whereas those in colon were positive for CCL28, suggesting their direct roles in extravasation of IgA ASCs. Consistently, in mice orally immunized with cholera toxin (CT), anti-CCL25 suppressed homing of CT-specific IgA ASCs into small intestine, whereas anti-CCL28 suppressed homing of CT-specific IgA ASCs into both small intestine and colon. Reciprocally, CT-specific ASCs and IgA titers in the blood were increased in mice treated with anti-CCL25 or anti-CCL28. Anti-CXCL12 had no such effects. Finally, both CCL25 and CCL28 were capable of enhancing alpha(4) integrin-dependent adhesion of IgA ASCs to mucosal addressin cell adhesion molecule-1 and VCAM-1. Collectively, CCL25 and CCL28 play essential roles in intestinal homing of IgA ASCs primarily by mediating their extravasation into intestinal lamina propria.
  • T Nakayama; Y Kato; K Hieshima; D Nagakubo; Y Kunori; T Fujisawa; O Yoshie
    JOURNAL OF IMMUNOLOGY 173 3 2078 - 2083 2004年08月 [査読有り]
     
    Liver-expressed chemokine (LEC)/CCL16 is a human CC chemokine that is constitutively expressed by the liver parenchymal cells and present in the normal plasma at high concentrations. Previous studies have shown that CCL16 is a low-affinity ligand for CCR1, CCR2, CCR5, and CCR8 and attracts monocytes and T cells. Recently, a novel histamine receptor termed type 4 (H4) has been identified and shown to be selectively expressed by eosinophils and mast cells. In this study, we demonstrated that CCL16 induced pertussis toxin-sensitive calcium mobilization and chemotaxis in murine L1.2 cells expressing H4 but not those expressing histamine receptor type 1 (H1) or type 2 (H2). CCL16 bound to H4 with a K-d of 17 nM. By RT-PCR, human and mouse eosinophils express H4 but not H3. Accordingly, CCL16 induced efficient migratory responses in human and mouse eosinophils. Furthermore, the responses of human and mouse eosinophils to CCL16 were effectively suppressed by thioperamide, an antagonist for H3 and H4. Intravenous injection of CCL16 into mice induced a rapid mobilization of eosinophils from bone marrow to peripheral blood, which was also suppressed by thioperamide. Collectively, CCL16 is a novel functional ligand for H4 and may have a role in trafficking of eosinophils.
  • T Shimaoka; T Nakayama; K Hieshima; N Kume; N Fukumoto; M Minami; K Hayashida; T Kita; O Yoshie; S Yonehara
    JOURNAL OF BIOLOGICAL CHEMISTRY 279 26 26807 - 26810 2004年06月 [査読有り]
     
    Chemokines are a family of cytokines that induce directed migration of various types of leukocytes through specific interactions with a group of seven transmembrane receptors. Scavenger receptors are a heterogenous family of transmembrane molecules that commonly bind and uptake oxidized low density lipoprotein and bacteria. Here, we show that not only CXC chemokine 16 (CXCL16)/SR-PSOX, a transmembrane chemokine with scavenger receptor activity, but also 12 out of 15 chemokines examined efficiently bound scavenger receptor ligands in competition with cells expressing their specific chemokine receptors. Furthermore both the chemotactic and scavenger receptor activities of SR-PSOX/CXCL16 were similarly impaired in a series of mutants altered in the chemokine domain, indicating that SR-PSOX/CXCL16 binds scavenger receptor ligands as well as CXCR6 using highly overlapping binding motifs. Taken together, chemokines generally have scavenger receptor-like activity through their receptor-binding domain, suggesting a close evolutionary relationship between chemokines and scavenger receptors.
  • J Shirane; T Nakayama; D Nagakubo; D Izawa; K Hieshima; Y Shimomura; O Yoshie
    CURRENT EYE RESEARCH 28 5 297 - 306 2004年05月 [査読有り]
     
    Purpose. CC chemokine-ligand 20 (CCL20) is known to be selectively expressed by surface-lining mucosal epithelial cells and skin epidermal keratinocytes and to attract cells such as immature dendritic cells and effector T cells via CCR6. This study evaluated the ability of corneal epithelial cells and stromal keratocytes to produce CCL20 in vitro and in vivo. Methods. Human corneal epithelial cells (HCE) and corneal keratocytes (HCK) were treated without or with various cytokines and expression of CCL20 mRNA and secreion of its protein were evaluated by RT-PCR and ELISA. Induction of CCL20 mRNA in HCE and HCK was also examined upon in vitro infection with HSV-1. Using a mouse model of herpetic stromal keratitis (HSK), induction of CCL20 expression and accumulation of cells expressing CCR6 were evaluated by RT-PCR and immunohistochemistry. Results. Not only corneal epithelial cells but also stromal keratocytes efficiently expressed CCL20 mRNA and protein upon stimulation with IL-1beta and TNF-alpha. In vitro infection with HSV-1 also induced CCL20 mRNA in both types of cells. In a mouse herpetic stromal keratitis model, prominent accumulation of CCL20 and CCR6 mRNA was revealed in HSV-1-infected corneas. Furthermore, immunohistochemistry demonstrated production of CCL20 by corneal epithelial cells as well as, stromal keratocytes and stromal infiltration of DEC205(+) dendritic cells, CD4(+) T cells and CD8(+) T cells. Double staining revealed that CCR6-expressing cells were mostly MHC class II+ dendritic cells. Conclusions. Not only epithelial cells but also stromal keratocytes are efficient producers of CCL20 in the cornea and recruit CCR6-expressing cells such as dendritic cells into inflamed cornea.
  • N Okada; JQ Gao; A Sasaki; M Niwa; Y Okada; T Nakayama; O Yoshie; H Mizuguchi; T Hayakawa; T Fujita; A Yamamoto; Y Tsutsumi; T Mayumi; S Nakagawa
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 317 1 68 - 76 2004年04月 [査読有り]
     
    In this study, we screened the anti-tumor activity of murine chemokines including CCL17. CCL19, CCL20, CCL21, CCL22, CCL27, XCL1, and CX3CL1 by inoculating murine B16BL6, CT26, or OV-HM tumor cells, all of which were transfected with chemokine-expressing fiber-mutant adenovirus vector, into immunocompetent mice. A tumor-suppressive effect was observed in mice inoculated with CCL19/B16BL6 and XCK1/B16BL6, and CCL22/OV-HM showed considerable retardation in tumor growth. In the cured mice inoculated with CCL22/OV-HM, a long-term specific immune protection against parental tumor was developed. However, we were unable to identify the chemokine that had a suppressive activity common to all three tumor models. Furthermore, an experiment using chemokine-transfected B16BL6 cells was also performed on mice sensitized with melanoma-associated antigen. A drastic enhancement of the frequency of complete rejection was observed in mice inoculated with CCL17-, CCL19-, CCL22-, and CCL27-transfected B16BL6. Altogether, our results suggest that the tumor-suppressive activity of chemokine-gene immunotherapy is greatly influenced by the kind of tumor and the activation state of the host's immune system. (C) 2004 Elsevier Inc. All rights reserved.
  • CCL20のヒト角膜組織における発現誘導とマウスヘルペス性角膜実質炎における役割
    白根 授美; 下村 嘉一; 中山 隆志; 長久保 大輔; 稗島 州雄; 義江 修
    日本眼科学会雑誌 108 臨増 277 - 277 (公財)日本眼科学会 2004年03月
  • Gao JQ; 義江 修; 中山 隆志; Alexandre LS; Tsuda Y; Katayama; K Eto Y; Sekiguchi F; Mizuguchi H; Hayakawa; T; Tsutsumi Y; Mayumi T; Nakagawa S
    Pharmazie 59 3 238 - 239 2004年03月
  • N Ohtani; H Ohtani; T Nakayama; H Naganuma; E Sato; T Imai; H Nagura; O Yoshie
    LABORATORY INVESTIGATION 84 3 368 - 375 2004年03月 [査読有り]
     
    Chronic gastritis is frequently associated with infection of Helicobacter pylori and characterized by tissue infiltration of neutrophils, lymphocytes, and plasma cells. To address the mechanism of lymphocyte infiltration in chronic gastritis, we examined the expression of chemokines and their receptors using frozen sections of chronic gastritis, obtained from 23 patients who underwent gastrectomy for gastric cancer. By immuno histochemistry, lymphocytes in inflamed gastric mucosa expressed CCR5 abundantly, CXCR3 less frequently, and CCR4 sparsely. The numbers of CCR5(+) cells, which were composed of mainly CD8(+) and partly CD4(+) T cells, were positively correlated with the degree of neutrophil infiltration, and decreased in areas with intestinal metaplasia or mucosal atrophy. RANTES/CCL5, one of the ligands of CCR5, was localized mainly in CD8(+) and partly CD4(+) T cells with a characteristic dotted pattern, and such lymphocytes were most densely distributed around the neck region of gastric glands. In situ hybridization confirmed the expression of CCLS mRNA in these cells, and immunoelectron microscopy revealed localization of CCL5 in the membrane-bound granules, which most probably corresponded to the cytolytic granules of cytotoxic T cells. The numbers of CCL5(+) lymphocytes showed a close correlation with the degree of neutrophil infiltration and markedly decreased in intestinal metaplasia. In conclusion, our data suggest that, together with neutrophils, CCL5+ T cells, presumably activated cytotoxic T cells, would play important roles in the active inflammatory process of chronic gastritis. Our data also suggest a self-recruiting mechanism involving CCR5 and CCL5 for tissue accumulation of such T cells.
  • H Hanamoto; T Nakayama; H Miyazato; S Takegawa; K Hieshima; Y Tatsumi; A Kanamaru; O Yoshie
    AMERICAN JOURNAL OF PATHOLOGY 164 3 997 - 1006 2004年03月 [査読有り]
     
    Classical Hodgkin's disease (HD) is characterized by rare neoplastic Hodgkin and Reed-Sternberg (H-RS) cells within abundant reactive cellular backgrounds. In most cases, H-RS cells originate from the B-cell lineage, but their immunophenotypes are unusual. Here we newly found frequent expression of chemokine receptors CXCR6 and CCR10 and their respective ligands CXCL16 and CCL28 in RD-derived cell lines. CCR10 is known to be selectively expressed by plasma cells, whereas CCL28 attracts eosinophils via CCR3 and plasma cells via CCR10 and CCR3. Therefore, we examined their expression in HD tissues by immunohistochemistry. We found that H-RS cells in 15 of 19 cases were positive for CCL28. Among them, seven cases were also positive for CCR10, suggesting a potential autocrine effect. In situ hybridization confirmed the expression of CCL28 mRNA in H-RS cells. The CCL28 positivity in H-RS cells did not significantly correlate with that of LMP-1, CCL17, CCL22, or CCL11. However, it significantly correlated with the background accumulation of eosinophils, plasma cells, and CCR10(+) cells. Thus, the production of CCL28 by H-RS cells may play a major role in tissue accumulation of eosinophils and/or plasma cells in classical HD. The frequent expression of CCR10 in H-RS cells themselves also supports their close relationship to plasma cells.
  • T Shimaoka; T Nakayama; N Fukumoto; N Kume; S Takahashi; J Yamaguchi; M Minami; K Hayashida; T Kita; J Ohsumi; O Yoshie; S Yonehara
    JOURNAL OF LEUKOCYTE BIOLOGY 75 2 267 - 274 2004年02月 [査読有り]
     
    Direct contacts between dendritic cells (DCs) and T cells or natural killer T (NKT) cells play important roles in primary and secondary immune responses. SR-PSOX/CXC chemokine ligand 16 (CXCL16), which is selectively expressed on DCs and macrophages, is a scavenger receptor for oxidized low-density lipoprotein and also the chemokine ligand for a G protein-coupled receptor CXC chemokine receptor 6 (CXCR6), expressed on activated T cells and NKT cells. SR-PSOX/CXCL16 is the second transmembrane-type chemokine with a chemokine domain fused to a mucin-like stalk, a structure very similar to that of fractalkine (FNK). Here, we demonstrate that SR-PSOX/CXCL16 functions as a cell adhesion molecule for cells expressing CXCR6 in the same manner that FNK functions as a cell adhesion molecule for cells expressing CX3C chemokine receptor 1 (CX(3)CR1) without requiring CX(3)CR1-mediated signal transduction or integrin activation. The chemokine domain of SR-PSOX/CXCL16 mediated the adhesion of CXCR6-expressing cells, which was not impaired by treatment with pertussis toxin, a Galphai protein blocker, which inhibited chemotaxis of CXCR6-expressing cells induced by SR-PSOX/CXCL16. Furthermore, the adhesion activity was up-regulated by treatment of SR-PSOX/CXCL16-expressing cells with a metalloprotease inhibitor, which increased surface expression levels of SRPSOX/CXCL16. Thus, SR-PSOX/CXCL16 is a unique molecule that not only attracts T cells and NKT cells toward DCs but also supports their firm adhesion to DCs.
  • T Nakayama; K Hieshima; D Nagakubo; E Sato; M Nakayama; K Kawa; O Yoshie
    JOURNAL OF VIROLOGY 78 4 1665 - 1674 2004年02月 [査読有り]
     
    Chemokines are likely to play important roles in the pathophysiology of diseases associated with Epstein-Barr virus (EBV). Here, we have analyzed the repertoire of chemokines expressed by EBV-infected B cells. EBV infection of B cells induced expression of TARC/CCL17 and MDC/CCL22, which are known to attract Th2 cells and regulatory T cells via CCR4, and also upregulated constitutive expression of MIP-1alpha/CCL3, MIP-1beta/CCL4, and RANTES/CCL5, which are known to attract Th1 cells and cytotoxic T cells via CCR5. Accordingly, EBV-immortalized B cells secreted these chemokines, especially CCL3, CCL4, and CCL22, in large quantities. EBV infection or stable expression of LMP1 also induced CCL17 and CCL22 in a B-cell line, BJAB. The inhibitors of the TRAF/NF-kappaB pathway (BAY11-7082) and the p38/ATF2 pathway (SB202190) selectively suppressed the expression of CCL17 and CCL22 in EBV-immortalized B cells and BJAB-LMP1. Consistently, transient-transfection assays using CCL22 promoter-reporter constructs demonstrated that two NF-kappaB sites and a single AP-1 site were involved in the activation of the CCL22 promoter by LMP1. Finally, serum CCL22 levels were significantly elevated in infectious mononucleosis. Collectively, LMP1 induces CCL17 and CCL22 in EBV-infected B cells via activation of NF-kappaB and probably ATF2. Production of CCL17 and CCL22, which attract Th2 and regulatory T cells, may help EBV-infected B cells evade immune surveillance by Th1 cells. However, the concomitant production of CCL3, CCL4, and CCL5 by EBV-infected B cells may eventually attract Th1 cells and cytotoxic T cells, leading to elimination of EBV-infected B cells at latency III and to selection of those with limited expression of latent genes.
  • T Shimaoka; T Nakayama; N Kume; S Takahashi; J Yamaguchi; M Minami; K Hayashida; T Kita; J Ohsumi; O Yoshie; S Yonehara
    JOURNAL OF IMMUNOLOGY 171 4 1647 - 1651 2003年08月 [査読有り]
     
    SR-PSOX and CXC chemokine ligand (CXCL) 16, which were originally identified as a scavenger receptor and a transmembrane-type chemokine, respectively, are indicated to be identical, In this study, we demonstrate that membrane-bound SR-PSOX/CXCL16 mediates adhesion and phagocytosis of both Gram-negative and Gram-positive bacteria. Importantly, our prepared anti-SR-PSOX mAb, which suppressed chemotactic activity of SR-PSOX, signficantly inhibited bacterial phagocytosis by human APCs including dendritic cells. Various scavenger receptor ligands inhibited the bacterial phagocytosis of SR-PSOX. In addition, the recognition specificity for bacteria was determined by only the chemokine domain of SR-PSOX/CXCL16. Thus, SR-PSOXICXCL16 may play an important role in facilitating uptake of various pathogens and chemotaxis of T and NKT cells by APCs through its chemokine domain.
  • JQ Gao; Y Tsuda; K Katayama; T Nakayama; Y Hatanaka; Y Tani; H Mizuguchi; T Hayakawa; O Yoshie; Y Tsutsumi; T Mayumi; S Nakagawa
    CANCER RESEARCH 63 15 4420 - 4425 2003年08月 [査読有り]
     
    In this study, we examined. antitumor activity of a mouse CC chemokine ILC/CCL27 and a mouse CX3C chemokine fractalkine/CX(3)CL1 in vivo. We generated recombinant adenovirus vectors with a fiber mutation, encoding mILC (Ad-RGD-mILC) and mFKN (Ad-RGD-mFKN). We confirmed tumor cells infected with Ad-RGD-mILC and Ad-RGD-mFKN to express and release these chemokines. Tumor rejection experiments in vivo were carried out by inoculating OV-HM cells infected with Ad-RGD-mILC or Ad-RGD-mFKN into immunocompetent mice. mILC significantly suppressed the tumor growth, whereas no such significant effect was observed by mFKN. The antitumor activity induced by mILC was T cell dependent, involving both CD4(+) and CD8(+) T cells. Immunohistochemical analysis revealed accumulation of both CD3(+) lymphocytes and NK cells in the tumor tissue transduced with mILC and mFKN. However, there was a significant difference in the distribution of infiltrating cells. Furthermore, mFKN appeared to hake an angiogenic activity, which might have masked its tumor suppressive activity. Collectively, ILC/CCL27 may be a good candidate molecule for cancer gene therapy.
  • W Iijima; H Ohtani; T Nakayama; Y Sugawara; E Sato; H Nagura; O Yoshie; T Sasano
    AMERICAN JOURNAL OF PATHOLOGY 163 1 261 - 268 2003年07月 [査読有り]
     
    Lichen planus is a chronic inflammatory disease of the skin and oral mucosa in which the cell-mediated cytotoxicity is regarded as a major mechanism of pathogenesis. To understand its pathophysiology further, the present study examined the in situ expression of chemokines and chemokine receptors in oral lichen planus. Immunohistochemical. analysis of 15 cases has consistently revealed that infiltrating CD4(+) and CD8(+) T cells in the submucosa predominantly expressed CCR5 and CXCR3. Furthermore, infiltrating T cells, particularly CD8(+) T cells, were positive for RANTES/CCL5 and IP-10/CXCL10, the ligands of CCR5 and CXCR3, respectively. By immunoelectron microscopy, these chemokines were localized in the cytolytic granules of CD8(+) T cells. Lesional keratinocytes also overexpressed the ligands of CXCR3, namely, MIG/CXCL9, CXCL10, and I-TAC/CXCL11. Our data suggest that the chemokines signaling via CCR5 and CXCR3, which are known to be selectively expressed by type 1 T cells, are predominantly involved in T-cell infiltration of oral lichen planus. Furthermore, the presence of CCL5 and CXCL10 in the cytolytic granules of tissue-infiltrating CD8(+) T cells expressing CCR5 and CXCR3 reveals a potential self-recruiting mechanism involving activated effector cytotoxic T cells.
  • 加藤 佳子; 藤澤 隆夫; 中山 隆志; 義江 修; 森 晶夫
    アレルギー 52 2-3 359 - 359 (一社)日本アレルギー学会 2003年03月
  • T Nakayama; K Hieshima; D Izawa; Y Tatsumi; A Kanamaru; O Yoshie
    JOURNAL OF IMMUNOLOGY 170 3 1136 - 1140 2003年02月 [査読有り]
     
