Analysis of pathophysiology and novel therapeutic approach for rheumatic diseases by arthritis-regulated proteins

2008 Fiscal Year Final Research Report

• Project/Area Number: 18390290
• Research Category: Grant-in-Aid for Scientific Research (B)
• 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: MIMORI Tsuneyo Kyoto University, 大学院医学研究科医学研究科・内科学講座臨床免疫学, 教授 (10157589)
• Co-Investigator(Renkei-kenkyūsha): FUJII Takao 京都大学, 大学院・医学研究科, 講師 (70255462) ; USUI Takashi 京都大学, 大学院・医学研究科, 准教授 (90362483) ; TANAKA Masao 金沢医科大学, 医学部, 講師 (10332719)
• Research Collaborator: ITO Yoshinaga 京都大学, 大学院・医学研究科, 大学院生 ; HASHIMOTO Mikiko 京都大学, 大学院・医学研究科, 大学院生 ; MURAKLAMI Kosaku 京都大学, 大学院・医学研究科, 大学院生
• Project Period (FY): 2006 – 2008
• Keywords: 関節リウマチ / 自己抗体 / カルパイン / カルパスタチン / FRP / コラーゲン誘発関節炎

Research Abstract

本研究は、以前に見出した関節リウマチ(RA)の新たな自己抗体である抗カルパスタチン抗体と抗FRP抗体の対応抗原がいずれも関節炎抑制作用を示したことから、これらの自己抗体がRAの発症と増悪に関与する病原性自己抗体ではないかと考え、これら自己抗原および自己抗体の制御によって関節炎を治療できる可能性を追求した。カルパイン(カルシウム依存性中性プロテアーゼ)の特異的インヒビターであるカルパスタチンは線維芽細胞のIL-6産生を抑制するだけでなく、T細胞分化にも影響することが判明した。関節炎モデルにおいてはカルパスタチンは炎症を抑制しカルパインは増強した。フォリスタチン関連蛋白(FRP)はヒトとマウスで炎症の制御に関して異なる働きを有する可能性が示唆され、マウス関節炎に対してヒトFRPは抑制したが逆にマウスFRPは増強した。これらの炎症制御蛋白の解析により関節炎病態の理解と新たな治療法開発の可能性が示唆される。

Research Products

• [Journal Article] Autoimmune autonomic ganglionopathy with Sjogren's syndrome : Significance of ganglionic acetylcholine receptor antibody and therapeutic approach (2009)
  • Author(s): Kondo T, Inoue H, Usui T, Mimori T, Tomimoto H, Vernino S, Takahashi R
  • Journal Title: Auton Neurosci. Auton Neurosci 146(1-2) Pages: 33-5
  • Peer Reviewed
• [Journal Article] Impaired TCR signaling through dysfunction of lipid rafts in sphingomyelin synthase 1 (SMS1)-knockdown T cells (2008)
  • Author(s): Jin ZX, Huang CR, Dong L, Goda S, Kawanami T, Sawaki T, Sakai T, Tong XP, Masaki Y, Fukushima T, Tanaka M, Mimori T, Tojo H, Bloom ET, Okazaki T, Umehara H
  • Journal Title: Int Immunol 20(11) Pages: 1427-37
  • Peer Reviewed
• [Journal Article] Aseptic meningitis in mixed connective tissue disease : cytokine and anti-U1RNP antibodies in cerebrospinal fluids from two different cases (2008)
  • Author(s): Fujita Y, Fujii T, Nakashima R, Tanaka M, Mimori T
  • Journal Title: Mod Rheumatol 18(2) Pages: 84-8
  • Peer Reviewed
• [Journal Article] Efficacy and safety of mizoribine for the treatment of Sjogren's syndrome : a multicenter open-label clinical trial (2007)
  • Author(s): Nakayamada S, Saito K, Umehara H, Ogawa N, Sumida T, Ito S, Minota S, Nara H, Kondo H, Okada J, Mimori T, Yoshifuji H, Sano H, Hashimoto N, Sugai S, Tanaka Y
  • Journal Title: Mod Rheumatol 17(6) Pages: 464-9
  • Peer Reviewed
• [Journal Article] Autoantibodies in idiopathic inflammatory myopathy : an update on clinical and pathophysiological significance (2007)
  • Author(s): Mimori T, Imura Y, Nakashima R, Yoshifuji H
  • Journal Title: Curr Opin Rheumatol 19(6) Pages: 523-9
  • Peer Reviewed
• [Journal Article] Incidence of pulmonary hypertension and its clinical relevance in patients with interstitial pneumonias : comparison between idiopathic and collagen vascular disease associated interstitial pneumonias (2007)
  • Author(s): Handa T, Nagai S, Miki S, Ueda S, Yukawa N, Fushimi Y, Ito Y, Ohta K, Mimori T, Mishima M, Izumi T
  • Journal Title: Intern Med 46(12) Pages: 831-7
  • Peer Reviewed
• [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(2) 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 T
  • Journal Title: Mod Rheumatol 17(2) Pages: 167-70
  • Peer Reviewed
• [Journal Article] Clinical and immunogenetic features of patients with autoantibodies to asparaginyl-transfer RNA synthetase (2007)
  • Author(s): Hirakata M, Suwa A, Takada T, Sato S, Nagai S, Genth E, Song YW, Mimori T, Targoff IN
  • Journal Title: Arthritis Rheum 56(4) Pages: 1295-303
  • Peer Reviewed
• [Journal Article] Successful treatment of primary Sjogren's syndrome with chronic natural killer lymphocytosis by high-dose prednisolone and indomethacin farnesil (2007)
  • Author(s): Fujita Y, Fujii T, Takeda N, Tanaka M, Mimori T
  • Journal Title: Intern Med 46(5) Pages: 251-4
  • Peer Reviewed
• [Journal Article] Efficacy of rituximab(anti-CD20)for refractory systemic lupus erythematosus involving the central nervous system (2007)
  • Author(s): Tokunaga M, Saito K, Kawabata D, Imura Y, Fujii T, Nakayamada S, Tsujimura S, Nawata M, Iwata S, Azuma T, Mimori T, Tanaka Y
  • Journal Title: Ann Rheum Dis 66(4) Pages: 470-5
  • 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, Fujii T, Kobayashi S, Imura Y, Fujita Y, Kawabata D, Usui T, Tanaka M, Nagai S, Umehara H, Mimori T
  • Journal Title: Autoimmunity 39(3) Pages: 233-241
  • Peer Reviewed
• [Journal Article] Anti-p97/VCP antibodies : an autoantibody marker for a subset of primary biliary cirrhosis patients with milder disease (2006)
  • Author(s): Miyachi K, Hosaka H, Nakamura N, Miyakawa H, Mimori T, Shibata M, Matsushima S, Chinoh H, Horigome T, Hankins RW, Zhang M, Fritzler MJ
  • Journal Title: Scand J Immunol 63(5) Pages: 376-382
  • 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
  • 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 (in press)
  • Peer Reviewed