Analysis on the mechanism of action of biologic agents using mouse models of autoimmune disorders

2011 Fiscal Year Final Research Report

• Project/Area Number: 21591276
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: National Institute of Biomedical Innovation
• Principal Investigator: FUJIMOTO Minoru 独立行政法人医薬基盤研究所, 創薬基盤推進研究部, 主任研究員 (00379190)
• Project Period (FY): 2009 – 2011
• Keywords: 膠原病学 / 自己免疫疾患 / サイトカイン / 生物学的製剤 / モデルマウス

Research Abstract

This study was aimed to investigate the mechanism of action of biologic agents by using mouse models of autoimmune diseases. The analysis of the inflammatory bowel disease model revealed that both anti-TNF antibody and anti-IL-6 receptor antibody can restrain expansion of colitogenic helper T cells, thereby exhibiting potent inhibitory effect on colitis. Anti-IL-6R antibody also could regulate the balance between Th17 cells and Treg cells. In contrast, another agent TNFR-Fc exhibited no suppressive effect on colitis. This study thus characterized the difference in the mechanism between biologic agents. Further studies on the new agent(abatacept) and on the new mouse model of microscopic polyangiitis are currently in progress.

Research Products

• [Journal Article] Serum leucine-rich alpha-2 glycoprotein is a disease activity biomarker in ulcerative colitis (2012)
  • Author(s): Serada S, Fujimoto M, Terabe F, Iijima H, Shinzaki S, Matsuzaki S, Ohkawara T, Nezu R, Nakajima S, Kobayashi T, Plevy SE, Takehara T, Naka T
  • Journal Title: Inflamm Bowel Dis Volume: (in press)
  • DOI: Doi:10.1002/ibd.22936
  • Peer Reviewed
• [Journal Article] Dysregulation of melanocyte function by Th17-related cytokines : significance of Th17 cell infiltration in autoimmune vitiligo vulgaris (2012)
  • Author(s): Kotobuki Y, Tanemura A, Yang L, Itoi S, Wataya-Kaneda M, Murota H, Fujimoto M, Serada S, Naka T, Katayama I
  • Journal Title: Pigment Cell Melanoma Res Volume: 25(2) Pages: 219-230
  • DOI: Doi:10.1111/j.1755-148X.2011.00945.x
  • Peer Reviewed
• [Journal Article] Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma (2012)
  • Author(s): Kitaba S, Murota H, Terao M, Azukizawa H, Terabe F, Shima Y, Fujimoto M, Tanaka T, Naka T, Kishimoto T, Katayama I
  • Journal Title: Am J Pathol Volume: 180(1) Pages: 165-176
  • DOI: Doi:10.1016/j.ajpath.2011.09.013
  • Peer Reviewed
• [Journal Article] IL-6-mediated Th17 differentiation through ROR{gamma} t is essential for the initiation of experimental autoimmune myocarditis (2011)
  • Author(s): Yamashita T, Iwakura T, Matsui K, Kawaguchi H, Obana M, Hayama A, Maeda M, Izumi Y, Komuro I, Ohsugi Y, Fujimoto M, Naka T, Kishimoto T, Nakayama H, Fujio Y
  • Journal Title: Cardiovasc Res Volume: 91(4) Pages: 640-648
  • DOI: Doi:10.1093/cvr/cvr148
  • Peer Reviewed
• [Journal Article] Comparative analysis of the effects of anti-IL-6 receptor mAb and anti-TNF mAb treatment on CD4+T-cell responses in murine colitis (2011)
  • Author(s): Terabe F, Fujimoto M, Serada S, Shinzaki S, Iijima H, Tsujii M, Hayashi N, Nomura S, Kawahata H, Jang MH, Miyasaka M, Mihara M, Ohsugi Y, Kishimoto T, Naka T
  • Journal Title: Inflamm Bowel Dis Volume: 17(2) Pages: 491-502
  • DOI: Doi:10.1002/ibd.21384
  • Peer Reviewed
• [Journal Article] Overexpression of SOCS3 exhibits preclinical antitumor activity against malignant pleural mesothelioma (2011)
  • Author(s): Iwahori K, Serada S, Fujimoto M, Nomura S, Osaki T, Lee CM, Mizuguchi H, Takahashi T, Ripley B, Okumura M, Kawase I, Kishimoto T, Naka T
  • Journal Title: Int J Cancer Volume: 129(4) Pages: 993-1005
  • DOI: Doi:10.1002/ijc.25716
  • Peer Reviewed