    We systematically examined the repertoire of chemokine receptors expressed by human plasma cells. Fresh bone marrow plasma cells and myeloma cells consistently expressed CXCR4, CXCR6, CCR10, and CCR3. Accordingly, plasma cells responded to. their respective ligands in chemotaxis and very late Ag-4-dependent cell adhesion to fibronectin. Immobilized CXC chemokine ligand (CXCL)16, a novel transmembrane-type chemokine and CXCR6 ligand, also directly induced adhesion of plasma cells without requiring G(alphai) signaling or divalent cations. Furthermore, we revealed consistent expression of CXCL12 (CXCR4 ligand), CXCL16 (CXCR6 ligand), and CC chemokine ligand 28 (CCR10 and CCR3 ligand) in tissues enriched with plasma cells including bone marrow, and constitutive expression. of CXCL12, CXCL16, and CC chemokine ligand 28 by cultured human bone marrow stromal cells. Collectively, plasma cells are likely to be recruited to bone marrow and other target tissues via CXCR4, CXCR6, CCR10, and CCR3. CXCR6 may also contribute to tissue localization of plasma cells through its direct binding to membrane-anchored CXCL16.
  • K Hieshima; H Ohtani; M Shibano; D Izawa; T Nakayama; Y Kawasaki; F Shiba; M Shiota; F Katou; T Saito; O Yoshie
    JOURNAL OF IMMUNOLOGY 170 3 1452 - 1461 2003年02月 [査読有り]
     
    CCL28 is a CC chemokine signaling via CCR10 and CCR3 that is selectively expressed in certain mucosal tissues such as exocrine glands, trachea, and colon. Notably, these tissues commonly secrete low-salt fluids. RT-PCR analysis demonstrated that salivary glands expressed CCL28 mRNA at the highest levels among various mouse tissues. Single cells prepared from mouse parotid glands indeed contained a major fraction of CD3(-)B220(low) cells that expressed CCR10 at high levels and CCR3 at low levels and responded to CCL28 in chemotaxis assays. Morphologically, these cells are typical plasma cells. By immunohistochemistry, acinar epithelial cells in human and mouse salivary glands were strongly positive for CCL28. Furthermore, human saliva and milk were found to contain CCL28 at high concentrations. Moreover, the C terminus of human CCL28 has a significant sequence similarity to histatin-5, a histidine-rich candidacidal peptide in human saliva. Subsequently, we demonstrated that human and mouse CCL28 had a potent antimicrobial activity against Candida albicans, Gram-negative bacteria, and Gram-positive bacteria. The C-terminal 28-aa peptide of human CCL28 also displayed a selective candidacidal activity. In contrast, CCL27, which is most similar to CCL28 and shares CCR10, showed no such potent antimicrobial activity. Like most other antimicrobial peptides, CCL28 exerted its antimicrobial activity in low-salt conditions and rapidly induced membrane permeability in target microbes. Collectively, CCL28 may play dual roles in mucosal immunity as a chemoattractant for cells expressing CCR10 and/or CCR3 such as plasma cells and also as a broad-spectrum antimicrobial protein secreted into low-salt body fluids.
  • F Katou; H Ohtani; T Nakayama; H Nagura; O Yoshie; K Motegi
    JOURNAL OF PATHOLOGY 199 1 98 - 106 2003年01月 [査読有り]
     
    De novo formation of lymphoid tissue is one of the characteristic features of chronic inflammation. The formation of T cell-mature dendritic cell (DC) clusters has been previously demonstrated in chronically inflamed skin infected with Candida albicans. A functional similarity was also found between chronic inflammation and the T-cell zone of lymph nodes (LNs), since a substantial fraction of phenotypically mature DCs in both tissues expressed CCL22 (macrophage-derived chemokine; MDC) and were closely surrounded by memory-type T cells expressing its receptor, CCR4. To analyse the nature of T cell-mature DC interactions further in chronically inflamed skin and LNs, the present study focuses on another chemokine system, namely CCL19 (EBI1 ligand chemokine; ELC), CCL21 (secondary lymphoid tissue chemokine; SLC) and their shared receptor, CCR7. RT-PCR analysis revealed expression of CCL19, CCL21, and CCR7 at high levels in LNs and at low levels in inflamed skin. Using immunohistochemistry, the majority of DC-Lamp(+) mature DCs in the T-cell area of LNs expressed CCL19 and were surrounded by CCR7(+) naive-type lymphocytes, while CCL21 was expressed in reticular stromal cells and vascular endothelial cells. Very few mature DCs in LNs were found to express CCR7. In contrast, the majority of DC-Lamp+ mature DCs in inflamed skin were totally negative for CCL19 and were surrounded by CCR7(-) memory-type T cells. Furthermore, CCL21 expression in the inflamed skin was detected in dermal lymphatic endothelial cells and rare CCR7(+) mature DCs were mostly seen within the lymphatic vessels. In normal skin, on the other hand, no cells immunoreactive for CCL19, CCL21, or CCR7 were found. The present study thus reveals a striking difference in the function of mature DCs between LNs and chronically inflamed skin. Copyright (C) 2002 John Wiley Sons, Ltd.
  • T Horikawa; T Nakayama; Hikita, I; H Yamada; R Fujisawa; T Bito; S Harada; A Fukunaga; D Chantry; PW Gray; A Morita; R Suzuki; T Tezuka; M Ichihashi; O Yoshie
    INTERNATIONAL IMMUNOLOGY 14 7 767 - 773 2002年07月 [査読有り]
     
    Thymus and activation-regulated chemokine (TARC)/CCL17 and macrophage-derived chemokine (MDC)/CCL22 are a pair of CC chemokines known to selectively attract T(h)2 type memory T cells via CCR4. Here we examined circulating levels of TARC and MDC in patients with atopic dermatitis (AD) and control subjects by using plasma samples, which reflect blood contents of chemokines more accurately than serum samples. The plasma levels of TARC and MDC were significantly elevated in AD patients. These values also strongly correlated with disease severity and serum lactate dehydrogenase levels, and weakly correlated with serum total IgE levels and blood eosinophilia. Previous studies demonstrated TARC immunoreactivity in the epidermal layer of AD lesional skin and production of TARC by a human keratinocytic cell line HaCaT upon stimulation with IFN-gamma. Here we demonstrated MDC immunoreactivity in the epidermal layer of AD skin at levels stronger than that of TARC. Furthermore, primary epidermal keratinocytes expressed both TARC and MDC mRNA upon stimulation with IFN-gamma, but efficiently secreted only MDC. These results suggest a post-transcriptional regulation in TARC production. IFN-gamma also induced TARC and MDC mRNA in mouse skin. Collectively, both TARC and MDC play important roles in the local accumulation of T(h)2 cells in AD lesional skin. Production of T(h)2-attracting chemokines by epidermal keratinocytes upon treatment with IFN-gamma, which is also the potent inducer of T(h)1-attracting chemokines, may underline the pivotal role of IFN-gamma in the chronic phase of AD where both T(h)1 and T(h)2 responses are mixed.
  • T Fujisawa; R Fujisawa; Y Kato; T Nakayama; A Morita; H Katsumata; H Nishimori; K Iguchi; H Kamiya; PW Gray; D Chantry; R Suzuki; O Yoshie
    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 110 1 139 - 146 2002年07月 [査読有り]
     
    Background: T(H)2 cells and eosinophils selectively express CC chemokine receptor 4 and CCR3, respectively, and their chemokine ligands are likely to play important roles in the pathogenesis of atopic dermatitis (AD). Objective: The purpose of this study was to demonstrate the presence of thymus and activation-regulated chemokine (TARC) in platelets and its release during clotting and to evaluate the circulating levels of TARC, macrophage-derived chemokine (MDC), and eotaxin in control subjects and patients with AD. Methods: We compared plasma and serum contents of TARC, MDC, and eotaxin. We measured TARC contents in platelet lysates. We analyzed the correlation of plasma levels of TARC, MDC, and eotaxin with various clinicolaboratory parameters in patients with AD. Results: Serum contents of TARC rapidly, increased during clotting, whereas those or MDC and eotaxin increased only slightly. We demonstrated that platelets contained TARC, and its levels were dramatically elevated in patients with AD. Platelets also released TARC on stimulation with thrombin. We therefore evaluated circulating levels of these chemokines in control subjects and patients with AD by using plasma samples. Plasma TARC levels were significantly increased in patients with AD (P <.0001) and showed significant correlations with severity scoring of atopic dermatitis (SCORAD) index (r = 0.665, P <.00001), serum lactate dehydrogenese levels (r = 0.696, P= .00001), cosinophil counts (r = 0.381, P = .007), and platelet counts (r = 0.562, P <.0001). Similarly, plasma MDC levels were significantly increased in patients with AD (P <.0001) and showed significant correlations with SCORAD index (r = 0.727, P <.0001), serum lactate dehydrogenese levels (r = 0.861, P <.0001), eosinophil counts (r = 0.505, P = .005), and platelet counts (r = 0.370, P = .01). On treatment, plasma TARC and MDC levels were dramatically decreased in accordance with improved SCORAD scores (P = .0012 and P = .0007, respectively). On the other hand, plasma eotaxin levels did not show any significant increase or correlation with any of the clinical parameters in patients with AD. Conclusion: Platelets from patients with AD contain high levels of TARC. Thus platelets might play an important role in AD pathogenesis by releasing T(H)2-attracting TARC on activation. Furthermore, circulating levels of TARC and MDC, but not those of eotaxin, correlate well with the disease activity of AD.
  • M Nishimura; H Umehara; T Nakayama; O Yoneda; K Hieshima; M Kakizaki; N Dohmae; O Yoshie; T Imai
    JOURNAL OF IMMUNOLOGY 168 12 6173 - 6180 2002年06月 [査読有り]
     
    Fractalkine/CX3C ligand 1 and its receptor CX3CR1 are known to mediate both cell adhesion and cell migration. Here we show that CX3CR1 defines peripheral blood cytotoxic effector lymphocytes commonly armed with intracellular perforin and granzyme B, which include NK cells, gammadelta T cells, and terminally differentiated CD8(+) T cells. In addition, soluble fractalkine preferentially induced migration of cytotoxic effector lymphocytes. Furthermore, interaction of cytotoxic effector lymphocytes with membrane-bound fractalkine promoted subsequent migration to the secondary chemokines, such as macrophage inflammatory protein-1beta/CC ligand 4 or IL-8/CXC ligand 8. Thus, fractalkine expressed on inflamed endothelium may function as a vascular regulator for cytotoxic effector lymphocytes, regardless of their lineage and mode of target cell recognition, through its ability to capture them from blood flow and to promote their emigration in response to other chemokines.
  • O Yoshie; R Fujisawa; T Nakayama; H Harasawa; H Tago; D Izawa; K Hieshima; Y Tatsumi; K Matsushima; H Hasegawa; A Kanamaru; S Kamihira; Y Yamada
    BLOOD 99 5 1505 - 1511 2002年03月 [査読有り]
     
    Chemokines and chemokine receptors play important roles In migration and tissue localization of various lymphocyte subsets. Here, we report the highly frequent expression of CCR4 In adult T-cell leukemia (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-immortalized T cells. Flow cytometric analysis revealed that ATL and HTLV-1-immortalized T-cell lines consistently expressed CCR4. Inducible expression of HTLV-1 transcriptional activator tax in a human T-cell line Jurkat did not, however, up-regulate CCR4 mRNA. In vitro Immortalization of peripheral blood T cells led to preferential outgrowth of CD4(+) T cells expressing CCR4. We further demonstrated highly frequent expression of CCR4 in fresh ATL cells by (1) reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of CCR4 expression in peripheral blood mononuclear cells (PBMCs) from patients with ATL and healthy controls; (2) flow cytometric analysis of CCR4-expressing cells in PBMCs from patients with ATL and healthy controls; (3) CCR4 staining of routine blood smears from patients with ATL; and (4) an efficient migration of fresh ATL cells to the CCR4 ligands, TARC/CCL17 and MDC/CCL22, in chemotaxis assays. Furthermore, we detected strong signals for CCR4, TARC, and MDC in ATL skin lesions by RT-PCR. Collectively, most ATL cases have apparently derived from CD4+ T cells expressing CCR4. It is now known that circulating CCR4(+) T cells are mostly polarized to Th2 and also contain essentially all skin-seeking memory T cells. Thus, HTLV-1-infected CCR4+ T cells may have growth advantages by deviating host immune responses to Th2. CCR4 expression may also account for frequent infiltration of ATL into tissues such as skin and lymph nodes. (C) 2002 by The American Society of Hematology.
  • T Nakayama; R Fujisawa; D Izawa; K Hieshima; K Takada; O Yoshie
    JOURNAL OF VIROLOGY 76 6 3072 - 3077 2002年03月 [査読有り]
     
    Compared to peripheral blood resting B cells, Epstein-Barr virus (EBV)-immortalized B cells consistently express CCR6 and CCR10 at high levels and CXCR4 and CXCR5 at low levels. Accordingly, these cells vigorously responded to the ligands of CCR6 and CCR10 but not to those of CXCR4 and CXCR5. In a human EBV-negative B-cell line, BJAB, stable expression of EBNA2 upregulated CCR6, while stable expression of EBNA2 as well as LMP1 downregulated CXCR4. On the other hand, upregulation of CCR10 or downregulation of CXCR5 was not induced in BJAB by stable expression of EBNA2 or LMP1. Thus, these changes may be due to a plasmablast-like stage of B-cell differentiation fixed by EBV immortalization. EBV-infected B cells in infectious mononucleosis are known to avoid germinal centers and accumulate under the mucosal surfaces. EBV-associated opportunistic lymphomas also tend to occur in extranodal sites. These preferred sites of in vivo localization are consistent with the unique profile of chemokine receptor expression exhibited by EBV-immortalized B cells.
  • S Fujiie; K Hieshima; D Izawa; T Nakayama; R Fujisawa; H Ohyanagi; O Yoshie
    INTERNATIONAL IMMUNOLOGY 13 10 1255 - 1263 2001年10月 [査読有り]
     
    Liver and activation-regulated chemokine (LARC)/CCL20 is expressed by surface-lining epithelial and epidermal cells, and is likely to link innate and acquired immunity by attracting immature dendritic cells, effector memory T cells and B cells via CCR6. Here we examined the mechanism of LARC expression in epithelial-type cells. Either IL-1 beta or tumor necrosis factor (TNF)-alpha strongly induced LARC mRNA in intestinal cell lines Caco-2 and T84, while both were effective on HEK 293T cells. Induction of LARC was also demonstrated in the intestinal epithelium of BALB/c mice upon treatment with IL-1 alpha or TNF-alpha. Transient transfection assays using murine LARC promoter-reporter constructs identified a region essential for IL-1 beta, or TNF-alpha -induced promoter activation in Caco-2 and 293T cells. Using site-directed mutagenesis, we demonstrated that an NF-kappaB site located between -96 and -87 bp upstream from the transcriptional start site was both necessary and sufficient for IL-1 beta- or TNF-alpha -induced promoter activation in Caco-2 and 293T cells. Electrophoretic mobility shift assays demonstrated that p50/p65 heterodimer and p65 homodimer of NF-kappaB bound to this site in 293T cells upon treatment with IL-1 beta and TNF-alpha, and p50/p65 heterodimer bound to this site in Caco-2 cells upon treatment with IL-1 beta. Co-expression of constitutively active p65 strongly activated the promoter construct carrying the intact NF-kappaB site in 293T and Caco-2 cells. Collectively, LARC expression in intestinal epithelial-type cells is induced by proinflammatory cytokines such as IL-1 and TNF-alpha primarily through activation of NF-kappaB.
  • H Nomiyama; K Hieshima; T Nakayama; T Sakaguchi; R Fujisawa; S Tanase; H Nishiura; K Matsuno; H Takamori; Y Tabira; T Yamamoto; R Miura; O Yoshie
    INTERNATIONAL IMMUNOLOGY 13 8 1021 - 1029 2001年08月 [査読有り]
     
    Liver-expressed chemokine (LEC)/CCL16 is a human CC chemokine selectively expressed in the liver. Here, we investigated its receptor usage by calcium mobilization and chemotactic assays using mouse L1.2 pre-B cell lines stably expressing a panel of 12 human chemokine receptors. At relatively high concentrations, LEG induced calcium mobilization and chemotaxis via CCR1 and CCR2. LEG also induced calcium mobilization, but marginal chemotaxis via CCR5. Consistently, LEG was found to bind to CCR1, CCR2 and CCR5 with relatively low affinities. The binding of LEG to CCR8 was much less significant. In spite of its binding to CCR5, LEG was unable to inhibit infection of an R5-type HIV-1 to activated human peripheral blood mononuclear cells even at high concentrations. In human liver sections, hepatocytes were strongly stained by anti-LEC antibody. HepG2, a human hepatocarcinoma cell line, was found to constitutively express LEC. LEG was also present in the plasma samples from healthy adult donors at relatively high concentrations (0.3-4 nM). Taken together, LEG is a new low-affinity functional ligand for CCR1, CCR2 and CCR5, and is constitutively expressed by liver parenchymal cells. The presence of LEG in normal plasma at relatively high concentrations may modulate inflammatory responses.
  • F Katou; H Ohtani; T Nakayama; K Ono; K Matsushima; A Saaristo; H Nagura; O Yoshie; K Motegi
    AMERICAN JOURNAL OF PATHOLOGY 158 4 1263 - 1270 2001年04月 [査読有り]
     
    Our previous study demonstrated formation of T cell-dendritic cell (DC) clusters in inflamed dermis of intraorally autotransplanted skin flaps. Such T cell-DC clusters are supposed to be important for close interactions between T cells and DCs including the specific antigen presentation. Here we show the involvement of the macrophage-derived chemokine (MDC/CCL22) and its specific receptor CC chemokine receptor 4 (CCR4) in the formation of T cell-DC clusters. Reverse transcriptase-polymerase chain reaction analysis revealed high levels of mRNA expression for MDC and CCR4 in inflamed skin and neck lymph nodes (LNs), but not In normal skin. Immunohistochemically, MDC+ cells and CCR4(+) cells were mainly located within the T cell-DC clusters both in the dermis of inflamed skin and the T cell area of LNs. MDC+ cells were identified to be DCs both in inflamed skin and LNs. The majority of CCR4+ cells were CD4(+) T cells, accounting for approximately one-third of total CD4(+) T cells in the inflamed skin. Our data suggest that the MDC-CCR4 system plays an important role in the formation of T cell-DC clusters both in inflamed skin and LNs.
  • S Kawasaki; H Takizawa; H Yoneyama; T Nakayama; R Fujisawa; M Izumizaki; T Imai; O Yoshie; Homma, I; K Yamamoto; K Matsushima
    JOURNAL OF IMMUNOLOGY 166 3 2055 - 2062 2001年02月 [査読有り]
     
    Thymus- and activation-regulated chemokine (TARC; CCL17) is a lymphocyte-directed CC chemokine that specifically chemoattracts CC chemokine receptor 4-positive (CCR4(+)) Th2 cells. To establish the pathophysiological roles of TARC in vivo, we investigated here whether an mAb against TARC could inhibit the induction of asthmatic reaction in mice elicited by OVA, TARC was constitutively expressed in the lung and was up-regulated in allergic inflammation. The specific Ab against TARC attenuated OVA-induced airway eosinophilia and diminished the degree of airway hyperresponsiveness with a concomitant decrease in Th2 cytokine levels. Our results for the first time indicate that TARC is a pivotal chemokine for the development of Th2-dominated experimental allergen-induced asthma with eosinophilia and AHR. This study also represents the first success in controlling Th2 cytokine production in vivo by targeting a chemokine.
  • T Nakayama; R Fujisawa; H Yamada; T Horikawa; H Kawasaki; K Hieshima; D Izawa; S Fujiie; T Tezuka; O Yoshie
    INTERNATIONAL IMMUNOLOGY 13 1 95 - 103 2001年01月 [査読有り]
     
