Dynamism of T helper cells in systemic lupus erythematosus

• Project/Area Number: 17K10010
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: Nakayamada Shingo 産業医科大学, 医学部, 講師 (60389426)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 全身性エリテマトーデス / 濾胞性ヘルパーT細胞 / 免疫フェノタイプ / エピジェネティクス / JAK阻害薬 / 形質芽細胞 / 免疫フェノタイピング / 内科 / 免疫学 / トランスレーショナルリサーチ

Outline of Final Research Achievements

We have used an immunophenotyping approach to categorize patients with SLE into distinct subgroups by comprehensive multicolor flow cytometric analysis. We identified three distinct subgroups based on T cell heterogeneity, including a T cell-independent group, a T follicular helper (Tfh) cell-dominant group and a T regulatory (Treg) cell-dominant group. The percentage of patients who were resistant to immunosuppressive treatment was highest among the Tfh cell-dominant group. In vitro analysis demonstrated that IL-12-mediated co-activation of STAT1 and STAT4 alters histone modification, resulting in development of pathogenic Tfh-Th1-like cells. Finally, Tfh/Th1 differentiation was inhibited by selective TYK2 inhibitors. Collectively, our data indicated that the IL-12-TYK2-STAT pathway is a candidate for new therapeutic target for SLE.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果により、SLEの病態においてT細胞ダイナミズムによるheterogeneityが存在することが明らかとなった。SLEの病態に関与するTfh細胞への分化偏向はJAK-STAT経路を介したエピジェネティクス機序で制御されており、これらを標的とした創薬はSLEの治療抵抗性難治性病態への新たな治療戦略に有望である。本研究は、免疫難病であるSLEへの疾患特異的治療の開発に重要な示唆を与え、医療および社会の発展に資するものである。

Research Products

• [Journal Article] Baricitinib for the treatment of rheumatoid arthritis and systemic lupus erythematosus: a 2019 update. (2019)
  • Author(s): Kubo S, Nakayamada S, Tanaka Y
  • Journal Title: Expert Rev Clin Immunol Volume: 14 Issue: 7 Pages: 693-700
  • DOI: 10.1080/1744666x.2019.1608821
  • Peer Reviewed
• [Journal Article] JAK阻害薬 (2019)
  • Author(s): 中山田真吾, 田中良哉
  • Journal Title: 薬局 Volume: 70 Pages: 1143-1149
• [Journal Article] 全身性エリテマトーデス (2019)
  • Author(s): 中山田真吾, 田中良哉
  • Journal Title: 炎症と免疫 Volume: 27 Pages: 305-309
• [Journal Article] SLEに対するJAK阻害療法 (2019)
  • Author(s): 佐藤 友梨恵, 中山田真吾,田中良哉
  • Journal Title: SLEに対するJAK阻害療法 Volume: 62 Pages: 266-272
• [Journal Article] Expansion of T follicular helper-T helper 1 like cells through epigenetic regulation by signal transducer and activator of transcription factors (2018)
  • Author(s): Ma X, Nakayamada S, Kubo S, Sakata K, Yamagata K, Miyazaki Y, Yoshikawa M, Kitanaga Y, Zhang M, Tanaka Y.
  • Journal Title: Annals of Rheumatic Diseases Volume: 88 Issue: 9 Pages: 1354-1361
  • DOI: 10.1136/annrheumdis-2017-212652
  • Peer Reviewed / Open Access
• [Journal Article] Peripheral Immunophenotyping Identifies Three Subgroups Based on T Cell Heterogeneity in Lupus Patients. (2017)
  • Author(s): Kubo S, Nakayamada S, Yoshikawa M, Miyazaki Y, Sakata K, Nakano K, Hanami K, Iwata S, Miyagawa I, Saito K, Tanaka Y.
  • Journal Title: Arthritis Rheumatol. Volume: 69(10) Issue: 10 Pages: 2029-2037
  • DOI: 10.1002/art.40180
  • Peer Reviewed / Int'l Joint Research