• [Journal Article] Antiproliferative effect of SOCS-1 through the suppression of STAT3 and p38 MAPK activation in gastric cancer cells (2011)
  • Author(s): Souma Y, Nishida T, Serada S, Iwahori K, Takahashi T, Fujimoto M, Ripley B, Nakajima K, Miyazaki Y, Mori M, Doki Y, Sawa Y, Naka T
  • Journal Title: Int J Cancer Volume: (in press)
  • DOI: Doi:10.1002/ijc.27350
  • Peer Reviewed
• [Journal Article] Blockade of interleukin-6 signaling suppresses not only th17 but also interphotoreceptor retinoid binding protein-specific Th1 by promoting regulatory T cells in experimental autoimmune uveoretinitis (2011)
  • Author(s): Haruta H, Ohguro N, Fujimoto M, Hohki S, Terabe F, Serada S, Nomura S, Nishida K, Kishimoto T, Naka T
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 52(6) Pages: 3264-3271
  • DOI: Doi:10.1167/iovs.10-6272
  • Peer Reviewed
• [Journal Article] The influence of excessive IL-6 production in vivo on the development and function of Foxp3+regulatory T cells (2011)
  • Author(s): Fujimoto M, Nakano M, Terabe F, Kawahata H, Ohkawara T, Han Y, Ripley B, Serada S, Nishikawa T, Kimura A, Nomura S, Kishimoto T, Naka T
  • Journal Title: J Immunol Volume: 186(1) Pages: 32-40
  • DOI: Doi:10.4049/jimmunol.0903314
  • Peer Reviewed
• [Journal Article] iTRAQ-based proteomic identification of leucine-rich alpha-2 glycoprotein as a novel inflammatory biomarker in autoimmune diseases (2010)
  • Author(s): Serada S, Fujimoto M, Ogata A, Terabe F, Hirano T, Iijima H, Shinzaki S, Nishikawa T, Ohkawara T, Iwahori K, Ohguro N, Kishimoto T, Naka T
  • Journal Title: Ann Rheum Dis Volume: 69(4) Pages: 770-774
  • DOI: Doi:10.1136/ard.2009.118919
  • Peer Reviewed
• [Journal Article] Green tea polyphenol epigallocatechin gallate inhibits cell signaling by inducing SOCS1 gene expression (2010)
  • Author(s): Ripley BJ, Fujimoto M, Serada S, Ohkawara T, Nishikawa T, Terabe F, Matsukawa Y, Stephanou A, Knight RA, Isenberg DA, Latchman DS, Kishimoto T, Naka T
  • Journal Title: Int Immunol Volume: 22(5) Pages: 359-366
  • DOI: Doi:10.1093/intimm/dxq015
  • Peer Reviewed
• [Journal Article] Blockade of interleukin-6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses (2010)
  • Author(s): Hohki S, Ohguro N, Haruta H, Nakai K, Terabe F, Serada S, Fujimoto M, Nomura S, Kawahata H, Kishimoto T, Naka T
  • Journal Title: Exp Eye Res Volume: 91(2) Pages: 162-170
  • DOI: Doi:10.1016/j.exer.2010.04.009
  • Peer Reviewed
• [Journal Article] SOCS1, a Negative Regulator of Cytokine Signals and TLR Responses, in Human Liver Diseases (2010)
  • Author(s): Fujimoto M, Naka T
  • Journal Title: Gastroenterol Res Pract Pages: 470468
  • DOI: Doi:10.1155/2010/470468
  • Peer Reviewed
• [Journal Article] Th17細胞とレギュラトリーT細胞のバランスを決定する要因 (2010)
  • Author(s): 藤本穣
  • Journal Title: 臨床免疫・アレルギー科 Volume: 53巻 Pages: 413-418
• [Journal Article] IL-6阻害による自己免疫性関節炎治療効果はTh17抑制を介している (2010)
  • Author(s): 大河原知治、藤本穣、仲哲治
  • Journal Title: リウマチ科 Volume: 43巻 Pages: 62-67
• [Presentation] Leucine rich alpha 2 glycoprotein(LRG) is a novel biomarker for monitoring disease activity in patients with Ulcerative Colitis (2011)
  • Author(s): Satoshi Serada, Minoru Fujimoto, Fumitaka Terabe, Tetsuji Naka
  • Organizer: 第40回日本免疫学会総会
  • Place of Presentation: 幕張メッセ(千葉市)
  • Year and Date: 2011-11-28
• [Presentation] TGFbeta1 promotes bleomycin induced murine dermal sclerosis via its downstream molecule of periostin (2011)
  • Author(s): Yan L, Fujimoto M, Serada S, Murota H, Kotobuki Y, Kitaba S, Katayama I, Naka T
  • Organizer: 9th Joint Meeting of International Cytokine Society and International Society for Interferon and Cytokine Research
  • Place of Presentation: イタリア(フィレンツェ)
  • Year and Date: 2011-10-11