    Liver- and activation-regulated chemokine (LARC)/macrophage inflammatory protein (MIP)3 alpha/ CCL20 is a CC chemokine which is constitutively expressed by follicle-associated epithelial cells in the mucosa, and attracts cells expressing CCR6 such as immature dendritic cells and alpha (4)beta (high)(7) intestine-seeking memory T cells. Here, we examine LARC/CCL20 expression in the skin. LARC/CCL20 mRNA and protein were induced in primary human keratinocytes upon stimulation with proinflammatory cytokines such as IL-1 alpha and tumor necrosis factor (TNF)-alpha, In mice, intradermal injection of IL-l a and TNF-a rapidly induced a local accumulation of transcripts for LARC/CCL20 and its receptor CCR6 with a lag of several hours in the latter. In humans, immunostaining of LARC/CCL20 was weak if any in normal skin tissues but strongly augmented in lesional skin tissues with atopic dermatitis. Furthermore, massive infiltration of cells with markers such as CD1a, CD3 or HLA-DR was present in atopic skin lesions. Many infiltrating cells were also found to be CCR6(+) by a newly generated monoclonal anti-CCR6, However, Langerhans cells residing within the epidermis were hardly stained by anti-CCR6 in normal and atopic skin tissues. Furthermore, plasma levels of LARC/CCL20 were found to be elevated in patients with atopic dermatitis. Collectively, our results suggest that epidermal keratinocytes produce LARC/CCL20 upon stimulation with proinflammatory cytokines such as IL-1 alpha and TNF-alpha, and attract CCR6-expressing immature dendritic cells and memory/effector T cells into the dermis of inflamed skin such as atopic dermatitis. LARC/CCL20 may not, however, play a major role in homeostatic migration of Langerhans cells into the skin.
  • Ishikawa-Mochizuki, I; M Kitaura; M Baba; T Nakayama; D Izawa; T Imai; H Yamada; K Hieshima; R Suzuki; H Nomiyama; O Yoshie
    FEBS LETTERS 460 3 544 - 548 1999年11月 [査読有り]
     
    Molluscum contagiosum virus (MCV) encodes a CC chemokine MC148R which is likely to have been acquired from the host. By a homology search employing MC148R as a probe, we hale identified a novel CC chemokine whose gene exists next to the IL-11 receptor alpha (IL-11R alpha) gene in both humans and mice. Thus, this chemokine maps to chromosome 9p13 in humans where IL-11R alpha has been assigned, We term this novel chemokine IL-11R alpha-locus chemokine (ILC), ILC has the highest homology to MC148R among the known human CC chemokines. Furthermore, ILC is strongly and selectively expressed in the skin where infection of MCV also takes place, Thus, ILC is likely to be the original chemokine of MC148R. (C) 1999 Federation of European Biochemical Societies.
  • T Yoshida; D Izawa; T Nakayama; K Nakahara; M Kakizaki; T Imai; R Suzuki; M Miyasaka; O Yoshie
    FEBS LETTERS 458 1 37 - 40 1999年09月 [査読有り]
     
    Single C motif-1 (SCM-1)/lymphotactin is a C-type member of the chemokine superfamily, Previously, we identified its specific receptor XCR1. Here we isolated the murine homologue of XCR1 (mXCR1). To demonstrate its biological activity, we produced recombinant mouse SCM-1 by the baculovirus expression system, B300-19 murine pre-B cells expressing mXCR1 responded to mSCM-1 in chemotactic and calcium-mobilization assays. mXCR1 mRNA was weakly expressed in spleen and lung of normal C57BL/6 mice. In spleen, CD8(+) cells and NK1.1(+) cells were found to express mXCR1. Identification of mXCR1 will now allow us to study the role of this unique cytokine system in the mouse models of inflammation and immunity, (C) 1999 Federation of European Biochemical Societies.
  • T Nakayama; T Yaoi; G Kuwajima; O Yoshie; T Sakata
    FEBS LETTERS 453 1-2 77 - 80 1999年06月 [査読有り]
     
    N-copine is a novel two C2 domain protein that shows Ca2+-dependent phospholipid binding and membrane association. By using yeast two-hybrid assays, we identified OS-9 as a protein capable of interacting with N-copine, We further revealed that the second C2 domain of N-copine bound with the carboxy-terminal region of OS-9, Their interaction in vivo nas also confirmed by co-immunoprecipitation from 293E cells co-expressing transfected N-copine and OS-9, In vitro binding assays showed that this interaction was Ca2+-dependent. By Northern blot analysis, N-copine and OS-9 were co-expressed in the same regions of human brain. These results reveal that OS-9 is a potential target of N-copine. (C) 1999 Federation of European Biochemical Societies.
  • T Nakayama; T Yaoi; G Kuwajima
    JOURNAL OF NEUROCHEMISTRY 72 1 373 - 379 1999年01月 [査読有り]
     
    N-Copine is a novel protein with two C2 domains. Its expression is brain specific and up-regulated by neuronal activity such as kainate stimulation and tetanus stimulation evoking hippocampal CA1 long-term potentiation. We examined the localization and subcellular distribution of N-copine in mouse brain. In situ hybridization analysis showed that N-copine mRNA was expressed exclusively in neurons of the hippocampus and in the main and accessory olfactory bulb, where various forms of synaptic plasticity and memory formation are known to occur. In immunohistochemical analyses, N-copine was detected mainly in the cell bodies and dendrites in the neurons, whereas presynaptic proteins such as synaptotagmin I and rab3A were detected in the regions where axons pass through. In fractionation experiments of brain homogenate, N-copine was associated with the membrane fraction in the presence of Ca2+ but not in its absence. As a GST-fusion protein with the second C2 domain of N-copine showed Ca2+-dependent binding to phosphatidylserine, this domain was considered to be responsible for the Ca2+-dependent association of N-copine with the membrane. Thus, N-copine may have a role as a Ca2+ sensor in postsynaptic events, in contrast to the known roles of "double C2 domain-containing proteins," including synaptotagmin I, in presynaptic events.
  • T Nakayama; T Yaoi; M Yasui; G Kuwajima
    FEBS LETTERS 428 1-2 80 - 84 1998年05月 [査読有り]
     
    Neuronal activity is often associated with changes in gene expression. By a two-dimensional cDNA-display system, restriction landmark cDNA scanning, we identified a novel gene whose expression in the hippocampus was up-regulated by kainate stimulation. The mRNA expression was detected only in brain and up-regulated by the stimulation making CA3-CA1 long-term potentiation. The encoded protein contains two copies of C2-domain, known as the Ca2+-binding domain of PKC-gamma and shows 49% identity with human copine I. We designated this protein N-copine (neuronal-copine), N-copine may have a role in synaptic plasticity. (C) 1998 Federation of European Biochemical Societies.

書籍

  • 新臨床腫瘍学 第4版.がん薬物療法専門医のために ”感染と発がん”
    中山 隆志 (担当:分担執筆範囲:)南江堂 2015年07月
  • 新臨床腫瘍学 第3版.がん薬物療法専門医のために ”感染と発がん”
    中山 隆志 (担当:分担執筆範囲:)南江堂 2012年12月
  • 臨床免疫・アレルギー科 サイトカインのすべて(完全改訂版)
    中山 隆志 (担当:分担執筆範囲:)科学評論社 2012年05月
  • アレルギー科 好酸球のヒスタミン受容体 ヒスタミンの新しい役割について
    藤澤 隆夫; 中山 隆志; 平井 浩一; 義江 修 (担当:共著範囲:)科学評論社 2004年10月
  • 最新医学 ヘルペスウイルス感染症とケモカイン
    中山 隆志; 義江 修 (担当:共著範囲:)最新医学社 2004年04月
  • 医学のあゆみ・別冊:免疫疾患, リンパ球サブセットとケモカイン受容体
    中山 隆志; 義江 修 (担当:共著範囲:)医歯薬出版 2002年03月
  • アレルギー科 リンパ球サブセットとケモカイン受容体
    中山 隆志; 義江 修 (担当:共著範囲:)科学評論社 2001年08月
  • Molecular Medicine 免疫反応制御因子としてのケモカイン
    中山 隆志; 義江修 (担当:共著範囲:)中山書店 2001年02月
  • ケモカインハンドブック:“ILC/CTACK” “MEC/CCL28” “MCV MC148R” “CCR10”
    中山 隆志 (担当:分担執筆範囲:)細胞工学・別冊 2000年11月
  • 臨床免疫・特別増刊号:免疫担当細胞上の細胞表面分子とその機能, CXCR1~CXCR5
    中山 隆志; 義江 修 (担当:共著範囲:)科学評論社 2000年07月
  • 臨床免疫・特別増刊号:免疫担当細胞上の細胞表面分子とその機能, CCR6~CCR9
    中山 隆志; 義江 修 (担当:共著範囲:)科学評論社 2000年07月

講演・口頭発表等

  • ウイルス学的シナプス形成によるCCR4陽性T細胞選択的HTLV-1伝播はHTLV-1感染細胞でのTax依存的なFosB誘導性CCL22発現に起因する.  [通常講演]
    樋口 智紀; 稗島 州雄; 中山 隆志; 義江 修
    日本癌学会 2012年10月 日本癌学会
  • Fra-2-SOX4 oncogenic cascade plays a critical role in cell growth of CCR4+ mature T-cell malignancies  [通常講演]
    樋口 智紀; 中山 隆志; 井上 暁子; 義江 修
    JSICR-MMCB2011 2011年05月 JSICR-MMCB2011
  • Common oncogenic role of Fra-2 in mature T-cell malignancies expressing CCR4.  [通常講演]
    義江 修; 中山 隆志; 樋口 智紀; 稗島 州雄
    Gordon Reserch Conferences 2010年06月 Gordon Reserch Conferences
  • CCR4発現T細胞リンパ腫における新規発癌遺伝子Fra-2.  [通常講演]
    中山 隆志; 樋口 智紀; 稗島 州雄; 義江 修
    第75回 日本インターフェロン・サイトカイン学会 2010年06月 第75回 日本インターフェロン・サイトカイン学会
  • Identification of Fra-2-SOX4 oncogenic cascade in CCR4+ mature T-cell malignancies  [通常講演]
    樋口 智紀; 中山 隆志; 重田 暁子; 白川 愛子; 稗島 州雄; 義江 修
    14th International Congress of Immunology 2010年 14th International Congress of Immunology
  • Common oncogenic role of FRA-2 in mature T-cell lymphoma expressing CCR4.  [通常講演]
    義江 修; 樋口 智紀; 中山 隆志
    International Association of Inflammation Societie T-cell Lymphoma Forum 2010年01月 International Association of Inflammation Societie T-cell Lymphoma Forum
  • ケモカインEotaxin-3/CCL26のCX3CR1を介した細胞傷害性リンパ球遊走作用.  [通常講演]
    中山 隆志; 樋口 智紀; 重田 暁子; 稗島 州雄; 義江 修; 渡邉賀子
    日本分子生物学会年会 2009年12月 日本分子生物学会年会
  • Taxによる翻訳伸長因子eEF1A2の誘導とそのHTLV-1によるT細胞がん化での役割の解明  [通常講演]
    稗島 州雄; 重田 暁子; 中山 隆志; 樋口 智紀; 義江 修
    第2回HTLV-1研究会 2009年08月 東京 第2回HTLV-1研究会
     
    我々は最近、Taxを発現しているHTLV-1感染細胞株においてTax siRNAにより発現が変動する遺伝子をマイクロアレイにより解析した結果、Tax依存性発現の可能性のある多数の遺伝子を同定した。その中に最近注目を浴びている翻訳伸長因子のeukaryotic elongation factor 1 alpha 2 (eEF1A2)が含まれていた。eEF1A2はEF-1αサブユニットのイソ型で、eEF1A1がハウスキーピング遺伝子として筋肉以外の多くの組織で発現しているのに対し、eEF1A2は主に筋肉と神経で発現している。両者は異なる染色体上にマップされ、92%のアミノ酸相同性を持つものの互いに排他的な発現調節を受けている。さらに興味深いことに、異所性に発現したeEF1A2はがん化との関連が報告されている。したがって、eEF1A2は発がん遺伝子としての性格も有しているが、その作用メカニズムについてはまだ十分明らかにされていない。 我々がeEF1A2に特に注目する理由は、最近明らかになってきているeEF1A2の翻訳伸長因子以外の作用である。eEF
  • CXCR7 induced by Tax promotes proliferation of HTLV-1 infected T cells  [通常講演]
    白川 愛子; 長久保 大輔; 中山 隆志; 稗島 州雄; 義江 修
    The 9th World Congress on Inflammation 2009年07月 Tokyo The 9th World Congress on Inflammation
  • The role of Fra-2 and c-Myb oncogenic cascade in CD4+ mature T-cell lymphomas  [通常講演]
    樋口 智紀; 中山 隆志; 長久保 大輔; 重田 暁子; 白川 愛子; 稗島 州雄; 義江 修
    日本癌学会 2009年 日本癌学会
  • Fra-2 and c-Myb oncogenic cascade is involved in cell growth in CD4+ mature T-cell lymphomas  [通常講演]
    樋口 智紀; 中山 隆志; 長久保 大輔; 重田 暁子; 白川 愛子; 稗島 州雄; 義江 修
    日本分子生物学会 2009年 日本分子生物学会
  • HTLV-1感染におけるTh2関連転写因子c-Mafの機能解析  [通常講演]
    稗島 州雄; 中山 隆志; 長久保 大輔; 重田 暁子; 樋口 智紀; 白川 愛子; 義江 修
    第68回 日本癌学会学術総会 2008年10月 名古屋 第68回 日本癌学会学術総会
  • Aberrantly expressed Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia.  [通常講演]
    大磯 直毅; 中山 隆志; 稗島 州雄; 荒尾 徳三; 川原 繁; 西尾 和人; 義江 修; 川田 暁
    International Investigative Dermatology 2008年05月 Kyoto International Investigative Dermatology
     
    成人T細胞性白血病において、Fra-2の過剰発現がCCR4と細胞増殖を引き起こすことを報告した。
  • Liver-Expressed Chemokine/CCL16のヒスタミンH4レセプターを介した好酸球遊走作用.  [通常講演]
    中山 隆志
    第81回 日本薬理学会年会 2008年03月 横浜 第81回 日本薬理学会年会
  • Taxにより誘導されるCXCR7の発現はHTLV-1感染T細胞の増殖を促進する.  [通常講演]
    長久保 大輔; 白川 愛子; 中山 隆志; 重田 暁子; 樋口 智紀; 稗島 州雄; 義江 修; 竹川 澄男
    日本癌学会 2008年 日本癌学会
  • Induction of CCR10 expression by 1,25-Dihydroxyvitamin D3 in Terminally Differentiating Human B Cells  [通常講演]
    白川 愛子; 長久保 大輔; 稗島 州雄; 中山 隆志; 金 哲; 義江 修
    Keystone Symposia 2008 2008年01月 Keystone, Colorado, USA Keystone Symposia 2008
  • CCR4を発現するATLとCTCLにおけるFra-2の異常発現.  [通常講演]
    中山 隆志; 樋口 智紀; 長久保 大輔; 重田 暁子; 白川 愛子; 稗島 州雄; 義江 修; 竹川 澄男
    日本癌学会 2008年 日本癌学会
  • Role of Fra-2/JunD heterodimer in CCR4 expression and cell proliferation in adult T-cell leulemia  [通常講演]
    中山 隆志; 稗島 州雄; 金哲; 長久保 大輔; 白川 愛子; 義江 修
    第37回 日本免疫学会総会 2007年11月 第37回 日本免疫学会総会
  • Induction of CCR10 expression by 1,25-Dihydroxyvitamin D3 in Terminally Differentiating Human B Cells  [通常講演]
    白川 愛子; 長久保 大輔; 稗島 州雄; 中山 隆志; 金 哲; 義江 修
    第37回日本免疫学会総会 2007年11月 東京 第37回日本免疫学会総会
  • HTLV-1のCD4+T細胞への感染におけるケモカイン/ケモカイン受容体CCL22/CCR4の役割  [通常講演]
    稗島 州雄; 長久保 大輔; 中山 隆志; 白川 愛子; 金 哲; 義江 修
    第55回日本ウイルス学会学術集会 2007年10月 札幌 第55回日本ウイルス学会学術集会
     
    【目的と意義】HTLV-1が感染してから数十年の潜伏感染の後、一部の感染者に成人T細胞白血病(ATL)が発症する。ATL腫瘍細胞の特徴は、本来は末梢血CD4+T細胞の20%程度しか発現していないケモカイン受容体CCR4の高頻度発現(>90%)である。前回我々は、HTLV-1感染細胞がTax依存性にCCL22を産生し、末梢血CCR4+CD4+T細胞を選択的に遊走させることを報告した。今回、HTLV-1初期感染におけるCCL22/CCR4の役割をさらに追究し、CD4+T細胞への感染におけるCCL22/CCR4の役割を検討した。 【材料と方法】HTLV-1の感染様式を理解するために、①感染開始となる細胞間接着時、②感染早期(1週間前後)、③感染後期(2~3ヶ月)の各時期に分けて検討した。HTLV-1感染細胞株と末梢血CCR4+CD4+T細胞を共培養し、CCR4特異的阻害剤あるいは百日咳毒素(PTX)処理が細胞間結合に与える影響を検討した。また、マイトマイシンC処理したHTLV-1感染細胞とPHA処理した末梢血単核球細胞(PBMC)を共培養してHTLV-1感染実験
  • HTLV-1 Tax誘導性ケモカインCCL22のHTLV-1初期感染における役割  [通常講演]
    稗島 州雄; 中山 隆志; 長久保 大輔; 白川 愛子; 金 哲; 義江 修
    第66回 日本癌学会学術総会 2007年10月 横浜 第66回 日本癌学会学術総会
     
    We examined the effect of Tax on expression of CCL22, a ligand of CCR4. Most Tax-expressing HTLV-1+ T cell lines produced a large amount of CCL22 in their culture supernatants. Transient expression of Tax also induced CCL22. Knockdown of Tax gene by siRNA resulted in a reduction of CCL22 mRNA. These results indicate CCL22 is one of the target genes of Tax. Culture supernatants from the HTLV-1+ T cell lines selectively attracted primary CCR4+CD4+ T cells in chemotaxis assays. The migration was blocked by pretreatment of the supernatants with anti-CCL22 Ab or pretreatment of PBMCs with a CCR4-specific antagonist. Further, HTLV-1+ T cell lines showed significant CCR4-dependent cell-to-cell interactions with sorted primary CCR4+CD4+ T cells, and anti-CCL22 Ab inhibited HTLV-1 primary infection. These results indicate that HTLV-1-infected T cells produce CCL22 upon expression of Tax and selectively recruit CCR4+CD4+ T cells, resulting in preferential transmission of HTLV-1 to these cells.
  • Fra-2とJunDのヘテロダイマーはATL細胞におけるCCR4発現と細胞増殖を促進する  [通常講演]
    中山 隆志; 稗島 州雄; 金哲; 長久保 大輔; 白川 愛子; 義江 修; 山田恭暉; 藤井雅寛
    日本癌学会66回総会 2007年10月 日本癌学会66回総会
  • Potential role of CCR9 in gastrointestinal involvement of ATL cells.  [通常講演]
    長久保 大輔; 金哲; 稗島 州雄; 中山 隆志; 白川 愛子; 義江 修
    IMMUNOLOGY 2007, The American Association of Immunologists 2007年05月 IMMUNOLOGY 2007, The American Association of Immunologists
  • Involvement of fra-2 and JunD in CCR4 expression and cell proliferation in adult T cell leukemia  [通常講演]
    中山 隆志; 稗島 州雄; 金哲; 長久保 大輔; 白川 愛子; 義江 修; 山田恭暉; 藤井雅寛
    13th International Conference on Human Retrovirology HTLV and Related Viruses 2007年05月 13th International Conference on Human Retrovirology HTLV and Related Viruses
  • HTLV-1 Tax-induced CCL22 promotes cell-cell interactions between HTLV-1-infected cells and peripheral blood CCR4+CD4+ T cells  [通常講演]
    稗島 州雄; 長久保 大輔; 中山 隆志; 白川 愛子; 義江 修
    The 13th International Conference on Human Retrovirology; HTLV and Related Viruses 2007年05月 Hakone The 13th International Conference on Human Retrovirology; HTLV and Related Viruses
     
