Establishment of disease specific immunotherapy using specific antigen and immunoregulatory molecule

• Project/Area Number: 18591106
• 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: Kyoto University
• Principal Investigator: USUI Takshi Kyoto University, Faculty of Medicine, Assistant Professor (90362483)
• Co-Investigator(Kenkyū-buntansha): NISHIKOMORI Ryuta Kyoto University, Faculty of Medicine, Assistant Professor (70359800) ; WAKATSUKI Yoshio Kyoto University, Faculty of Medicine, Lecturer (40220826) ; MIMORI Tsuneyo Kyoto University, Faculty of Medicine, Professor (10157589)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥270,000); Fiscal Year 2007: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2006: ¥2,600,000 (Direct Cost: ¥2,600,000)
• Keywords: helper T cell / autoimmune disease / rheumatoid arthritis / arthritis model mouse / IL-17 / Th17 / IFN-gamma / Th1 / TGF-beta / レトロウイルス / gamma / delta T cell

Research Abstract

Introduction The aim of this research is to establish disease-specific immunotherapy using antigen-specific T cells and immunoregulatory genes. To perform this, it is very important to know what is the true pathology of mouse arthritis models and human rheumatoid arthritis.
Objective. Although interleukin-17 (IL-17)-producing γδ T cells were reported to play pathogenic roles in collagen-induced arthritis (CIA), their characteristic remain unknown. The aim of this study was to clarify which are the predominant IL-17-producing cells, γδ T cells or CD4^+ T cells, and what stimulates γδ T cells to secret IL-17 in CIA. The involvement of IL-17-producing γδ T cells in SKG arthritis and rheumatoid arthritis (RA) was also investigated.
Methods. IL-17-producing cells in the affected joints of CIA were counted at six distinct disease phases by intracellular cytokine staining, and these cells were stimulated with various combinations of cytokines or specific antigen to determine the signaling requirements. Similar studies were performed using SKG arthritis and RA.
Results γδ T cells were the predominant population in IL-17-producing cells at swollen joints in CIA and the absolute numbers of these cells increased in parallel with disease activities. IL-17-producing γδ T cells expressed CC chemokine receptor (CCR6) and were maintained by IL-23 but not by type II collagen (CII) in vitro and were induced antigen-independently in vivo. Furthermore, IL-17-production by γδ T cells was T cell receptor (TCR)-independently induced by IL-1β+IL-23. In contrast to CIA mice, IL-17-producing γδ T cells were nearly absent in the affected joints of SKG mice and RA, and Th1 cells were predominant in the joints of RA.
Conclusion. γδ T cells were antigen-independently stimulated by inflammation at affected joints and produced enhanced amounts of IL-17 to exacerbate arthritis in CIA but not in SKG arthritis or RA.

Research Products

• [Journal Article] Gamma/delta T cells are the predominant source of interleukin-17 in affected joints in collagen-induced arthritis, but not in rheumatoid arthritis (2009)
  • Author(s): Ito Y, Usui T, Kobayashi S, Iguchi-Hashimoto M, Ito H, Yoshitomi H, Nakamura T, Shimizu M, Kawabata D, Yukawa N, Hashimoto M, Sakaguchi N, Sakaguchi S, Yoshifuji H, Nojima T, Ohmura K, Fujii T, Mimori T.
  • Journal Title: Arthritis Rheum 60 Pages: 2294-303
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Vaccination with autoreactive CD4(+)Th1 clones in lupus-prone MRL/Mp-Fas(lpr/lpr)mice (2009)
  • Author(s): Fujii T, Okada M, Fujita Y, Sato T, Tanaka M, Usui T, Umehara H, Mimori T.
  • Journal Title: J Autoimmun 33 Pages: 125-34
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] γδT Cells Are the Predominant Source of IL-17 in the Affected Joints of Collagen-Induced Arthritis, but Not in Rheumatoid Arthritis (2009)
  • Author(s): Ito Y, Usui T, Kobayashi S, Iguchi-Hashimoto M, Ito H, Yoshitomi H, Nakamura T, Hashimoto M, Sakaguchi N, Sakaguchi S, Shimizu M, Yoshifuji H, Nojima T, Ohmura K, Kawabata D, Fujii T, Mimori T.
  • Journal Title: Arthritis Rheum. 30
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Vaccination with autoreactive CD4(+)Th1 clones in lupus-prone MRL/Mp-Fas(lpr/lpr)mice (2009)
  • Author(s): Fujii T, Okada M, Fujita Y, Sato T, Tanaka M, Usui T, Umehara H, Mimori T
  • Journal Title: J Autoimmun. 33(2) Pages: 125-34
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Severe subcutaneous generalized edema in a patient with dermatomyositis (2007)
  • Author(s): Ito Y, Kawabata D, Yukawa N, Yoshifuji H, Usui T, Tanaka M, Fujii T, Mimori T.
  • Journal Title: Mod Rheumatol 17 Pages: 171-3
  • Peer Reviewed
• [Journal Article] Successful treatment of a patient with refractory adult Still's disease by tacrolimus (2007)
  • Author(s): Murakami K, Fujii T, Yukawa N, Yoshifuji H, Kawabata D, Tanaka M, Usui T, Mimori
  • Journal Title: Mod Rheumatol 17 Pages: 167-70
  • Peer Reviewed
• [Journal Article] Anti-aminoacyl-tRNA synthetase antibodies in clinical course prediction of interstitial lung disease complicated with idiopatc inflammatory myopathies (2007)
  • Author(s): Yoshifuji H, Fujii T, Kobayashi S, Imura Y, Fujita Y, Kawabata D, Usui T, Tanaka M, Nagai S, Umehara H, Mimori T.
  • Journal Title: Autoimmunity 39 Pages: 233-41
  • Peer Reviewed
• [Journal Article] Anti-aminoacyl-tRNA synthetase antibodies in clinical course prediction of interstitial lung disease complicated with idiopathic inflammatory myopathies. (2006)
  • Author(s): Yoshifuji H
  • Journal Title: Autoimmunity 39(3) Pages: 233-241
• [Journal Article] T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription (2006)
  • Author(s): Usui T
  • Journal Title: J Exp Med. 203(3) Pages: 755-766
• [Presentation] γδ T cells are the predominant IL-17-producing cells in affected joints of collagen-induced arthritis (2008)
  • Author(s): Ito Y, Usui T, Kobayashi S, Iguch M, Ito H, Yoshitomi H, Nakamura T, Hashimoto M, Sakaguchi N, Sakaguchi S, Mimori T
  • Organizer: 第38回日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 2008-12-03
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] γδT cells are the predominant IL-17-producing cells in affected joints of collagen-induced arthritis (2008)
  • Author(s): Ito Y, Usui T, Kobayashi S, Iguch M, Ito H, Yoshitomi H, Nakamura T, Hashimoto M, Sakaguchi N, Sakaguchi S, Mimori T.
  • Organizer: The 38^<th> Annual Meeting of the Japanese society of immunology
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2008-12-03
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 疾患特異的な免疫制御法の開発の可能性 (2007)
  • Author(s): 臼井 崇
  • Organizer: 第51回日本リウマチ学会総会・学術集会・シンポジウム10(関節リウマチの新たなる治療ターゲット〜生物学的製剤を超えて〜)
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-04-28