• [Presentation] Nuclear receptor PPAR-gamma interacts with IRF7 to negatively regulate TLR7/9-mediated type I interferon production and the development of murine lupus (2011)
  • Author(s): Ripley B, Fujimoto M, Han A, Millrine D, Lee S, Kawai T, Akira S, Naka T, Kishimoto T
  • Organizer: 9th Joint Meeting of International Cytokine Society and International Society for Interferon and Cytokine Research
  • Place of Presentation: イタリア(フィレンツェ)
  • Year and Date: 2011-10-10
• [Presentation] Tregの分化、機能におけるIL-6の作用 (2011)
  • Author(s): 藤本穣、仲哲治
  • Organizer: 第31回日本臨床免疫学会総会(招待講演)
  • Place of Presentation: 京王プラザ(東京)
  • Year and Date: 2011-09-17
• [Presentation] 定量的プロテオーム解析による子宮内膜癌抗原蛋白質の探索 (2011)
  • Author(s): Satoshi Serada, Takuhei Yokoyama, Takayuki Enomoto, Shinya Matsuzaki, Akiko Morimoto, Ayako Kim, Minoru Fujimoto, Tadashi Kimura, Tetsuji Naka
  • Organizer: 第9回日本プロテオーム学会
  • Place of Presentation: 新潟市朱鷺メッセ
  • Year and Date: 2011-07-29
• [Presentation] MYD88 GENE KNOCKOUT INHIBITS THE DEVELOPMENT OF LUPUS-LIKE DISEASE IN NZB/W F1 MICE (2011)
  • Author(s): T. Ohkawara, B. Ripley, M. Fujimoto, T. Naka
  • Organizer: EULAR
  • Place of Presentation: イギリス(ロンドン)
  • Year and Date: 2011-05-28
• [Presentation] NUCLEAR RECEPTOR PPAR-GAMMA NEGATIVELY REGULATES TYPE I INTERFERON PRODUCTION VIA INTERACTION WITH IRF7 (2011)
  • Author(s): B. Ripley, M. Fujimoto, S. Serada, L.-L. Yang, F. Terabe, Y.-M. Han, T. Ohkawara, T. Nishikawa, T. Naka
  • Organizer: EULAR
  • Place of Presentation: イギリス(ロンドン)
  • Year and Date: 2011-05-27
• [Presentation] PERIOSTIN GENE KNOCKOUT IS PROTECTIVE AGAINST THE DEVELOPMENT OF BLEOMYCIN-INDUCED MURINE SKIN SCLERODERMA (2011)
  • Author(s): L. Yang, M. Fujimoto, S. Serada, H. Murota, B. Ripley, S. Kitaba, Y. Kotobuki, T. Naka, I. Katayama
  • Organizer: EULAR
  • Place of Presentation: イギリス(ロンドン)
  • Year and Date: 2011-05-27
• [Presentation] Quantitative proteomic analysis of cell-surface membrane proteins : Biomarker discovery in endometrial cancer (2011)
  • Author(s): Takuhei Yokoyama, Takayuki Enomoto, Satoshi Serada, Shinya Matsuzaki, Toshihiro Kimura, Yutaka Ueda, Masami Fujita, Kiyoshi Yoshino, Ayako Kim, Minoru Fujimoto, Tadashi Kimura, Tetsuji Naka
  • Organizer: AACR
  • Place of Presentation: アメリカ(オーランド)
  • Year and Date: 2011-04-06
• [Presentation] SOCS-1,-3 gene delivery in gastric cancer cells induces a potent anti-proliferative effect via the suppression of JAK/STAT and P38 MAPK signaling pathways (2011)
  • Author(s): Maiko Urase, Satoshi Serada, Yoshihito Souma, Kouta Iwahori, Kazuki Shimada, Toshirou Nishida, Minoru Fujimoto, Tetsuji Naka
  • Organizer: AACR
  • Place of Presentation: アメリカ(オーランド)
  • Year and Date: 2011-04-04
• [Presentation] The effect of IL-6 overproduction in vivo on wound healing, Cytokines in Infectious Diseases (2010)
  • Author(s): Fujimoto M, Kotobuki Y, Kitaba S, Ukita T, Terabe F, Haruta H, Kishimoto T, Naka T
  • Organizer: Autoimmune Disorders and Cancer(Cytokines 2010)
  • Place of Presentation: アメリカ(シカゴ)
  • Year and Date: 2010-10-04
• [Presentation] The effect of IL-6 overproduction on T helper cell differentiation in vivo (2010)
  • Author(s): Fujimoto M, Terabe F, Ukita T, Mei Y, Serada S, Nishikawa T, Ripley B, Kishimoto T, Naka T
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: ポートピアホテル(神戸)
  • Year and Date: 2010-08-25
• [Presentation] Myd88 gene knockout inhibits the development of lupus-like disease in NZB/W F1 mice (2009)
  • Author(s): Ohkawara T, Fujimoto M and Naka T
  • Organizer: Tri-Society Annual Conference
  • Place of Presentation: ポルトガル(リスボン)
  • Year and Date: 2009-10-20
• [Remarks] 参照ホームページ
  • URL: http://www.nibio.go.jp/cgi-bin/new/view.cgi?no=939