    Most Tax+ HTLV-1+ T cell lines produced large amounts of CCL22 in their culture supernatants. Transient Tax expression also expressed CCL22. siRNA-induced knockdown of Tax resulted in a significant reduction of CCL22 mRNA in Tax+ cells. These results indicated CCL22 is one of the target genes of Tax. By using PBMCs from healthy donors in chemotaxis assays, it was demonstrated that culture supernatants of Tax+ cells strongly mobilized CCR4+CD4+ T cells. The migration was blocked by pretreatment of the supernatants with anti-CCL22 neutralizing antibody or pretreatment of the PBMCs with a CCR4-specific inhibitor. Further, Tax+ cells showed significant CCR4-dependent cell-cell interactions with the sorted CCR4+CD4+ T cells. These results imply that HTLV-1+ T cells, which were vertically transmitted from the breast milk of a carrier mother, produced CCL22 upon expression of Tax and preferentially recruited CCR4+CD4+ T cells in the child.
  • CCL27 transgenic mice showed enhanced contact hypersensitivity reaction to repeated challenges with fluorescein isothiocyanate.  [通常講演]
    鑑慎司; 中山 隆志; 義江 修; 佐伯秀久; 常深祐一郎; 中村晃一郎; 小宮根真弓; 玉置邦彦
    Society for Investigative Dermatology Annual Meeting 2007年05月 Society for Investigative Dermatology Annual Meeting
  • 単純ヘルペスウイルス1型に対するケモカインの抗ウイルス活性の検討  [通常講演]
    白根 授美; 中山 隆志; 義江 修; 三島 弘; 下村 嘉一
    第111回日本眼科学会総会 2007年04月 大阪 第111回日本眼科学会総会
     
    (目的)ケモカインは白血球の主要な遊走制御因子であるが、近年、一部のケモカインにおいて抗菌活性を有することが報告された。抗菌ペプチドの一部はエンベロープウイルスに対しても抗ウイルス活性を持つことから、今回、ケモカインによる抗ウイルス活性について検討を行った。 (方法)単純ヘルペスウイルス1型(HSV-1)のプラーク解析を指標に、ケモカインによる抗ウイルス活性を探索した。結合解析によりケモカインとHSV-1との直接の結合を確認した。ケモカインのHSV-1粒子構造への影響を電子顕微鏡により検討した。さらに、ヘルペス性角膜実質炎(HSK)モデルマウスを用いて、ケモカインによる治療効果についても検討を行った。 (結果)22のケモカインのうちRANTES、MIP-1aおよびMIP-1bを含む8つのケモカインはHSV-1のVero細胞への感染を優位に抑制した。これらのケモカインは直接HSV-1と結合し、その結合はエンベロープタンパクgBに対する中和抗体で特異的に阻害された
  • 大腸癌におけるCXCL16の発現と腫瘍浸潤リンパ球および予後との関連  [通常講演]
    北條荘三; 中山 隆志; 義江 修; 橋本伊佐也; 小泉桂一; 有田貴久; 南貴之; 篠原看奈; 櫻井宏明; 済木育夫; 塚田一博
    日本外科学会 2007年 日本外科学会
  • Rapamycin投与による胃癌腹膜播種抑制  [通常講演]
    橋本伊佐也; 中山 隆志; 義江 修; 北條荘三; 小泉桂一; 南貴之; 篠原看奈; 櫻井宏明; 済木育夫; 塚田一博
    日本外科学会 2007年 日本外科学会
  • HTLV-1感染細胞におけるケモカインMDC/CCL22遺伝子発現誘導機構の解析  [通常講演]
    稗島 州雄; 中山 隆志; 長久保 大輔; 白川 愛子; 金 哲; 義江 修; 藤井 雅寛
    第54回日本ウイルス学会学術集会 2006年11月 名古屋 第54回日本ウイルス学会学術集会
     
    目的と意義】HTLV-1が感染してから数十年の潜伏感染の後、一部の感染者に成人T細胞白血病(ATL)が発症する。我々は以前、ATL腫瘍細胞の特徴として、本来末梢血CD4+T細胞で高々10%程度しか発現していないケモカイン受容体CCR4が高頻度に発現していることを報告した(Blood, 2002)。今回、ATL細胞がCCR4+CD4+T細胞に集束されるメカニズムの1つとして、HTLV-1感染初期に発現すると考えられるTax蛋白との関係に注目した。Taxは、細胞遺伝子の発現制御や発がん関連遺伝子の修飾を通して腫瘍化の初期に重要な役割を果たすと考えられている。我々はCCR4発現細胞を選択的に細胞遊走するケモカインMDCとTaxとの関係を検討した。 【材料と方法】各種HTLV-1感染細胞株、Tax発現誘導系細胞株JPX-9、Jurkat T細胞株などを用いて、RT-PCR、ELISA、siRNA、プロモーター解析、Noshift転写因子解析などにより検討した。 【結果】HTLV-1感染細胞株の多くがTaxを強発現しており、解析したTax発現細胞のほとんどでMDCの遺
  • 破骨細胞分化に伴うCCL22の発現亢進と肺がんの骨転移機序  [通常講演]
    小泉 桂一; 義江 修; 中山 隆志; 小林 光夫; 中村エリアネ静; 済木 育夫
    第71回日本インターフェロン・サイトカイン学会学術集会 2006年07月 西宮市 第71回日本インターフェロン・サイトカイン学会学術集会
  • ケモカインCXCR4を介した新たな胃癌腹膜播種成立機序の解明  [通常講演]
    安本 和生; 義江 修; 中山 隆志; 小泉 桂一; 川島 篤弘; 済木 育夫; 高橋 豊
    第71回日本インターフェロン・サイトカイン学会学術集会 2006年07月 西宮市 第71回日本インターフェロン・サイトカイン学会学術集会
  • 大腸癌におけるCXCL16の発現と予後との関連  [通常講演]
    北條荘三; 中山 隆志; 義江 修; 小泉桂一; 有田貴久; 篠原看奈; 南貴之; 橋本伊佐也; 櫻井宏明; 塚田一博; 済木育夫
    日本癌学会65回総会 2006年 日本癌学会65回総会
  • Senile/Age-Related EBV+B-Cell Lymphoproliferative Disorder(SLPD)におけるケモカイン発現と腫瘍局所浸潤T細胞の解析  [通常講演]
    金哲; 中山 隆志; 白川 愛子; 長久保 大輔; 稗島 州雄; 義江 修; 中村栄男
    日本癌学会65回総会 2006年 日本癌学会65回総会
  • Chemokine receptor CXCR4阻害による胃癌腹膜播種の抑制  [通常講演]
    安本和生; 中山 隆志; 義江 修; 小泉桂一; 済木育夫; 川島篤弘; 高橋豊
    日本癌学会65回総会 2006年 日本癌学会65回総会
  • CCL27トランスジェニックマウスはFITCによるcontact hypersensitivityが亢進する  [通常講演]
    鑑慎司; 中山 隆志; 義江 修; 佐伯秀久; 常深祐一郎; 中村晃一郎; 玉置邦彦
    日本研究皮膚科学会年次学術大会・総会プログラム31回 2006年 日本研究皮膚科学会年次学術大会・総会プログラム31回
  • 成人T細胞白血病の腸管浸潤におけるケモカイン受容体CCR9の役割  [通常講演]
    長久保 大輔; 義江 修; 金 哲; 中山 隆志; 稗島 州雄
    日本免疫学会総会 2005年12月 横浜 日本免疫学会総会
  • ドーパミンレセプターD3を介したナイーブCD8陽性T細胞の遊走とリンパ節ホーミング  [通常講演]
    渡邊 賀子; 義江 修; 中山 隆志; 長久保 大輔; 稗島 州雄
    日本免疫学会 2005年12月 横浜 日本免疫学会
  • Senile EBV+ B-cell lymphoproliferative disorder (SLPD)におけるケモカイン発現と病態形成  [通常講演]
    金 哲; 義江 修; 中山 隆志; 長久保 大輔; 稗島 州雄
    日本免疫学会総会 2005年12月 横浜 日本免疫学会総会
  • 破骨細胞分化誘導に伴うCCL22産生とヒト小細胞肺癌株SBC-5細胞の骨転移機構の解明  [通常講演]
    小泉 桂一; 義江 修; 中山 隆志; 小林 光夫; 中村; エリアネ静; 斎藤; 百合花; 櫻井; 宏明; 済木; 育夫; 亀田 陽一
    第64回日本癌学会学術総会 2005年09月 札幌 第64回日本癌学会学術総会
  • ヒト前立腺癌細胞株におけるDHT-AR誘導によるケモカイン受容体の発現亢進と細胞機能の変化について  [通常講演]
    明石 拓也; 義江 修; 中山 隆志; 永川 修; 布施; 有田 貴久; 小泉; 桂一; 斎藤; 百合花; 篠原; 看奈; 南; 貴久; 櫻井; 宏明; 済木 育夫
    第64回日本癌学会学術総会 2005年09月 第64回日本癌学会学術総会
  • Chemokine receptor CXCR4発現胃癌が腹膜播種形成に関与する  [通常講演]
    安本 和生; 義江 修; 中山 隆志; 稗島 州雄; 高橋 豊; 麿伊; 小泉 桂一; 櫻井; 宏明; 済木 育夫; 川島 篤弘
    第64回日本癌学会学術総会 2005年09月 札幌 第64回日本癌学会学術総会
  • CCL21により誘導されるマウス肺癌細胞の転移関連因子の検索およびその受容体CCR7の発現機構の解析  [通常講演]
    有田 貴久; 義江 修; 中山 隆志; 稗島 州雄; 小泉 桂一; 櫻井; 宏明; 済木 育夫
    第64回日本癌学会学術総会 2005年09月 札幌 第64回日本癌学会学術総会
  • 成人T細胞白血病細胞の腸管浸潤におけるケモカイン系の役割  [通常講演]
    長久保 大輔; 義江 修; 金 哲; 中山 隆志; 稗島 州雄
    第70回日本インターフェロン・サイトカイン学会学術集会 2005年07月 京都 第70回日本インターフェロン・サイトカイン学会学術集会
  • Senile EBV+ B-cell lymphoproliferative disorderにおけるケモカイン/ケモカインレセプターの発現解析  [通常講演]
    金 哲; 義江 修; 中山 隆志; 長久保 大輔; 稗島 州雄; 竹川 澄男; 尾山 卓; 中村
    第70回日本インターフェロン・サイトカイン学会学術集会 2005年07月 京都 第70回日本インターフェロン・サイトカイン学会学術集会
  • ヒト前立腺癌細胞株におけるケモカイン受容体の発現に及すアンドロゲンの影響について  [通常講演]
    明石拓也; 義江 修; 中山 隆志; 稗島 州雄; 永川修; 小泉桂一; 中村エリアネ静; 小林光夫; 済木育夫; 布施秀樹
    日本泌尿器科学会 2005年03月 日本泌尿器科学会
  • IL-12とCCL27の併用による抗腫瘍効果増強機構の解明  [通常講演]
    杉田敏樹; 義江 修; 中山 隆志; 高建青; 金川尚子; 飯田恵介; 本村吉章; 畑中豊; 谷一; 水口裕之; 早川尭夫; 岡田直貴; 堤康央; 弓忠範; 中川晋作
    日本薬学会123年会講演 2005年03月 日本薬学会123年会講演
  • senile EBV+ B-Cell lymphoproliferative disorderにおけるケモカイン発現とリンパ球浸潤  [通常講演]
    金哲; 中山 隆志; 竹川澄男; 長久保 大輔; 稗島 州雄; 義江 修; 尾山卓 中村栄男
    EBウイルス研究会シンポジウム 2005年 EBウイルス研究会シンポジウム
  • IgA抗体産生細胞の腸管粘膜固有層へのホーミングを誘導するケモカインの解析  [通常講演]
    稗島 州雄; 中山 隆志; 長久保 大輔; 義江 修
    日本免疫学会 2004年12月 第34回日本免疫学会総会・学術集会(札幌) 日本免疫学会
  • 角膜上皮細胞と角膜実質細胞におけるケモカイン産生能の解析  [通常講演]
    白根 授美; 福田 昌彦; 下村 嘉一; 中山 隆志; 稗島 州雄; 義江 修
    第70回日本中部眼科学会 2004年11月 大阪 第70回日本中部眼科学会
     
    角膜上皮細胞と角膜実質細胞は炎症性サイトカインやHSV-1感染により、様々なケモカインの発現を誘導した。マウスヘルペス性角膜実質炎では、その急性期には細胞性免疫を担うTh1、一方治癒に向かう後期には液性免疫を担うTh2が優勢な環境が形成されることが示唆された。
  • ケモカイン発現ベクターの腫瘍内投与による抗腫瘍効果と免疫細胞浸潤  [通常講演]
    岡田直貴; 義江 修; 中山 隆志; 中川晋作; 畑中豊; 谷洋一; 水口裕之; 早川高夫; 藤田卓也; 山本昌
    日本免疫学会総会 2004年11月 日本免疫学会総会
  • Liver-Expressed Chemokine/CCL16のヒスタミンH4レセプターに対する作用と好酸球遊走  [通常講演]
    中山 隆志; 稗島 州雄; 長久保 大輔; 義江 修; 加藤佳子; 藤
    第34回 日本免疫学会総会・学術集会 2004年11月 第34回 日本免疫学会総会・学術集会
  • IL-12及びCCL27発現アデノウイルスベクターの併用投与による抗腫瘍効果と免疫系細胞の浸潤(会議録)  [通常講演]
    杉田敏樹; 義江 修; 中山 隆志; 畑中豊 谷洋一; 水口裕之; 早川高夫; 岡田直貴; 堤康央; 真弓忠範; 中川晋作
    日本免疫学会総会・学術集会記録 2004年11月 日本免疫学会総会・学術集会記録
  • EBV感染B細胞におけるケモカイン発現の網羅的解析  [通常講演]
    中山 隆志; 長久保 大輔; 稗島 州雄; 義江 修
    第27回 日本分子生物学会年会 2004年11月 第27回 日本分子生物学会年会
  • IgA抗体産生細胞の腸管ホーミングに関与するケモカイン系の解析  [通常講演]
    川崎ゆり; 義江 修; 稗島 州雄; 花本 仁; 中山 隆志; 長久保 大輔; 金丸 昭久
    近畿大学医学雑誌 2004年10月 近畿大学医学雑誌
  • マウス肺癌のリンパ節転移に対するCCR7の発現とCCL21/Secondary Lymphoid-tissue Chemokine (SLC) の影響  [通常講演]
    有田貴久; 義江 修; 中山 隆志; 稗島 州雄; 小林光夫; 小澤陽子; 大橋養賢; 中村エリアネ静; 青塚保志; 斉藤百合花; 櫻井宏明; 小泉桂一; 済木育夫
    Cancer Science 2004年09月 Cancer Science
  • 角膜ヘルペスにおけるケモカイン系の役割  [通常講演]
    白根 授美; 福田 昌彦; 下村 嘉一; 中山 隆志; 稗島 州雄; 義江 修
    第19回ヘルペスウイルス研究会 2004年07月 名古屋 第19回ヘルペスウイルス研究会
     
    角膜上皮細胞と角膜実質細胞は炎症性サイトカインやHSV-1感染により、それぞれ独自のパターンで、未熟樹状細胞、単球やT細胞などを遊走するケモカインを産生することが明らかとなった。マウスヘルペス性角膜実質炎では、その急性期には細胞性免疫を担うTh1、一方治癒に向かう後期には液性免疫を担うTh2が優勢な環境が形成されることが示唆された。
  • ホジキン細胞/Reed-Sternberg細胞におけるケモカインCCL28の発現と好酸球/形質細胞浸潤との関連性の検討  [通常講演]
    花本 仁; 金丸 昭久; 宮里肇; 辰巳 陽一; 中山 隆志; 竹川澄男; 稗島 州雄; 義江 修
    第44回日本リンパ網内系学会学術総会 2004年07月 京都 第44回日本リンパ網内系学会学術総会
  • EBV感染B細胞でのケモカイン/ケモカインレセプター発現の網羅的解析  [通常講演]
    義江 修; 中山 隆志; 稗島 州雄
    第1回EBウイルス研究会シンポジウム 2004年07月 札幌 第1回EBウイルス研究会シンポジウム
  • CCL20のヒト角膜組織における発現誘導とマウスヘルペス性角膜実質炎における役割  [通常講演]
    白根 授美; 福田 昌彦; 下村 嘉一; 中山 隆志; 長久保 大輔; 稗島 州雄; 義江 修
    第108回日本眼科学会総会 2004年04月 東京 第108回日本眼科学会総会
     
