Identification of novel therapeutic targets for rheumatoid arthritis by genome-wide analysis of gene expression in peripheral CD4 positive T cells

• Project/Area Number: 24591441
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Chiba University
• Principal Investigator: IKEDA Kei 千葉大学, 医学部附属病院, 助教 (10456014)
• Co-Investigator(Kenkyū-buntansha): NAKAJIMA Hiroshi 千葉大学, 医学部附属病院, 教授 (00322024) ; TAKATORI Hiroaki 千葉大学, 医学部附属病院, 助教 (30568225)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 関節リウマチ / IL-6 / ヘルパーT細胞 / ARID5A / Helios / Bcl-3 / Th17細胞 / CD4陽性T細胞 / トシリズマブ / DNAマイクロアレイ / DNAアレイ / RORgt

Outline of Final Research Achievements

We analyzed the comprehensive gene expression in peripheral CD4 positive T cells from patients with rheumatoid arthritis (RA) who achieved a good response after treatment with tocillizumab. We focused on ARID5A, Helios, and Bcl-3, the expression of which significantly decreased after treatment and further investigated the mechanisms.
We demonstrated that ARID5A is a novel molecule which inhibits Th17 differentiation probably through direct binding to RORgt. We also demonstrated that Helios potentiates the function of regulatory T cells cooperatively with FoxP3. We also demonstrated that Bcl-3 is involved in follicular helper T cell differentiation and the pathophysiology of RA.

Research Products

• [Journal Article] The quest to search for biomarkers in rheumatoid arthritis (2014)
  • Author(s): Sanayama Y, Ikeda K, Yamagata M, Furuta S, Ohara O, Nakajima H
  • Journal Title: Arthritis Rheumatol Volume: 66 Issue: 12 Pages: 3524-3525
  • DOI: 10.1002/art.38858
  • Peer Reviewed
• [Journal Article] Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis – biomarkers identified by analyses of gene expression in peripheral blood mononuclear cells using genome-wide DNA microarray (2014)
  • Author(s): Sanayama Y, Ikeda K, Saito Y, Kagami S, Yamagata M, Furuta S, Kashiwakuma D, Iwamoto I, Umibe T, Nawata Y, Matsumura R, Sugiyama T, Sueishi M, Hiraguri M, Nonaka K, Ohara O, Nakajima H
  • Journal Title: Arthritis Rheumatol Volume: in press Issue: 6 Pages: 1421-1431
  • DOI: 10.1002/art.38400
  • Peer Reviewed
• [Journal Article] AT-rich interactive domain-containing protein 5a functions as a negative regulator of RORγt-induced Th17 cell differentiation. (2014)
  • Author(s): Saito Y, Kagami SI, Sanayama Y, Ikeda K, Suto A, Kashiwakuma D, Furuta S, Iwamoto I, Nonaka K, Ohara O, Nakajima H.
  • Journal Title: Arthritis and Rheumatology Volume: 印刷中 Issue: 5 Pages: 1185-94
  • DOI: 10.1002/art.38324
  • Peer Reviewed
• [Journal Article] B and T lymphocyte attenuator inhibits LPS-induced endotoxic shock by suppressing Toll-like receptor 4 signaling in innate immune cells (2013)
  • Author(s): Kobayashi Y, Iwata A, Suzuki K, Suto A, Kawashima S, Saito Y, Owada T, Kobayashi M, Watanabe N, Nakajima H
  • Journal Title: Proc Natl Acad Sci U S A Volume: 110(13) Issue: 4 Pages: 890-8
  • DOI: 10.1002/art.37848
  • Peer Reviewed
• [Journal Article] beta-glucan Curdlan induces IL-10-producing CD4+T cells and inhibits allergic airway inflammation (2012)
  • Author(s): Kawashima S, Hirose K, Iwata A, Takahashi K, Ohkubo A, Tamachi T, Ikeda K, Kagami S, Nakajima H
  • Journal Title: J Immunol Volume: 189 Issue: 12 Pages: 5713-5721
  • DOI: 10.4049/jimmunol.1201521
  • Peer Reviewed
• [Journal Article] Roles of CRTH2+ CD4+ T cells in immunoglobulin G4-related lacrimal gland enlargement. (2012)
  • Author(s): Saito Y, Kagami S, Kawashima S, Takahashi K, Ikeda K, Hirose K, Oshitari T, Yamamoto S, Okamoto Y, Nakajima H
  • Journal Title: Int Arch Allergy Immunol Volume: 158 Suppl 1 Issue: Suppl. 1 Pages: 42-46
  • DOI: 10.1159/000337761
  • Peer Reviewed
• [Presentation] Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis using biomarkers identified by genome-wide DNA microarray analysis in peripheral blood mononuclear cells (2014)
  • Author(s): Sanayama Y, Ikeda K, Saito Y, Kagami S, Yamagata M, Furuta S, Kashiwakuma D, Iwamoto I, Umibe T, Nawata Y, Matsumura R, Sugiyama T, Sueishi M, Hiraguri M, Nonaka K, Ohara O, Nakajima H
  • Organizer: 2014 European Colleague Against Rheumatism Congress
  • Place of Presentation: Paris, France
  • Year and Date: 2014-06-13