    炎症性サイトカインやHSV-1感染により角膜上皮細胞や角膜実質細胞からCCL20が産生されることが分かった。また、ヘルペス性角膜実質炎において、CCL20はその受容体であるCCR6を介した樹状細胞浸潤を誘導することにより、ヘルペス性角膜実質炎の病態形成に重要な役割を果たすと考えられた。
  • リンパ組織移行性を増強した樹状細胞ワクチンの創製  [通常講演]
    森直樹; 義江 修; 中山 隆志; 岡田直貴; 是友良介; 岡田裕香; 水口裕之; 早川尭夫; 中川晋作; 真弓忠範; 藤田卓也; 山本昌
    日本薬学会124年会講演 2004年03月 日本薬学会124年会講演
  • ケモカイン発現ベクターの腫瘍内投与を併用した樹状細胞ワクチンの抗腫瘍効果  [通常講演]
    佐々木明徳; 義江 修; 中山 隆志; 岡田直貴; 丹羽正和; 岡田裕香; 畑中豊; 谷洋一; 水口裕之; 早川尭夫; 中川晋作; 真弓忠範; 藤田卓也; 山本昌
    日本薬学会124年会講演 2004年03月 日本薬学会124年会講演
  • ヒト胃癌腹膜播種形成におけるSDF-1a/CXCR-4リガンド・レセプターシステムの関与  [通常講演]
    安本和生; 中山 隆志; 稗島 州雄; 義江 修; 小泉桂一; 済木育夫; 櫻井宏明; 川島篤弘; 高橋豊; 磨伊正義
    第63回 日本癌学会総会 2004年 第63回 日本癌学会総会
  • ドーパミンレセプターD3を介したCD8陽性T細胞の遊走  [通常講演]
    渡辺賀子; 中山 隆志; 長久保 大輔; 稗島 州雄; 義江 修
    第34回 日本免疫学会総会 2004年 第34回 日本免疫学会総会
  • EBV感染B細胞でのケモカイン/ケモカインレセプター発現の網羅的解析  [通常講演]
    義江 修; 中山 隆志; 金哲; 長久保 大輔; 稗島 州雄
    第69回 日本インターフェロン・サイトカイン学会 2004年 第69回 日本インターフェロン・サイトカイン学会
  • CCL21/Secondary lymphoid-tissue chemokine(SLC)によるヒト非小細胞肺癌(NSCLC)のリンパ節転移亢進の可能性  [通常講演]
    小泉桂一; 中山 隆志; 稗島 州雄; 義江 修; 小澤陽子; 大橋養賢; 中村エリアネ静; 青塚保志; 小林光夫; 斉藤百合花; 有田貴久; 桜井宏明; 済木育夫; 土岐善紀; 一木克之
    第17回富山癌治療懇話学会術講演会 2004年 第17回富山癌治療懇話学会術講演会
  • 腸管免疫におけるケモカインCCL28/CCR10系の役割  [通常講演]
    稗島 州雄; 川崎ゆり; 花本 仁; 中山 隆志; 義江 修
    日本免疫学会 2003年12月 第33回日本免疫学会総会・学術集会(福岡) 日本免疫学会
  • ケモカインCCL28/MECの唾液腺における役割(学会奨励賞受賞講演)  [通常講演]
    稗島 州雄; 伊澤 大; 中山 隆志; 川崎ゆり; 義江 修; 斎藤 卓也; 大谷明夫
    日本唾液腺学会 2003年12月 第48回日本唾液腺学会(東京) 日本唾液腺学会
  • 細胞外基質蛋白による好酸球遊走の活性化  [通常講演]
    加藤佳子; 義江 修; 中山 隆志; 藤澤隆夫
    炎症・再生 2003年11月 炎症・再生
  • ケモカイン遺伝子導入を併用したDC癌免疫療法プロトコールの有効性評価  [通常講演]
    佐々木明徳; 義江 修; 中山 隆志; 岡田直貴; 畑中豊; 谷洋一; 中川晋作; 真弓忠範; 早川高夫; 藤田卓也; 山本昌
    日本免疫学会総会・学術集会 2003年11月 日本免疫学会総会・学術集会
  • ケモカインファミリー分子の多くはスカベンジャー受容体活性を有する  [通常講演]
    島岡猛士; 義江 修; 中山 隆志; 稗島 州雄; 米原伸
    日本免疫学会総会・学術集会 2003年11月 日本免疫学会総会・学術集会
  • EBV不死化B細胞におけるケモカイン発現とその制御機構の解析  [通常講演]
    中山 隆志; 長久保 大輔; 稗島 州雄; 義江 修
    第33回 日本免疫学会総会・学術集会 2003年11月 第33回 日本免疫学会総会・学術集会
  • CCケモカインレセプター(CCR7)遺伝子を導入した樹状細胞のin vitro及びin vivo遊走能  [通常講演]
    森直樹; 義江 修; 中山 隆志; 岡田直貴; 井上恵美子; 中川晋作; 真弓忠範; 早川高夫; 藤田卓也; 山本昌
    日本免疫学会総会・学術集会 2003年11月 日本免疫学会総会・学術集会
  • ATLLにおけるケモカインレセプター発現の網羅的解析  [通常講演]
    義江 修; 中山 隆志; 長久保 大輔; 稗島 州雄
    日本免疫学会総会・学術集会 2003年11月 日本免疫学会総会・学術集会
  • MEC/CCL28 Has Dual Functions in Mucosal Immunity as a Chemoattractant with Broad-Spectrum Antimicrobial Activity  [通常講演]
    稗島 州雄; 川崎ゆり; 中山 隆志; 義江 修
    日本樹状細胞研究会、12th International Symposium on Molecular and Cellular Biology of Macrophages 2003年06月 宇都宮 日本樹状細胞研究会、12th International Symposium on Molecular and Cellular Biology of Macrophages
  • 樹状細胞免疫療法の有効性改善を目指したケモカイン発現ベクターの併用  [通常講演]
    佐々木明徳; 義江 修; 中山 隆志; 岡田直貴; 大久保米起; 岡田裕香; 水口裕之; 早川尭夫; 中川晋作; 真弓忠範; 藤田卓也; 山本昌
    Drug Delivery System 2003年05月 Drug Delivery System
  • 気道上皮細胞によるTh2細胞のトランスマイグレーション  [通常講演]
    加藤佳子; 義江 修; 中山 隆志; 藤澤隆夫; 森昌
    アレルギー 2003年03月 アレルギー
  • ケモカイン発現RGDファイバーミュータントアデノウイルスベクターの樹状細胞免疫療法への応用に関する基礎的検討  [通常講演]
    佐々木明徳; 義江 修; 中山 隆志; 岡田直貴; 大久保米起; 岡田裕香; 水口裕之; 早川尭夫; 中川晋作; 真弓忠範; 藤田卓也; 山本昌
    日本薬学会123年会講演 2003年03月 日本薬学会123年会講演
  • ケモカイン及びサイトカイン発現アデノウイルスベクターの併用による癌遺伝子治療の最適化  [通常講演]
    高建青; 義江 修; 中山 隆志; 形山和史; Soares Alexandre Learth; 水口裕之; 早川尭夫; 堤康央; 真弓忠範; 中川晋作
    薬剤学 2003年03月 薬剤学
  • CCL28 has a dual role in mucosal immunity as chemokine with a broad-spectrum antimicrobial activity.  [通常講演]
    稗島 州雄; 伊澤 大; 中山 隆志; 川崎ゆり; 義江 修; 斎藤 卓也; 大谷明夫
    Keystone Symposia 2003 2003年01月 Breckenridge, Colorado, U.S.A. Keystone Symposia 2003
  • Anti-tumor effect by a CC chemokine, CCL27, introduces into tumor cells through a recombinant adenovirus vector  [通常講演]
    Gao JQ; 中山 隆志; 義江 修; Tsuda Y Katayama; K; Hatanaka; Y; Tani; Y; Mizuguchi H; Hayakawa; T; Tsutsumi Y; Mayumi T; Nakagawa S
    2003年
  • ケモカインCCL28/MECの唾液腺における役割  [通常講演]
    稗島 州雄; 伊澤 大; 中山 隆志; 義江 修; 斎藤 卓也; 大谷明夫
    日本免疫学会 2002年12月 第32回日本免疫学会総会・学術集会(東京) 日本免疫学会
  • 大腸癌先進部におけるケモカイン及びケモカインレセプターの発現  [通常講演]
    武者宏昭; 義江 修; 中山 隆志; 溝井賢幸; 大谷明夫; 椎葉健一; 佐々木巖
    日本癌学会61回総会 2002年10月 日本癌学会61回総会
  • 大腸癌先進部におけるケモカイン及びケモカインレセプターの発現  [通常講演]
    武者宏昭; 義江 修; 中山 隆志; 椎葉健一; 溝井賢幸; 大谷明夫; 佐々木巖
    日本免疫学会総会・学術集会 2002年10月 日本免疫学会総会・学術集会
  • ヒト骨髄腫細胞及び骨髄形質細胞におけるケモカイン受容体CXCR4,CXCR6とCCR10の選択的発現  [通常講演]
    中山 隆志; 稗島 州雄; 伊澤 大; 義江 修
    第32回 日本免疫学会総会・学術集会 2002年10月 第32回 日本免疫学会総会・学術集会
  • ヒト非小細胞肺癌(NSCLC)に対するSecondary Lymphoid-tissue Chemokine (SLC) のリンパ節転移亢進因子としての可能性  [通常講演]
    小泉桂一; 義江 修; 中山 隆志; 小澤陽子; 大橋養賢; 中村エリアネ静; 櫻井宏明; 済木育夫
    日本癌学会61回総会 2002年10月 日本癌学会61回総会
  • ヒト巨核球によるthymus and activation-regulated chemokine (TARC/CCL17) 産生 アレルギー炎症における血小板関与の可能性  [通常講演]
    西森久史; 義江 修; 中山 隆志; 藤澤隆夫; 加藤佳子; 勝又元 熱田純
    日本免疫学会総会・学術集会 2002年10月 日本免疫学会総会・学術集会
  • ケモカイン活性とスカベンジャー受容体活性を有するSR-PSOX/CXCL16の自然免疫と獲得免疫における役割解析  [通常講演]
    島岡猛士; 義江 修; 中山 隆志; 米原伸
    日本免疫学会総会・学術集会 2002年10月 日本免疫学会総会・学術集会
  • 気道上皮細胞が好酸球トランスマイグレーションに果たす役割について  [通常講演]
    加藤佳子; 義江 修; 中山 隆志; 藤澤隆夫
    炎症・再生 2002年06月 炎症・再生
  • 新しいケモカイン その生理活性と臨床的意義 ケモカイン活性とスカベンジャー受容体活性を有するSR-PSOX/CXCL16の自然免疫と獲得免疫における役割解析  [通常講演]
    島岡猛士; 義江 修; 中山 隆志; 久米典昭; 南学; 林田和隆; 北徹 米原伸
    炎症・再生 2002年06月 炎症・再生
  • Cell Delivery による癌治療法の開発 新規ケモカインILCのin vivoにおける細胞遊走能評価と癌治療への応用  [通常講演]
    津田育宏; 義江 修; 中山 隆志; 形山和史; 畑中豊; 谷洋一; 水口裕之; 早川尭夫; 中川晋作; 真弓忠範
    薬剤学 2002年03月 薬剤学
  • 転写因子NF-κBによるケモカインLARC/CCR20遺伝子の活性化機構  [通常講演]
    稗島 州雄; 伊澤 大; 中山 隆志; 藤澤 隆一; 義江 修; 藤家 悟; 大柳 治正
    日本免疫学会 2001年12月 第31回日本免疫学会総会・学術集会(大阪) 日本免疫学会
  • ケモカインによるLFA-1/ICAM-1の接着性亢進にはRap 1及びCdc42が関与する  [通常講演]
    下中美香; 義江 修; 中山 隆志; 稗島 州雄; 片桐晃子; 前田明人; 木梨達雄
    日本免疫学会総会・学術集会 2001年12月 日本免疫学会総会・学術集会
  • EBV不死化B細胞におけるケモカイン受容体の発現制御機構の解析  [通常講演]
    中山 隆志; 藤澤 隆一; 伊澤 大; 稗島 州雄; 義江 修; 高田 賢蔵
    第31回 日本免疫学会総会・学術集会 2001年12月 第31回 日本免疫学会総会・学術集会
  • ケモカインを用いた癌免疫療法の基礎的検討  [通常講演]
    津田育宏; 義江 修; 中山 隆志; 中川晋作; 塚田有希子; 水口裕之; 早川尭夫; 真弓忠範
    薬剤学 2001年03月 薬剤学
  • CCケモカインLARC/MIP-3α/CCL20のケラチノサイトにおける発現誘導とアトピー性皮膚炎における役割  [通常講演]
    中山 隆志; 藤澤 隆一; 稗島 州雄; 伊澤 大; 義江 修; 山田秀和; 手塚 正; 藤家 悟; 河崎 寛
    第23回 日本分子生物学会年会 2000年12月 第23回 日本分子生物学会年会
  • アトピー性皮膚炎患者における好酸球のケモカインレセプター発現について  [通常講演]
    山田 秀和; 杉原 和子; 弓立 達夫; 手塚 正; 中山 隆志; 義江 修; 松倉 正治
    第50回日本アレルギー学会総会 2000年 横浜 第50回日本アレルギー学会総会
  • Production of CC Chemokine LARC/MIP-3a by Epidermal Keratinocytes and ITS Role in Atopic Dermatitis  [通常講演]
    山田 秀和; 弓立 達夫; 手塚 正; 中山 隆志; 松倉 正治
    25th Annual Meeting 2000年 岐阜 25th Annual Meeting

MISC

  • 山下絢香; 松尾一彦; 須佐美陽子; 早坂晴子; 原雄大; 中山隆志 日本薬学会年会要旨集(Web) 143rd 2023年
  • 西田晃尚; 山本真也; 松尾一彦; 早坂晴子; 海堀祐一郎; 長久保大輔; 原雄大; 義江修; 義江修; 中山隆志 日本薬学会年会要旨集(Web) 143rd 2023年
  • ケモカインCCL28はHippo経路を介して大腸杯細胞分化を誘導する
    海堀 祐一郎; 松尾 一彦; 中山 隆志; 長久保 大輔 日本生化学会大会プログラム・講演要旨集 95回 3P -229 2022年11月
  • 高活性型ケモカインXCL1はCTL誘導ワクチンアジュバントとして抗腫瘍効果を増強する
    亀井 萌百; 松尾 一彦; 原 雄大; 中山 隆志 日本がん免疫学会総会プログラム・抄録集 26回 113 -113 2022年06月
  • 高活性型XCL1の腫瘍局所投与によるcDC1の集積と腫瘍免疫活性化
    松尾 一彦; 亀井 萌百; 吉田 裕亮; 原 雄大; 権 英淑; 神山 文男; 中山 隆志 日本がん免疫学会総会プログラム・抄録集 26回 153 -153 2022年06月
  • アトピー性皮膚炎モデルマウスにおけるアスコルビン酸誘導体DDH-1のTh2型免疫応答抑制効果
    藤井 太希; 松尾 一彦; 北畑 孝祐; 須佐美 陽子; 西川 莉央; 原 雄大; 権 英淑; 神山 文男; 中山 隆志 日本薬学会年会要旨集 142年会 28M -pm05S 2022年03月
  • 高活性型XCL1の腫瘍局所投与によるXCR1陽性樹状細胞の集積向上は、腫瘍微小環境を改善して抗腫瘍効果を示す
    吉田 裕亮; 亀井 萌百; 松尾 一彦; 大月 真由子; 原 雄大; 権 英淑; 神山 文男; 中山 隆志 日本薬学会年会要旨集 142年会 28M -pm06S 2022年03月
  • 高活性型XCL1のワクチンアジュバントとしての免疫誘導特性
    長谷 尚俊; 亀井 萌百; 松尾 一彦; 森末 悠亮; 古川 玲緒奈; 原 雄大; 中山 隆志 日本薬学会年会要旨集 142年会 28PO6 -02S 2022年03月
  • 森川敏生; 森川敏生; 萬瀬貴昭; 坂本裕介; 楡光世; 綿原光司; 原雄大; 松尾一彦; 中山隆志 日本栄養・食糧学会大会講演要旨集 76th 2022年
  • 坂本裕介; 萬瀬貴昭; 楡光世; 綿原光司; 原雄大; 松尾一彦; 中山隆志; 森川敏生; 森川敏生 日本農芸化学会大会講演要旨集(Web) 2022 2022年
  • 乾癬におけるケモカイン受容体CCR4を介したTh17細胞の遊走制御機構と病理的役割
    松尾 一彦; 北畑 孝祐; 中山 隆志 アレルギーの臨床 41 (11) 1018 -1022 2021年10月
  • 乾癬におけるTh17細胞増殖に対するケモカイン受容体CCR4の役割
    松尾 一彦; 北畑 孝祐; 中山 隆志 別冊Bio Clinica: 慢性炎症と疾患 10 (1) 132 -136 2021年05月
  • ケモカイン受容体CCR4の関節リウマチ発症および増悪における役割
    本澤 龍茉; 松尾 一彦; 原 雄大; 中山 隆志 日本薬学会年会要旨集 141年会 27V08 -am05S 2021年03月
  • 乾癬モデルマウスにおけるTh17細胞増幅に対するCCR4の寄与
    北畑 孝祐; 松尾 一彦; 海堀 祐一郎; 長久保 大輔; 義江 修; 中山 隆志 日本薬学会年会要旨集 141年会 27V08 -am10S 2021年03月
  • 高活性型ケモカインXCL1の経皮ワクチンシステムへの応用によるメモリーCTL誘導効率の増強
    大月 真由子; 亀井 萌百; 松尾 一彦; 今西 遥香; 原 雄大; 権 英淑; 神山 文男; 岡田 直貴; 中山 隆志 日本薬学会年会要旨集 141年会 29P01 -113S 2021年03月
  • ケモカイン受容体CCR4の関節リウマチ発症および増悪における役割
    本澤 龍茉; 松尾 一彦; 原 雄大; 中山 隆志 日本薬学会年会要旨集 141年会 27V08 -am05S 2021年03月
  • 高活性型ケモカインXCL1の経皮ワクチンシステムへの応用によるメモリーCTL誘導効率の増強
    大月 真由子; 亀井 萌百; 松尾 一彦; 今西 遥香; 原 雄大; 権 英淑; 神山 文男; 岡田 直貴; 中山 隆志 日本薬学会年会要旨集 141年会 29P01 -113S 2021年03月
  • 森川敏生; 森川敏生; 萬瀬貴昭; 坂本祐介; 綿原光司; 原雄大; 松尾一彦; 中山隆志 日本生薬学会年会講演要旨集 67th 152 -152 2021年
  • 大腸粘液・唾液の産生メカニズムの解析
    海堀 祐一郎; 松尾 一彦; 中山 隆志; 長久保 大輔 日本生化学会大会プログラム・講演要旨集 93回 [1Z06 -444)] 2020年09月
  • 高活性型XCL1による局在制御システムを応用したがんワクチンアジュバントの創製
    亀井 萌百; 松尾 一彦; 原 雄大; 義江 修; 中山 隆志 日本DDS学会学術集会プログラム予稿集 36回 151 -151 2020年08月
  • 松尾 一彦; 中山 隆志 ファルマシア 56 (4) 309 -313 2020年04月
  • ヨウバイヒのメタノール抽出物によるアトピー性皮膚炎の改善効果
    須佐美 陽子; 松尾 一彦; 森川 敏生; 中山 隆志 日本薬学会年会要旨集 140年会 26Z -am01S 2020年03月
  • 構造安定化XCL1の経肺投与によるメモリーCTL誘導効果
    亀井 萌百; 松尾 一彦; 義江 修; 中山 隆志 日本薬学会年会要旨集 140年会 26Z -am02S 2020年03月
  • ケモカイン受容体CCR4はメモリーTh17細胞増幅を介して乾癬発症に関与する
    北畑 孝祐; 松尾 一彦; 海堀 祐一郎; 長久保 大輔; 義江 修; 中山 隆志 日本薬学会年会要旨集 140年会 26Z -am03S 2020年03月
  • ケモカイン受容体CCR4はTreg遊走を介して食物アレルギーの抑制に寄与する
    長尾 遥佳; 松尾 一彦; 義江 修; 中山 隆志 日本薬学会年会要旨集 140年会 26Z -am04S 2020年03月
  • ケモカインによる粘液・唾液生成制御機構の解析
    海堀 祐一郎; 松尾 一彦; 中山 隆志; 長久保 大輔 日本薬学会年会要旨集 140年会 26Z -am11 2020年03月
  • ケモカインCCL28は気管支喘息病態の発現に寄与する
    藤原 加奈; 原 雄大; 中山 葵; 松尾 一彦; 松田 将也; 奈邉 健; 義江 修; 中山 隆志 日本薬学会年会要旨集 140年会 28Q -pm027S 2020年03月
  • ケモカイン受容体CCR4の阻害薬投与による動脈硬化モデルマウスの病変形成の促進
    嶋本 美咲; 佐々木 直人; 野口 恵美; 有地 珠里; 大内 友梨香; Amin Hilman Zulkifli; 堀部 紗世; 河内 正二; 松尾 一彦; 中山 隆志; 平田 健一; 力武 良行 日本薬学会年会要旨集 140年会 28Q -pm033S 2020年03月
  • EBV陽性膿胸関連リンパ腫はCCR4陽性制御性T細胞の誘引に寄与するケモカインCCL17およびCCL22を発現する(EBV+ pyothorax-associated lymphoma expresses CCL17 and CCL22 chemokines that recruit CCR4+ regulatory T cells)
    樋口 智紀; 橋田 裕美子; 氏原 隆子; 谷口 亜裕子; 中山 隆志; 大畑 雅典 日本癌学会総会記事 78回 J -1017 2019年09月
  • 松尾 一彦; 中山 隆志 日本血栓止血学会誌 30 (4) 610 -618 2019年08月
  • Th17依存的な乾癬モデルマウスの作製とケモカイン受容体CCR4の役割
    本澤 龍茉; 松尾 一彦; 北畑 孝祐; 長沼 孝典; 有馬 優香; 岩間 有咲; 長久保 大輔; 義江 修; 中山 隆志 日本薬学会年会要旨集 139年会 (3) 62 -62 2019年03月
  • 制御性T細胞を標的としたワクチンアジュバントの開発
    東山 慎太郎; 松尾 一彦; 山本 真也; 長久保 大輔; 義江 修; 中山 隆志 日本薬学会年会要旨集 139年会 (3) 62 -62 2019年03月
  • 抗炎症作用を有する新規アスコルビン酸誘導体DDH-1の乾癬病態における改善効果
    北畑 孝祐; 松尾 一彦; 長沼 孝典; 西川 莉央; 中山 隆志 日本薬学会年会要旨集 139年会 (3) 62 -62 2019年03月
  • ケモカインCCL28の欠損はIgAを介した粘膜免疫を減弱させる
    松尾 一彦; 山本 真也; 長久保 大輔; 義江 修; 中山 隆志 日本薬学会年会要旨集 139年会 (3) 88 -88 2019年03月
  • CD103陽性樹状細胞を標的としたCTL誘導ケモカインアジュバントの開発
    亀井 萌百; 松尾 一彦; 北畑 孝祐; 義江 修; 中山 隆志 日本薬学会年会要旨集 139年会 (3) 88 -88 2019年03月
  • ケモカインCCL28欠損はメラノーマ細胞の増殖を促進する
    山崎 真子; 松尾 一彦; 長久保 大輔; 義江 修; 中山 隆志 日本薬学会年会要旨集 139年会 (3) 111 -111 2019年03月
  • フタル酸ジブチルを用いた新規アトピー性皮膚炎モデルマウスの作製とケモカイン受容体CCR4の役割
    須佐美 陽子; 松尾 一彦; 長尾 遥佳; 中山 隆志 日本薬学会年会要旨集 139年会 (3) 111 -111 2019年03月
  • CD70陽性樹状細胞を標的としたTh17細胞依存的CTL誘導アジュバントの開発
    岩間 有咲; 松尾 一彦; 山本 真也; 三嶋 樹; 中山 隆志 日本薬学会年会要旨集 139年会 (3) 112 -112 2019年03月
  • 森川 敏生; 松尾 一彦; 八幡 郁子; 二宮 清文; 村岡 修; 中山 隆志 天然有機化合物討論会講演要旨集 56 (0) 2018年07月
  • 高活性型XCL1/lymphotactinによる抗原特異的メモリーCTLの効率的な誘導
    亀井 萌百; 松尾 一彦; 北畑 孝祐; 吉岡 靖雄; 義江 修; 中山 隆志 日本薬学会年会要旨集 138年会 (3) 168 -168 2018年03月
  • ケモカインCCL28のIgA産生細胞に対する活性化因子としての役割
    山本 真也; 松尾 一彦; 神原 弘和; 長久保 大輔; 義江 修; 中山 隆志 日本薬学会年会要旨集 138年会 (3) 168 -168 2018年03月
  • 新規アスコルビン酸誘導体の乾癬に対する予防的ならびに治療的効果
    長沼 孝典; 松尾 一彦; 中山 隆志 日本薬学会年会要旨集 138年会 (3) 169 -169 2018年03月
  • ケモカイン受容体CCR4は急性期アトピー性皮膚炎の発症に重要な役割を担う
    竹内 つぐみ; 松尾 一彦; 竹田 なつみ; 長久保 大輔; 西脇 啓二; 義江 修; 中山 隆志 日本薬学会年会要旨集 138年会 (3) 169 -169 2018年03月
  • ケモカイン受容体CCR4およびCCR6は乾癬発症において異なる役割を担う
    有馬 優香; 松尾 一彦; 岩間 有咲; 長沼 孝典; 西脇 啓二; 義江 修; 中山 隆志 日本薬学会年会要旨集 138年会 (3) 169 -169 2018年03月
  • 筋肉内投与ワクチンにおいてCCR4阻害剤はTregの筋肉組織への遊走を阻害することで抗原特異的免疫応答を増強する
    東山 慎太郎; 松尾 一彦; 山本 真也; 長久保 大輔; 西脇 啓二; 義江 修; 中山 隆志 日本薬学会年会要旨集 138年会 (3) 169 -169 2018年03月
  • PKN1はリンパ球の細胞運動・トラフィッキングを制御する
    窪内 康二; 團野 紗莉; 野町 昭; 平田 多佳子; 松尾 一彦; 中山 隆志; 佐藤 亮介; 杉浦 麗子; 阿部 学; 崎村 建司; 若菜 茂晴; 大崎 博之; 鴨志田 伸吾; 向井 秀幸 生命科学系学会合同年次大会 2017年度 [1P -0369] 2017年12月
  • 森川敏生; 森川敏生; 八幡郁子; 松尾一彦; 西田枝里子; 二宮清文; 二宮清文; 義江修; 村岡修; 村岡修; 中山隆志 食品薬学シンポジウム講演要旨集 7th 134‐136 2017年10月
  • 西尾 和人; 田村 和朗; 西郷 和真; 杉浦 麗子; 中山 隆志; 奥野 清隆; 菰池 佳史; 万代 昌紀; 竹村 司; 伊藤 彰彦; 大磯 直毅; 浮田 真沙世; 坂井 和子 日本遺伝カウンセリング学会誌 38 (2) 35 -36 2017年05月
  • 高活性型lymphotactin/XCL1を用いたがんワクチンアジュバントの開発
    石橋 美保; 松尾 一彦; 川端 史花; 北畑 孝祐; 中山 隆志 日本薬学会年会要旨集 137年会 (3) 140 -140 2017年03月
  • ケモカインCCL28の欠損はDSS腸炎モデルマウスにおける病態を増悪させる
    神原 弘和; 松尾 一彦; 山本 真也; 長久保 大輔; 義江 修; 中山 隆志 日本薬学会年会要旨集 137年会 (3) 140 -140 2017年03月
  • 東山慎太郎; 松尾一彦; 松永奈緒子; 山田祐毅; 西脇敬二; 義江修; 中山隆志 日本薬学会年会要旨集(CD-ROM) 137th (3) ROMBUNNO.26PB‐am071S -140 2017年
  • 高橋周平; 松尾一彦; 小山篤; 西脇敬二; 義江修; 中山隆志 日本薬学会年会要旨集(CD-ROM) 137th (3) ROMBUNNO.26PB‐am068S -140 2017年
  • 伊藤茉奈; 松尾一彦; 長沼孝典; 西脇敬二; 義江修; 中山隆志 日本薬学会年会要旨集(CD-ROM) 137th (3) ROMBUNNO.26PB‐am070S -140 2017年
  • 木村勇太; 松尾一彦; 小森悠平; 畑中翔太; 西脇敬二; 義江修; 中山隆志 日本薬学会年会要旨集(CD-ROM) 137th (3) ROMBUNNO.26PB‐am069S -140 2017年
  • 大鳥徹; 井上知美; 細見光一; 中川博之; 高島敬子; 近藤尚美; 高田亜美; 伊藤栄次; 中山隆志; 和田哲幸; 石渡俊二; 前川智弘; 船上仁範; 中村真也; 窪田愛恵; 平出敦; 松山賢治; 西田升三 社会薬学 35 (2) 94‐101 -101 2016年12月
  • 大鳥 徹; 井上 知美; 細見 光一; 中川 博之; 高島 敬子; 近藤 尚美; 高田 亜美; 伊藤 栄次; 中山 隆志; 和田 哲幸; 石渡 俊二; 前川 智弘; 船上 仁範; 中村 真也; 窪田 愛恵; 平出 敦; 松山 賢治; 西田 升三 社会薬学 35 (2) 94 -101 2016年12月
  • 森川敏生; 松尾一彦; 奥川修平; 奥川修平; 北川仁一朗; 北川仁一朗; 二宮清文; 中西勇介; 村岡修; 村岡修; 中山隆志; 中山隆志 日本生薬学会年会講演要旨集 63rd 146 -146 2016年08月
  • イミキモド誘発性乾癬の発症におけるケモカイン受容体CCR4の寄与ならびにCCR4阻害剤の治療効果
    伊藤 茉奈; 松尾 一彦; 小森 悠平; 中山 隆志 日本薬学会年会要旨集 136年会 (3) 174 -174 2016年03月
  • 新規発がん遺伝子SOX4による成人T細胞白血病/リンパ腫(ATLL)の新たな発がん機構の解明
    小森 悠平; 樋口 智紀; 松尾 一彦; 義江 修; 中山 隆志 日本薬学会年会要旨集 136年会 (3) 198 -198 2016年03月
  • 新規迅速アトピー性皮膚炎モデルマウスの作製ならびにケモカイン受容体CCR4の寄与
    藤里 駿; 松尾 一彦; 小森 悠平; 権 英淑; 神山 文男; 中山 隆志 日本薬学会年会要旨集 136年会 (4) 196 -196 2016年03月
  • 抗原特異的免疫応答の誘導におけるケモカイン受容体CCR4の役割ならびにCCR4阻害剤のアジュバント活性評価
    小山 篤; 松尾 一彦; 西脇 敬二; 義江 修; 中山 隆志 日本薬学会年会要旨集 136年会 (4) 199 -199 2016年03月
  • ケモカインLymphotactin/XCL1を用いたCTL誘導アジュバントの開発
    川端 史花; 松尾 一彦; 長谷川 裕太; 西馬 怜; 中山 隆志 日本薬学会年会要旨集 136年会 (4) 204 -204 2016年03月
  • Katsuichi Miyamoto; Kota Moriguchi; Rino Ueno; Takashi Nakayama; Susumu Kusunoki MULTIPLE SCLEROSIS JOURNAL 22 (3) 433 -433 2016年03月
  • CREB,NF-κBおよびTaxによって相乗的に発現誘導されたFOSBは、結果的にHTLV-1感染細胞の生存能に関与する
    樋口 智紀; 稗島 州雄; 中山 隆志; 義江 修 日本癌学会総会記事 74回 P -1083 2015年10月
  • 成人ヒトT細胞白血病/リンパ腫(ATLL)発がんにおけるSOX4の役割の解明
    小森 悠平; 樋口 智紀; 松尾 一彦; 義江 修; 中山 隆志 日本薬学会年会要旨集 135年会 (4) 60 -60 2015年03月
  • ケモカインレセプターCCR4アンタゴニストの特性解析ならびにアジュバント活性評価
    小山 篤; 松尾 一彦; 西脇 敬二; 義江 修; 中山 隆志 日本薬学会年会要旨集 135年会 (3) 97 -97 2015年03月
  • 和漢薬ライブラリーを利用したケモカイン受容体CCR3及びCCR4のアンタゴニスト成分の探索
    北田 卓也; 松尾 一彦; 小泉 桂一; 義江 修; 中山 隆志 日本薬学会年会要旨集 135年会 (3) 167 -167 2015年03月
  • 大鳥 徹; 平出 敦; 窪田 愛恵; 松山 賢治; 西田 升三; 井上 知美; 細見 光一; 伊藤 栄次; 中山 隆志; 和田 哲幸; 石渡 俊二; 船上 仁範; 中村 真也 日本医療薬学会年会講演要旨集 25 (0) 491 -491 2015年
  • SOX4はHDAC8を発現誘導し、皮膚T細胞リンパ腫の細胞増殖に寄与する(SOX4 induces expression of HDAC8 and plays a critical role in cell growth of cutaneous T-cell lymphomas)
    樋口 智紀; 中山 隆志; 義江 修 日本癌学会総会記事 73回 P -3291 2014年09月
  • 森川敏生; 八幡郁子; 松尾一彦; 二宮清文; 村岡修; 中山隆志 日本生薬学会年会講演要旨集 61st 118 -118 2014年08月
  • 森川 敏生; 松尾 一彦; 八幡 郁子; 二宮 清文; 村岡 修; 中山 隆志 天然有機化合物討論会講演要旨集 56 (0) 2014年
  • 成人T細胞白血病の発がんにおけるFra-2-SOX4経路の役割(Fra-2-SOX4 oncogenic cascade plays a critical role in cell growth of adult T-cell leukemia/lymphoma)
    樋口 智紀; 中山 隆志; 義江 修 日本癌学会総会記事 72回 113 -113 2013年10月
  • 和漢薬の科学基盤 共同研究による先駆的統合的解明 標準和漢薬ライブラリーを用いたケモカイン受容体CCR3およびCCR4アンタゴニストの探索 アレルギー疾患を標的として
    中山 隆志; 田中 宏幸; 松尾 一彦; 小泉 桂一; 義江 修 日本薬学会年会要旨集 133年会 (1) 146 -146 2013年03月
  • ウイルス学的シナプス形成によるCCR4陽性T細胞選択的HTLV-1伝播はHTLV-1感染細胞でのTax依存的なFosB誘導性CCL22発現に起因する(Induction of FosB by Tax induces CCL22 in HTLV-1-infected T cells, leading to HTLV-1 transmission to CCR4+ T cells)
    樋口 智紀; 稗島 州雄; 中山 隆志; 義江 修 日本癌学会総会記事 71回 361 -361 2012年08月
  • 【サイトカインのすべて(完全改訂版)】サイトカインの種類 ケモカイン CCL17
    中山 隆志 臨床免疫・アレルギー科 57 (Suppl.21) 432 -435 2012年05月
  • 【サイトカインのすべて(完全改訂版)】サイトカインの種類 ケモカイン CCL22
    中山 隆志 臨床免疫・アレルギー科 57 (Suppl.21) 452 -455 2012年05月
  • 白川愛子; 長久保大輔; 稗島州雄; 中山隆志; 金哲, 義江修 日本栄養・食糧学会大会講演要旨集 65th 105 -105 2011年04月
  • Tax発現HTLV-1感染T細胞における翻訳伸長因子eEF1A2の細胞増殖/生存における役割(Role of eEF1A2 on cell growth and survival in Tax-expressing HTLV-1-infected T cells)
    重田 暁子; 稗島 州雄; 樋口 智紀; 中山 隆志; 白川 愛子; 長久保 大輔; 義江 修 日本癌学会総会記事 68回 124 -124 2009年08月
  • CD4+成熟T細胞リンパ腫におけるFra-2-c-Myb発癌遺伝子カスケードの役割(The role of Fra-2 and c-Myb oncogenic cascade in CD4+ mature T-cell lymphomas)
    樋口 智紀; 中山 隆志; 長久保 大輔; 重田 暁子; 白川 愛子; 稗島 州雄; 義江 修 日本癌学会総会記事 68回 133 -133 2009年08月
  • 樋口智紀; 中山隆志; 長久保大輔; 重田暁子; 白川愛子; 稗島州雄; 義江修 日本分子生物学会年会講演要旨集 32nd (Vol.1) 232 2009年
  • 加齢関連EBV+B細胞リンパ増殖症における多様なケモカインの発現(Expression of various chemokines in age-related EBV+ B-cell lymphoproliferative disorder)
    義江 修; 竹川 澄男; 中山 隆志; 白川 愛子; 樋口 智紀; 長久保 大輔; 重田 暁子; 稗島 州雄; 中村 栄男 日本癌学会総会記事 67回 394 -394 2008年09月
  • Taxにより誘導されるCXCR7の発現はHTLV-1感染T細胞の増殖を促進する(Induction of CXCR7 by Tax promotes cell proliferation of HTLV-1 infected T cells)
    長久保 大輔; 白川 愛子; 中山 隆志; 重田 暁子; 樋口 智紀; 竹川 澄男; 稗島 州雄; 義江 修 日本癌学会総会記事 67回 400 -400 2008年09月
  • HTLV-1感染におけるTh2関連転写因子c-Mafの機能解析(Functional analysis of the Th2-related transcription factor c-Maf in HTLV-1 infection)
    稗島 州雄; 中山 隆志; 長久保 大輔; 重田 暁子; 樋口 智紀; 白川 愛子; 義江 修 日本癌学会総会記事 67回 483 -483 2008年09月
  • CCR4を発現するATLとCTCLにおけるFra-2の異常発現(Aberrant expression of Fra-2 in CCR4-expressing adult T-cell leukemia and cutaneous T-cell lymphomas)
    中山 隆志; 樋口 智紀; 竹川 澄男; 長久保 大輔; 重田 暁子; 白川 愛子; 稗島 州雄; 義江 修 日本癌学会総会記事 67回 497 -497 2008年09月
  • HTLV-1 Tax誘導性ケモカインCCL22のHTLV-1初期感染における役割の検討(HTLV-1 Tax-induced CCL22 promotes primary infection of HTLV-1 to peripheral blood CCR4+CD4+ T cells)
    稗島 州雄; 中山 隆志; 長久保 大輔; 白川 愛子; 金 哲; 義江 修 日本癌学会総会記事 66回 238 -238 2007年08月
  • Fra-2とJunDのヘテロダイマーはATL細胞におけるCCR4発現と細胞増殖を促進する(Heterodimer formation of Fra-2 and JunD promotes CCR4 expression and cell proliferation in adultT-cell leukemia)
    中山 隆志; 稗島 州雄; 金 哲; 長久保 大輔; 白川 愛子; 山田 恭暉; 藤井 雅寛; 義江 修 日本癌学会総会記事 66回 289 -289 2007年08月
  • Kunio Hieshima; Daisuke Nagakubo; Takashi Nakayama; Aiko-Konno Shirakawa; Osamu Yoshie AIDS RESEARCH AND HUMAN RETROVIRUSES 23 (4) 646 -646 2007年04月
  • Takashi Nakayama; Kunio Hieshima; Zhe Jin; Daisuke Nagakubo; Aiko-Konno Shirakawa; Yasuaki Yamada; Masahiro Fujii; Osamu Yoshie AIDS RESEARCH AND HUMAN RETROVIRUSES 23 (4) 642 -643 2007年04月
  • S. Kagami; H. Saeki; Y. Tsunemi; K. Nakamura; T. Nakayama; O. Yoshie; M. Komine; K. Tamaki JOURNAL OF INVESTIGATIVE DERMATOLOGY 127 S113 -S113 2007年04月
  • Daisuke Nagakubo; Zhe Jin; Kunio Hieshima; Takashi Nakayama; Aiko-Konno Shirakawa; Osamu Yoshie JOURNAL OF IMMUNOLOGY 178 2007年04月
  • 北條 荘三; 橋本 伊佐也; 小泉 桂一; 有田 貴久; 南 貴之; 篠原 看奈; 中山 隆志; 櫻井 宏明; 義江 修; 済木 育夫; 塚田 一博 日本外科学会雑誌 108 (2) 254 -254 2007年03月
  • 橋本 伊佐也; 北條 荘三; 小泉 桂一; 南 貴之; 篠原 看奈; 櫻井 宏明; 中山 隆志; 義江 修; 済木 育夫; 塚田 一博 日本外科学会雑誌 108 (2) 379 -379 2007年03月
  • 大腸癌におけるCXCL16の発現と予後との関連
    北條 荘三; 小泉 桂一; 有田 貴久; 篠原 看奈; 南 貴之; 橋本 伊佐也; 中山 隆志; 櫻井 宏明; 義江 修; 塚田 一博; 済木 育夫 日本癌学会総会記事 65回 337 -338 2006年09月
  • Chemokine receptor CXCR4阻害による胃癌腹膜播種の抑制
    安本 和生; 小泉 桂一; 済木 育夫; 川島 篤弘; 中山 隆志; 義江 修; 高橋 豊 日本癌学会総会記事 65回 455 -455 2006年09月
  • JIN Zhe; 中山隆志; 白川愛子; 長久保大輔; 稗島州雄; 中村栄男; 義江修 日本癌学会学術総会記事 65th 125 -125 2006年08月
  • CCL27トランスジェニックマウスはFITCによるcontact hypersensitivityが亢進する
    鑑 慎司; 佐伯 秀久; 常深 祐一郎; 中村 晃一郎; 中山 隆志; 義江 修; 玉置 邦彦 日本研究皮膚科学会年次学術大会・総会プログラム 31回 85 -85 2006年04月
  • K Yasumoto; K Koizumi; A Kawashimu; Y Saitoh; Y Arita; K Shinohara; T Minami; T Nakayama; H Sakurai; Y Takahashi; O Yoshie; Saiki, I CANCER RESEARCH 66 (7) 3957 -3957 2006年04月
  • Y. Tsunemi; H. Saeki; K. Nakamura; D. Nagakubo; T. Nakayama; O. Yoshie; S. Kagami; K. Shimazu; T. Kadono; M. Sugaya; M. Komine; K. Matsushima; K. Tamaki JOURNAL OF INVESTIGATIVE DERMATOLOGY 126 109 -109 2006年04月
  • T Sugita; JQ Gao; N Kanagawa; Y Motomura; T Nakayama; O Yoshie; Y Hatanaka; Y Tani; H Mizuguchi; Y Tsutsumi; S Nakagawa JOURNAL OF GENE MEDICINE 8 (3) 397 -397 2006年03月
  • 渡辺賀子; 中山隆志; 長久保大輔; 稗島州雄; 義江修 日本免疫学会総会・学術集会記録 35 166 -166 2005年11月
  • JIN Zhe; 中山隆志; 長久保大輔; 稗島州雄; 義江修 日本免疫学会総会・学術集会記録 35 163 -163 2005年11月
  • 長久保大輔; JIN Zhe; 中山隆志; 稗島州雄; 義江修 日本免疫学会総会・学術集会記録 35 163 -163 2005年11月
  • CCL21により誘導されるマウス肺癌細胞の転移関連因子の検索およびその受容体CCR7の発現機構の解析
    有田 貴久; 小泉 桂一; 中山 隆志; 稗島 州雄; 義江 修; 櫻井 宏明; 済木 育夫 日本癌学会総会記事 64回 99 -99 2005年09月
  • 破骨細胞分化誘導に伴うCCL22の産生とヒト小細胞肺癌株SBC-5細胞の骨転移機構の解明
    小泉 桂一; 小林 光夫; 中村 エリアネ静; 斉藤 百合花; 中山 隆志; 櫻井 宏明; 亀田 陽一; 義江 修; 済木 育夫 日本癌学会総会記事 64回 168 -169 2005年09月
  • ヒト前立腺癌細胞株におけるDHT-AR誘導によるケモカイン受容体の発現亢進と細胞機能の変化について
    明石 拓也; 有田 貴久; 小泉 桂一; 永川 修; 斎藤 百合花; 篠原 看奈; 南 貴之; 中山 隆志; 義江 修; 櫻井 宏明; 済木 育夫; 布施 秀樹 日本癌学会総会記事 64回 294 -294 2005年09月
  • Chemokine Receptor CXCR4発現胃癌が腹膜播種形成に関与する
    安本 和生; 小泉 桂一; 櫻井 宏明; 済木 育夫; 中山 隆志; 稗島 州雄; 義江 修; 川島 篤弘; 高橋 豊; 磨伊 正義 日本癌学会総会記事 64回 387 -387 2005年09月
  • 下村嘉一; 松本長太; 福田昌彦; 丸山耕一; 日比野剛; 桧垣史郎; 宇野直樹; 菅原大輔; 妙中直子; 出合達則; 白根授美; 有村英子; 渡辺敬三; 義江修; 中山隆志; 長久保大輔; ひえ島州雄; 林こう三郎 臨床眼科 59 (6) 816 -825 2005年06月
  • 明石 拓也; 永川 修; 小泉 桂一; 中山 隆志; 中村 エリアネ静; 小林 光夫; 稗島 州雄; 義江 修; 済木 育夫; 布施 秀樹 日本泌尿器科學會雜誌 96 (2) 360 -360 2005年03月
  • IL-12とCCL27の併用による抗腫瘍効果増強機構の解明
    杉田 敏樹; 高 建青; 金川 尚子; 飯田 恵介; 本村 吉章; 畑中 豊; 谷 一; 中山 隆志; 義江 修; 水口 裕之; 早川 尭夫; 岡田 直貴; 堤 康央; 弓 忠範; 中川 晋作 日本薬学会年会要旨集 125年会 (2) 154 -154 2005年03月
  • 中山隆志; 長久保大輔; 稗島州雄; 義江修 日本分子生物学会年会プログラム・講演要旨集 27th 500 2004年11月
  • 渡辺賀子; 中山隆志; 長久保大輔; ひ島州雄; 義江修 日本免疫学会総会・学術集会記録 34 44 -44 2004年11月
  • 稗島州雄; 中山隆志; 長久保大輔; 義江修 日本免疫学会総会・学術集会記録 34 37 -37 2004年11月
  • 中山隆志; 加藤佳子; 稗島州雄; 長久保大輔; 藤沢隆夫; 義江修 日本免疫学会総会・学術集会記録 34 38 -38 2004年11月
  • 岡田 直貴; 中川 晋作; 畑中 豊; 谷 洋一; 中山 隆志; 義江 修; 水口 裕之; 早川 高夫; 藤田 卓也; 山本 昌 日本免疫学会総会・学術集会記録 34 215 -215 2004年11月
  • 杉田 敏樹; 畑中 豊; 谷 洋一; 中山 隆志; 義江 修; 水口 裕之; 早川 高夫; 岡田 直貴; 堤 康央; 真弓 忠範; 中川 晋作 日本免疫学会総会・学術集会記録 34 215 -215 2004年11月
  • ケモカインCCL28/MECの唾液腺における役割
    稗島 州雄; 伊澤 大; 中山 隆志; 川崎ゆり; 義江 修; 斎藤 卓也; 大谷明夫 日本唾液腺学会誌 45 80 -82 2004年11月
  • ヒト胃癌腹膜播種形成におけるSDF-1a/CXCR-4リガンド・レセプターシステムの関与
    安本 和生; 小泉 桂一; 済木 育夫; 櫻井 宏明; 中山 隆志; 稗島 州雄; 善江 修; 川島 篤弘; 高橋 豊; 磨伊 正義 日本癌学会総会記事 63回 320 -320 2004年09月
  • マウス肺癌のリンパ節転移に対するCCR7の発現とCCL21/Secondary Lymphoid-tissue Chemokine(SLC)の影響
    有田 貴久; 小林 光夫; 小澤 陽子; 大橋 養賢; 中村 エリアネ静; 青塚 保志; 齊藤 百合花; 櫻井 宏明; 中山 隆志; 稗島 州雄; 義江 修; 小泉 桂一; 済木 育夫 日本癌学会総会記事 63回 263 -263 2004年09月
  • 花本 仁; 中山 隆志; 宮里 肇; 竹川 澄男; 稗島 州雄; 辰巳 陽一; 義江 修; 金丸 昭久 日本リンパ網内系学会会誌 44 117 -117 2004年06月
  • 中山 隆志; 義江 修 最新医学 59 (4) 919 -925 2004年04月
  • 森直樹; 岡田直貴; 是友良介; 岡田裕香; 中山隆志; 義江修; 水口裕之; 早川尭夫; 中川晋作 日本薬学会年会要旨集 124th (4) 112 -112 2004年03月
  • 佐々木明徳; 岡田直貴; 丹羽正和; 岡田裕香; 中山隆志; 義江修; 畑中豊; 水口裕之; 中川晋作 日本薬学会年会要旨集 124th (4) 112 -112 2004年03月
  • 義江修; 中山隆志; 稗島州雄; 長久保大輔 免疫アレルギー疾患予防・治療研究事業研究報告書 平成15年度 第2分冊 66 -70 2004年
  • 稗島州雄; 大谷明夫; 伊沢大; 中山隆志; 川崎ゆり; 斎藤卓也; 義江修 日本唾液腺学会抄録集 48th 28 -29 2003年12月
  • 稗島州雄; 中山隆志; 長久保大輔; 義江修; 川崎ゆり; 花本仁 日本免疫学会総会・学術集会記録 33 228 -228 2003年11月
  • 中山隆志; 長久保大輔; 稗島州雄; 義江修 日本免疫学会総会・学術集会記録 33 231 -231 2003年11月
  • 義江修; 中山隆志; 長久保大輔; 稗島州雄; 原沢仁美; 山田恭あき 日本免疫学会総会・学術集会記録 33 232 -232 2003年11月
  • 佐々木明徳; 岡田直貴; 中山隆志; 義江修; 畑中豊; 谷洋一; 中川晋作; 早川高夫; 水口裕之 日本免疫学会総会・学術集会記録 33 327 -327 2003年11月
  • 森直樹; 岡田直貴; 井上恵美子; 中山隆志; 義江修; 中川晋作; 真弓忠範; 早川高夫; 水口裕之 日本免疫学会総会・学術集会記録 33 327 -327 2003年11月
  • 加藤 佳子; 藤澤 隆夫; 中山 隆志; 義江 修 炎症・再生 23 (6) 460 -460 2003年11月
  • ケモカインファミリー分子の多くはスカベンジャー受容体活性を有する
    島岡 猛士; 中山 隆志; 稗島 州雄; 義江 修; 米原 伸 日本免疫学会総会・学術集会記録 33 229 -229 2003年11月
  • 佐々木明徳; 岡田裕香; 中山隆志; 義江修; 水口裕之; 早川尭夫; 中川晋作; 真弓忠範; 山本昌 Drug Deliv Syst 18 (3) 248 -248 2003年05月
  • 高建青; 形山和史; SOARES A L; 水口裕之; 早川尭夫; 中山隆志; 義江修; 堤康央; 中川晋作 薬剤学 63 (Supplement) 232 -232 2003年03月
  • 佐々木明徳; 岡田直貴; 大久保米起; 岡田裕香; 中山隆志; 水口裕之; 中川晋作; 藤田卓也; 山本昌 日本薬学会年会要旨集 123rd (4) 81 -81 2003年03月
  • ヒト巨核球によるthymus and activation-regulated chemokine(TARC/CCL17)産生 アレルギー炎症における血小板関与の可能性
    西森 久史; 藤澤 隆夫; 加藤 佳子; 勝又 元; 熱田 純; 中山 隆志; 義江 修 日本免疫学会総会・学術集会記録 32 160 -160 2002年10月
  • ヒト骨髄腫細胞及び骨髄形質細胞におけるケモカイン受容体CXCR4,CXCR6とCCR10の選択的発現
    中山 隆志; 稗島 州雄; 伊澤 大; 義江 修 日本免疫学会総会・学術集会記録 32 160 -160 2002年10月
  • ケモカインCCL28/MECの唾液腺における役割
    稗島 州雄; 大谷 明夫; 伊澤 大; 中山 隆志; 義江 修 日本免疫学会総会・学術集会記録 32 160 -160 2002年10月
  • ヒト非小細胞肺癌(NSCLC)に対するSecondary Lymphoid-tissue Chemokine(SLC)のリンパ節転移亢進因子としての可能性
    小泉 桂一; 小澤 陽子; 大橋 養賢; 中村 エリアネ静; 中山 隆志; 櫻井 宏明; 義江 修; 済木 育夫 日本癌学会総会記事 61回 110 -110 2002年10月
  • 大腸癌先進部におけるケモカイン及びケモカインレセプターの発現
    武者 宏昭; 溝井 賢幸; 中山 隆志; 大谷 明夫; 椎葉 健一; 義江 修; 佐々木 巖 日本癌学会総会記事 61回 360 -361 2002年10月
  • 大腸癌先進部におけるケモカイン及びケモカインレセプターの発現
    武者 宏昭; 椎葉 健一; 溝井 賢幸; 中山 隆志; 大谷 明夫; 義江 修; 佐々木 巖 日本免疫学会総会・学術集会記録 32 162 -162 2002年10月
  • 島岡 猛士; 久米 典昭; 南 学; 林田 和隆; 中山 隆志; 義江 修; 北 徹; 米原 伸 炎症・再生 22 (4) 343 -343 2002年06月
  • 加藤 佳子; 藤澤 隆夫; 中山 隆志; 義江 修 炎症・再生 22 (4) 386 -386 2002年06月
  • 【免疫疾患 state of arts】免疫疾患をめぐる基礎的研究の進歩 リンパ球サブセットとケモカイン受容体
    中山 隆志; 義江 修 医学のあゆみ 別冊 (免疫疾患-state of arts Ver.2) 117 -123 2002年03月
  • M Nishimura; H Umehara; T Nakayama; O Yoneda; K Hieshima; M Kakizaki; N Dohmae; O Yoshie; T Imai FASEB JOURNAL 16 (5) A1212 -A1212 2002年03月
  • H Nishimori; T Fujisawa; Y Kato; Y Komadu; H Kamiya; T Nakayama; O Yoshie JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 109 (1) S64 -S64 2002年01月
  • EBV不死化B細胞におけるケモカイン受容体の発現制御機構の解析
    中山 隆志; 藤澤 隆一; 伊澤 大; 稗島 州雄; 高田 賢蔵; 義江 修 日本免疫学会総会・学術集会記録 31 310 -310 2001年12月
  • 転写因子NF-κBによるケモカインLARC/CCR20遺伝子の活性化機構
    稗島 州雄; 藤家 悟; 伊澤 大; 中山 隆志; 藤澤 隆一; 大柳 治正; 義江 修 日本免疫学会総会・学術集会記録 31 307 -307 2001年12月
  • ケモカインによるLFA-1/ICAM-1の接着性亢進にはRap1及びCdc42が関与する
    下中 美香; 片桐 晃子; 前田 明人; 中山 隆志; 稗島 州雄; 義江 修; 木梨 達雄 日本免疫学会総会・学術集会記録 31 227 -227 2001年12月
  • S Fujiie; K Hieshima; D Izawa; T Nakayama; R Fujisawa; H Ohyanagi; O Yoshie INTERNATIONAL IMMUNOLOGY 13 (11) U2 -U2 2001年11月
  • リンパ球サブセットとケモカイン受容体
    中山 隆志; 義江 修 アレルギー科 12 (2) 130 -139 2001年08月
  • 津田育宏; 中川晋作; 塚田有希子; 水口裕之; 早川尭夫; 中山隆志; 義江修; 真弓忠範 薬剤学 61 (Supplement) 74 -74 2001年03月
  • 中山 隆志; 義江 修 Molecular Medicine Molecular Medicine 38 (2) 126 -134 2001年01月
  • 【ケモカインハンドブック】ILC/CTACK
    中山 隆志 細胞工学 別冊 (ケモカインハンドブック) 134 -135 2000年11月
  • 【ケモカインハンドブック】ケモカインレセプター CCR10
    中山 隆志 細胞工学 別冊 (ケモカインハンドブック) 207 -209 2000年11月
  • 【ケモカインハンドブック】MCV MC148R
    中山 隆志 細胞工学 別冊 (ケモカインハンドブック) 155 -156 2000年11月
  • 【ケモカインハンドブック】MEC/CCL28
    中山 隆志 細胞工学 別冊 (ケモカインハンドブック) 136 -137 2000年11月
  • 中山 隆志; 義江 修 臨床免疫 34 (Suppl.19) 577 -582 2000年07月
  • 【免疫担当細胞上の細胞表面分子とその機能】サイトカインレセプター CXCR1~CXCR5
    中山 隆志; 義江 修 臨床免疫 34 (Suppl.19) 583 -587 2000年07月

産業財産権

受賞

  • 2011年 日本インターフェロン・サイトカイン学会・マクロファージ分子細胞生物学国際シンポジウム Excellent Poster Award
     
    受賞者: 中山 隆志

共同研究・競争的資金等の研究課題

  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2023年04月 -2026年03月 
    代表者 : 中山 隆志; 原 雄大; 松尾 一彦
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2023年04月 -2026年03月 
    代表者 : 原 雄大; 中山 隆志
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2020年04月 -2023年03月 
    代表者 : 中山 隆志; 松尾 一彦
     
    乾癬の発症には、Th17細胞が重要な役割を果たすことが知られている。ケモカイン受容体CCR4は、Th2細胞に発現し、Th2細胞の遊走を介してアトピー性皮膚炎等のアレルギー性疾患の発症に寄与している。近年、このCCR4がTh17細胞にも発現していることが明らかとなった。しかしながら、乾癬におけるCCR4の関与については不明である。本申請課題では、乾癬におけるCCR4を介したTh17細胞の遊走制御機構の解析を通じて、CCR4の乾癬の発症における役割を追究する。 前年度、イミキモド長期塗布により乾癬様病態を誘発したところ、野生型マウスと比べ、CCR4欠損マウスでは病態の軽減および病変部へのTh17細胞の浸潤の減少が認められた。 本年度は、CCR4の選択的阻害薬の投与による乾癬病態の変化について解析した。CCR4阻害薬compound22の2日に1回の投与により、臨床スコア(皮膚肥厚、紅斑、鱗屑)の軽減、病変皮膚および所属リンパ節でのTh17細胞の減少、乾癬関連遺伝子(IL-17A、IL-22、IL-23、STAT3、Keratin 14)の減少がみられた。以上より、CCR4の阻害が乾癬の治療戦略となる可能性が示された。
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2020年04月 -2023年03月 
    代表者 : 松尾 一彦; 中山 隆志
     
    本研究の目的は、P2受容体が粘膜特有のCD70陽性樹状細胞に発現すること、また、メモリーCTLの生存維持に関与することに着目し、P2受容体を介したエフェクター/メモリーCTL誘導およびその維持機構を解明し、P2受容体のアゴニストである加水分解性抵抗性APTのワクチンアジュバントとしての有用性を検証することである。 本年度は、加水分解抵抗性ATPによって誘導されたエフェクターあるいはメモリーCTLが抗腫瘍活性を示すかどうかについてin vivo担癌モデルマウスを用いて検討した。モデル抗原OVAと加水分解抵抗性ATPを経鼻投与し、エフェクター期およびメモリー期にOVA発現腫瘍細胞 (E.G7-OVA)を皮内に接種した。経日的に腫瘍体積をモニタリングした結果、加水分解抵抗性ATPを併用した場合において、有意な腫瘍増殖抑制効果を認められた。さらに、この効果はP2受容体の阻害剤であるスラミンの投与によって消失した。これらの結果から、加水分解性抵抗性ATPによって誘導されたCTLによって有意な抗腫瘍効果を示すことが明らかとなり、加水分解抵抗性ATPは機能的なCTLを誘導できるアジュバントとしての活性を有することを示した。
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 中山 隆志; 松尾 一彦
     
    本研究の目的は、ケモカインELC/CCL19とその新規受容体の相互作用解析を通じて、ELC/CCL19の新規受容体を介した生理的および病的役割を解明することにある。 研究代表者は、これまでにELC/CCL19はGPCR#13に対して既知受容体であるCCR7と同様に強い細胞遊走活性を示すことを見出した。そして、ヒト末梢血正常細胞において、GPCR#13は既知受容体CCR7の発現していないエフェクター細胞に広く発現することを明らかにした。 平成30年度は、ヒト乾癬患者の皮膚臨床検体のreal-time PCR解析により、ELC/CCL19および新規受容体GPCR#13の発現が認められ、特に重症度の高い患者の検体で高い値を示すことを明らかにした。 これらの結果は、ELC/CCL19はGPCR#13に対する機能的な新規アゴニストであり、エフェクター細胞の遊走を介して乾癬の病態形成において重要な役割を果たすことが示唆された。
  • 日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2015年04月 -2017年03月 
    代表者 : 池渕 良洋; 戸村 道夫; 楠本 豊; 守屋 大樹; 寺口 俊介; 中山 隆志; 松尾 一彦
     
    光変換蛋白質KikGRを発現するマウスによって同定可能な炎症皮膚に「来た」「留まった」制御性T細胞(Treg)を対象に、シングルセル遺伝子・蛋白質多因子発現解析を行い、異なるTreg機能分子を発現する複数のサブセットを同定した。サブセット間を比較すると、発現する遊走関連分子も、皮膚に「留まる」性質も異なった。機能分子と遊走関連分子の多因子発現解析により、KikGR発現データを用いずに皮膚に「来た」「留まった」Tregを区別した。Tregサブセットの分化責任因子の同定及び炎症皮膚への集積法の樹立も試みた。本研究により、異なる機能分子を発現するTregは異なる炎症組織間遊走を行うことが示唆された。
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2014年04月 -2017年03月 
    代表者 : 義江 修; 中山 隆志; 角田 郁生; 樋口 智紀; 金井 亨輔; 藤田 貢
     
    CCL28遺伝子欠損マウスでは、大腸粘膜でのIgA産生細胞の減少と分布異常、糞便中のIgA量の著明な減少、および個々のIgA産生細胞のIgA産生量の低下が見いだされ、CCL28は大腸粘膜でのIgA産生に重要な役割を担っていることが確認された。さらにCCL28遺伝子欠損マウスの糞便ではバシラス綱が相対的に増加していた。大腸でのIgA産生量の低下と細菌叢の変化と関連して、CCL28遺伝子欠損マウスではデキストラン硫酸誘発腸炎の増悪が見られ、それは抗菌薬投与で軽減された。
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2014年04月 -2017年03月 
    代表者 : 中山 隆志; 松尾 一彦
     
    これまでに研究代表者は和漢薬ライブラリーを用いて細胞遊走阻害活性を指標としたケモカインアンタゴニストの探索を行ってきた。本研究において、麻黄エキスがケモカイン受容体CCR3、CCR4、およびCCR8特異的なアンタゴニスト活性を示し、そのアンタゴニスト活性が麻黄エキスの酢酸エチル非可溶性分画に存在することを明らかとした。また、このアンタゴニスト成分による阻害活性にリガンド特異性はなく、受容体を直接阻害することが示唆された。 CCR3、CCR4、およびCCR8は、いずれもTh2細胞あるいは好酸球や好塩基球に選択的に発現することから、アレルギー性疾患において重要な役割を果たすと考えられる。
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2012年04月 -2014年03月 
    代表者 : 渡部 明子; 義江 修; 中山 隆志
     
    近年、特発性肺線維症(IPF)の9割にEBウイルス(EBV)を始めとしたヘルペスウイルス感染が報告され、ヘルペスウイルスのIPF発症・増悪化への関与が示唆されている。IPFは肺上皮細胞の障害に伴う慢性炎症を基盤とする難治性疾患であり、筋線維芽細胞が産生する細胞外基質の過剰沈着を主体とする。しかしその病態発症機序については未だ不明な点が多い。 ガレクチン9(Gal-9)は上記肺線維症の発症要因とされる炎症促進作用や細胞外基質産生誘導能を有するβ-ガラクトシド認識結合タンパクである。本研究ではこのGal-9がヘルペスウイルス感染肺上皮細胞に強く発現したことから、EBVに相同性の高いマウスγヘルペスウイルス(MHV68)による肺線維症モデルを構築し、Gal-9の肺線維化における役割を解析してきた。 本年度までに肺線維症モデルマウスを構築し、Gal-9欠損マウスではMHV68感染による炎症反応および肺線維化が著しく軽減されることを明らかにした。さらにMHV68感染後の野生型マウス肺で検出されたIL-27の発現がGal-9欠損マウスで顕著に低下していたため、IL-27に対する中和抗体をMHV68感染後の野生型マウスに連続投与したところ、感染後の肺に認められた一連のケモカイン発現上昇および炎症細胞亜集団の浸潤が劇的に抑制された。また組織学的解析およびハイドロキシプロリン量測定によりMHV68誘導性の肺線維化もIL-27中和抗体投与により有意に抑制された。以上のことから、Gal-9に制御されるIL27が肺線維化を抑制するための治療標的分子となる可能性を示した。
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2011年 -2013年 
    代表者 : 義江 修; 中山 隆志; 樋口 智紀
     
    我々は、成人T細胞白血病/リンパ腫(ATL)でのCCR4発現に関わる転写因子としてAP-1ファミリーのFRA-2を同定し、FRA-2はJUNDと共同してATLの増殖を促進するとともにc-Myb、SOX4などの原癌遺伝子の発現を誘導することを明らかにした。本研究では、ATLおよび皮膚T細胞リンパ腫(CTCL)でのCCR7発現に関与する転写因子を検討し、新規DNA結合配列GAGGAGを同定し、その部位にはZFYVE19が結合することを明らかにした。本研究から、ATLやCTCLでの新たな発がん遺伝子カスケードの存在が示唆され、これらの成熟型T細胞性腫瘍の診断や治療に有用な情報が提供された。
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2011年 -2013年 
    代表者 : 樋口 智紀; 義江 修; 中山 隆志
     
    これまでに我々は、成人T細胞白血病/リンパ腫(ATL)や皮膚T細胞リンパ腫(CTCL)でFra-2が一貫して発現し、CCR4発現誘導や細胞増殖に関与することを明らかにしてきた。本研究では、ATLとCTCL発癌におけるSOX4発現とその役割について検討した結果、ATLとCTCLにおいて、Fra-2-JunDが直接SOX4の転写活性を促進し、SOX4下流標的遺伝子として見出したGCKR、NAP1、HDAC8を発現誘導することでこれらの腫瘍の細胞増殖能を高めることを明らかにした。したがって、これらの知見からFra-2-SOX4経路はATLとCTCL発癌において重要な役割を有することが示唆された。
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2011年 -2013年 
    代表者 : 中山 隆志; 義江 修; 樋口 智紀
     
    本研究において研究代表者は、成熟T細胞リンパ腫での新規c-Myb標的遺伝子として薬物トランスポーターABCG2/BCRPを同定した。c-MybとABCG2/BCRPは、成熟T細胞リンパ腫において共発現することが確認された。さらにABCG2/BCRP特異的阻害剤であるKo143は、ドキソルビシンのATLL細胞株に対する抗腫瘍活性を優位に促進した。これらの結果より、c-Myb-ABCG2/BCRP経路は成熟T細胞リンパ腫の抗がん剤耐性機構において重要な役割を果たすことが示唆された。
  • 日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2009年 -2010年 
    代表者 : 中山 隆志
     
    本研究において研究代表者は、Fra-2とc-Mybが皮膚T細胞リンパ腫に普遍的に発現し、細胞増殖に関与することを見出した。また、c-MybはFra-2の直接的な標的遺伝子であることが示された。さらに細胞増殖に関わるc-Mybの下流標的遺伝子としてRas活性化因子であるRASGRP2を同定した。Fra-2-c-Myb経路は発癌遺伝子カスケードとして機能し、細胞増殖に寄与することが示唆された。
  • 日本学術振興会:科学研究費助成事業 特定領域研究
    研究期間 : 2008年 -2009年 
    代表者 : 義江 修; 中山 隆志; 白川 愛子; 稗島 州雄
     
    CCR4はTh2細胞、制御性T細胞、皮膚指向性T細胞などに選択的に発現するケモカイン受容体である。我々は成人T細胞白血病(ATL)でのCCR4の高頻度発現を初めて報告した(Yoshie et al., Blood 2002)。そしてATLでのCCR4発現の転写制御機構を調べることにより、ATLではAP-1ファミリーのFra-2が構成的に異常発現しており、Fra-2はJunDとヘテロダイマーを形成することにより、ATLでのCCR4の発現を誘導し、さらにc-Myb、MDM2、Bcl-6などの原がん遺伝子の発現も誘導していることを明らかにした(Nakayama et al., Oncogene 2008)。ATLでFra-2やこれらの原がん遺伝子の構成的発現が示されたのは初めてである。そこで本年度は、Fra-2/JunDによるc-Mybの発現誘導を転写レベルで証明した。また皮膚T細胞リンパ腫(CTCL)は菌状息肉腫やCD30陽性未分化大細胞型リンパ腫などの多様な成熟型T細胞リンパ腫よりなるが、ATLと同様にCCR4を高頻度で発現する。そこでCTCLでのFra-2の発現と役割を検討した。そ.の結果、CTCLでもCCR4の発現とともにFra-2とJunDの構成的な発現が確認され、ATLと同様にFra-2とJunDはCTCLの増殖に関与すること、さらにFra-2とJunDはCCR4の発現だけでなく、c-Myb、MDM2、Bcl-6の発現も誘導していることを明らかにした。これらの結果は、Fra-2の構成的発現と発がんにおける役割はATLに限られるものではなく、CTCLも含めてCCR4を発現する成熟型T細胞由来の白血病/リンパ腫に普遍的に当てはまるものであることを示す。そしてFra-2で発現が誘導されるCCR4はこれらの悪性腫瘍の有用な腫瘍マーカーであるとともに有望な治療標的でもあると言える。
  • 日本学術振興会:科学研究費助成事業 基盤研究(B)
    研究期間 : 2007年 -2009年 
    代表者 : 義江 修; 稗島 州雄; 中山 隆志; 長久保 大輔; 白川 愛子
     
    CCR4はTh2細胞、制御性T細胞、皮膚指向性T細胞などに選択的に発現するケモカイン受容体である。我々はTh2型のマウス気道炎症で低分子CCR4阻害剤の治療効果を示した。またCCR4とそのリガンドMDC/CCL22 は腸管膜リンパ節での樹状細胞と制御性T 細胞の相互作用を誘導して免疫寛容を誘導することを示した。さらにEB ウイルスやHTLV-1といったヒトの腫瘍ウイルスは共通してCCR4のリガンド、特にMDC/CCL22の発現を感染細胞に誘導し、それによって感染細胞の周囲にCCR4陽性のTh2細胞や制御性T細胞を動員して免疫回避やウイルス伝播に役立てていることを明らかにした。
  • 日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2007年 -2008年 
    代表者 : 中山 隆志
     
    ケモカインeotaxin-3/CCL26は、好酸球に高発現するCCR3のリガンドであり、炎症局所への好酸球浸潤に重要な役割を果たすことが報告されている.本研究において研究代表者は、CCL26が細胞傷害性リンパ球に高発現するCX3CL1受容体/CX3CR1の新しい機能的リガンドであることを見出した.CCL26は好酸球だけでなく細胞傷害性リンパ球も同時に炎症巣に誘導することにより、アレルギー性疾患の病態形成においてこれまで理解されていた以上の役割を果たすことが示唆された.
  • 日本学術振興会:科学研究費助成事業 特定領域研究
    研究期間 : 2006年 -2007年 
    代表者 : 義江 修; 稗島 州雄; 中山 隆志; 長久保 大輔
     
    CCR4のプロモーター解析によりATLでの転写活性化サイトとしてGATA-3サイトとAP-1サイトを同定した。GATA-3はTh2細胞で選択的に発現し、CCR4のTh2選択的発現に関係すると考えられた。一方、AP-1はFosファミリーとJunファミリーのホモダイマーあるいはヘテロダイマーとして機能する。そこでAP-1ファミリーのATLでの発現を検討した。その結果、ATLの臨床検体ではFra-2、JunD、JunBの構成的発現が見られた。さらにCCR4プロモーターの活性化はFra-2/JunDおよびFra-2/JunBのヘテロダイマーがきわめて特異的に誘導することを見出した。さらにFra-2の発現はHTLV-1の転写因子Taxでは誘導されないことも確認した。発がん遺伝子Fra-2の正常T細胞での発現やATLでの構成的活性化はいまだ報告されていない。そこでATLでのFra-2、JunD、JunBの役割をsiRNAノツクダウンで検討した。その結果、Fra-2とJunDのsiRNAがCCR4発現および細胞増殖を抑制した。またFra-2あるいはJunDをJurkatで強制発現すると細胞増殖を促進した。そこでATLでのFra-2の下流標的遺伝子をFra-2 siRNAによるノックダウンとマイクロアレイ解析で検討した。その結果、Fra-2のsiRNAによりATL細胞株で少なくとも49の遺伝子が3倍以上の低下を示した。この中には発がん遺伝子c-Myb、Bc1-6、MDM2も含まれていた。そしてこれらの発がん遺伝子の発現はJunDのsiRNAでも抑制され、Fra-2/JunDヘテロダイマーの下流遺伝子であることが示された。さらにATLの臨床検体でもこれらの発がん遺伝子の構成的発現が確認された。発がん遺伝子Fra-2、c-Myb、Bc1-6、MDM2のATLでの構成的発現は初めての知見である。
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2005年 -2006年 
    代表者 : 義江 修; 稗島 州雄; 中山 隆志; 長久保 大輔; 白川 愛子
     
    CCR10は皮膚特異的に発現するケモカインCCL27の受容体として同定され、皮膚指向性T細胞での発現が報告されたが、さらに各種の粘膜組織で発現しているCCL28の受容体であることも明らかにされた。そして我々はCCR10がB細胞では形質細胞の段階で発現してくることを世界に先駆けて報告した。またCCR10の発現はIgA産生細胞の腸管粘膜への帰巣に重要であることも報告した。形質細胞の分化にはXBP-1やBlimp-1などの転写因子が重要な役割をはたす。しかしながらCCR10のプロモーター領域にはこれらの転写因子の認識配列は存Eしない。そこで本研究では形質細胞におけるCCR10発現に関わる転写因子を同定し、それによって形質細胞分化における新たな転写制御機構を明らかにすることを目的とした。 活性化ヒトB細胞をIL-21の存在下で培養すると形質細胞に分化することが報告された。そこでこの分化系を用いてCCR10の発現を検討した。その結果、IL-21のみではCCR10の発現は誘導されないが、活性型ビタミンD3(VD3)を加えるとCCR10の発現が誘導された。そこでCCR10の開始コドンから上流-1500bpまでをクローニングし、pGL3に挿入してCCR10を発現しているヒト骨髄腫細胞株に導入してレポーターアッセイを行った。その結果、-71〜-62bpの領域に存在するEts-1認識配列がCCR10の発現誘導に基本的に重要であることが示された。そしてEts-1の結合を確認した。さらに-124〜-110bpにVD3応答サイトと見なしえる配列を見出し、そこに点変異を導入することによりVD3に対する反応性の消失を確認した。そしてVD3レセプターのVD3依存的結合を確認した。VD3は粘膜免疫を誘導することが報告されており、形質細胞でのCCR10発現誘導もそのメカニズムのひとつと考えられる。
  • 日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2005年 -2006年 
    代表者 : 中山 隆志
     
    上皮細胞でのケモカイン発現に対するEBV感染の影響を明らかにするため、上咽頭癌(NPC)細胞株、EBV陽性と陰性の上皮細胞株を用いてケモカインの網羅的発現解析を行ってきた。これまでに、これらのEBV感染上皮細胞とEBV感染B細胞におけるケモカイン発現プロファイルの比較解析により、EBV感染B細胞ではTh2型ケモカインTARC/CCL17とMDC/CCL22の発現が特異的に誘導され、EBV感染上皮細胞では対照的にTh1型ケモカインMIG/CXCL9とIP-10/CXCL10の発現が特異的に誘導されることを明らかにしている。 今回、EBV関連上皮系腫瘍の病態形成におけるケモカインの役割を臨床検体で明らかにするため、NPC腫瘍組織を用いてケモカインおよびケモカインレセプターの免疫染色を行った。その結果、NPCの腫瘍細胞はMIG/CXCL9とIP-10/CXCL10を強く発現していた。さらに、腫瘍細胞の周囲には、それらのレセプターであるCXCR3陽性の多数のT細胞浸潤が認められた。以上の結果から、MIG/CXCL9とIP-10/CXCL10の産生はCXCR3を介してTh1細胞を誘導することが示唆された。また、腫瘍細胞の周囲には、Foxp3^+IL-10^+CD69^-制御性T細胞の多数の浸潤が認められ、これらの細胞は従来報告されていたCCR4に加えてCXCR3を発現していた。NPC組織では、CCR4のリガンドであるTARC/CCL17とMDC/CCL22の発現は認められなかったため、制御性T細胞はCXCR3を介してNPC組織に誘導され腫瘍細胞に対する免疫反応の抑制に関与すると考えられた。
  • 日本学術振興会:科学研究費助成事業 特定領域研究
    研究期間 : 2005年 -2005年 
    代表者 : 義江 修; 稗島 州雄; 中山 隆志; 長久保 大輔
     
    我々は、ATLではケモカイン受容体CCR4が高頻度・強陽性であること、CCR4発現はATLの高頻度皮膚浸潤を説明するとともに、ATLの起源がTh2あるいは制御性T細胞であることを示唆することを報告した(Blood, 2002)。このようなATLでのCCR4高頻度・高レベル発現は、ATLの発がん機構と転写レベルで密接に関係している可能性がある。そこで本研究では、ATLでのCCR4発現に関わる転写因子を明らかにし、それらのATL発がんへの関与を検討する。まずATL細胞におけるCCR4の転写開始部位を5'-RACEによってマップした。その結果、ATL細胞でのCCR4転写はエクソン1の上流と第1イントロン内の2領域で開始されており、それぞれ第1プロモーターと第2プロモーターと命名した。そこで第1プロモーター1-kbおよび第2プロモーター2-kbをルシフェレースレポータープラスミドにクローニングし、レポーターアッセイを行った。その結果、これらのプロモーターはATL細胞で強い転写活性を示した。そこで、それぞれのプロモーター領域を5'側から削っていってレポーターアッセイを繰り返し、発現に必要な領域を絞り込んだ。そしてこれらの必要領域に存在する候補エレメントに次々と点変異を導入し、必要エレメントの同定を行っている。第1プロモーターおよび第2プロモーターともにTh2分化に関わるGATA-3の認識配列が重要であることをみいだしたが、それ以外にも共同して作用するエレメントが存在することが明らかになってきた。現在、これらのエレメントに結合する転写因子の同定とクローニングを進めている。今後はCCR4の発現に関与することが明らかになった転写因子について、それらのATL発がんにおける役割を強制発現系やsiRNAによるノックダウン実験によって明らかにする。さらに、ATL細胞でのこれらの転写因子の構成的な発現および機能亢進のメカニズムを分子レベルで明らかにする。それによっていまだ不明なところの多い遺伝子レベルでのATLの発がん機構に関して新たな知見をもたらす。
  • 日本学術振興会:科学研究費助成事業 特定領域研究
    研究期間 : 2004年 -2004年 
    代表者 : 済木 育夫; 櫻井 宏明; 小泉 桂一; 義江 修; 稗島 州男; 中山 隆志
     
    1.マウス肺がんのリンパ節転移に対するCCR7の発現とCCL21/Secondary Lymphoid-tissue Chemokine (SLC)による運動能の亢進 本研究では、同様にC57BL/6マウスにリンパ節転移を引き起こす肺がん細胞(LLC)を用いて、CCL21及びCCR7とリンパ節転移との関連性について検討した。その結果、LLC細胞におけるCCR7の発現がmRNAレベルで確認され、運動能についてもCCL21の濃度に依存して亢進することが明らかとなった。更に、CXCR5、CXCR6の発現も確認され、それぞれの受容体に対するケモカインにより、濃度依存的に運動能の亢進が確認出来た結果から、CCR7以外にもリンパ節転移に関与する新たな受容体を同定するに到った。種々がん細胞のリンパ節転移は、リンパ管新生の惹起により亢進することが明らかとなってきている。(発表論文1.) 2.リンパ節転移性マウス肺がん細胞(LLC)に対するCCL21によるシグナル伝達系の解明 上記(1)でリンパ節転移性マウス肺がん細胞(LLC)にCCR7の発現が確認されたことで、次に、CCL21によるシグナル伝達系の解明を、行った。その結果、細胞増殖や生存に関与するシグナル伝達分子であるAkt及びErkのリン酸化の亢進が確認できた。今回、我々はAkt及びErk分子により、マウス結腸がんの肺転移が制御されている事を報告した。(発表論文2-3.) 3.がん細胞におけるケモカイン受容体、CCR7の発現亢進メカニズムの解明 現在までに、ケモカイン受容体の発現とがん転移の関連性に関する研究は、著しい知見の集積がなされている現在ではあるが、がん細胞におけるケモカイン受容体発現亢進のメカニズムは全く解明されていない。最近我々は、サイトカインががん転移を含むがん細胞の増悪化を引き起こすことを報告した。(発表論文3.)
  • ケモカイン系の腫瘍、アレルギー性疾患やウイルス感染症における役割の解明
    科学研究費補助金
    研究期間 : 2000年
  • Study on Chemokine
    Grant-in-Aid for Scientific Research

担当経験のある科目

  • 化学療法学近畿大学薬学部
  • 微生物学近畿大学医学部・薬学部

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