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Development of a new treatment strategy for SLE by artificially restoring epigenomic memory in helper T cells

Research Project

Project/Area Number 20K08815
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54020:Connective tissue disease and allergy-related
Research InstitutionUniversity of Occupational and Environmental Health, Japan

Principal Investigator

Nakayamada Shingo  産業医科大学, 医学部, 准教授 (60389426)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords全身性エリテマトーデス / 濾胞性ヘルパーT細胞 / 濾胞制御性ヘルパーT細胞 / 末梢性ヘルパーT細胞 / エピジェネティクス / サイトカイン / ジェネティクス / ヘルパーT細胞 / ゲノム
Outline of Research at the Start

本研究では、(1) Tfh細胞の可塑性に関わるゲノム異常とエピゲノム修飾との関連、(2) Tfh細胞に特異的なスーパーエンハンサー・エピゲノム修飾とその誘導因子の同定、(3) Tfh細胞のエピゲノム制御による濾胞性制御性T細胞への形質転換の検証によって、Tfh細胞の人為的なエピゲノム制御によるT細胞の機能修復の可能性を探索する。

Outline of Final Research Achievements

In SLE patients, decreased IL-2 resulted in increased Tfh cells and decreased Tfr cells. IL-2 reduction in SLE patients was associated with genetic regulation of IL-2 by the disease susceptibility gene IL21-AS1. IL-2 induced the conversion of memory Tfh cells to functional Tfr cells by epigenetic regulation via activation of STAT3/STAT5. On the other hand, Tph cells increased in SLE, and their differentiation was induced by TGF-β3 produced from tissue macrophages, unlike Tfh cells, and promoted B cell differentiation and antibody production. These results suggest that IL-2 and TGF-β3, which are involved in the differentiation of pathological T cells in SLE, are novel therapeutic targets mediated by epigenome repair.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果は、SLEの病態においてT細胞の分化や機能の異常がゲノム異常により規定されるSLE特異的なエピゲノム記憶に基づく可能性を示唆する。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。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (5 results)

All 2022 2021

All Journal Article (5 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 5 results,  Open Access: 3 results)

  • [Journal Article] TGF-β3 in differentiation and function of Tph-like cells and its relevance to disease activity in patients with systemic lupus erythematosus.2022

    • Author(s)
      Shan Y, Nakayamada S, Nawata A, Yamagata K, Sonomoto K, Tanaka H, Satoh-Kanda Y, Nguyen MP, Todoroki Y, Nagayasu A, Ueno M, Kanda R, Fujita Y, Zhang T, Hao H, Zhou J, Ma X, Anan J, Nguyen AP, Tanaka Y.
    • Journal Title

      Rheumatology (Oxford).

      Volume: keac646. Issue: 7 Pages: 2464-2474

    • DOI

      10.1093/rheumatology/keac646

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Differentiation, functions, and roles of T follicular regulatory cells in autoimmune diseases.2021

    • Author(s)
      Hao H, Nakayamada S, Tanaka Y.
    • Journal Title

      Inflamm Regen.

      Volume: 41 Issue: 1 Pages: 14-14

    • DOI

      10.1186/s41232-021-00164-9

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Clinical relevance of T follicular helper cells in systemic lupus erythematosus.2021

    • Author(s)
      Nakayamada S, Tanaka Y.
    • Journal Title

      Expert Rev Clin Immunol.

      Volume: 17 Issue: 10 Pages: 1143-1150

    • DOI

      10.1080/1744666x.2021.1976146

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Involvement of lncRNA IL21-AS1 in interleukin-2 and T follicular regulatory cell activation in systemic lupus erythematosus.2021

    • Author(s)
      Hao H, Nakayamada S, Ohkubo N, Yamagata K, Zhang M, Shan Y, Iwata S, Zhang T, Tanaka Y.
    • Journal Title

      Arthritis Res Ther.

      Volume: 23 Issue: 1 Pages: 302-312

    • DOI

      10.1186/s13075-021-02682-w

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] IL-2 drives conversion of T follicular helper cells to T follicular regulatory cells through transcriptional regulation in systemic lupus erythematosus.2021

    • Author(s)
      Hao H, Nakayamada S, Yamagata K, Ohkubo N, Iwata S, Inoue Y, Zhang M, Zhang T, Kanda Satoh Y, Shan Y, Otsuka T, Tanaka Y.
    • Journal Title

      Arthritis Rheumatol.

      Volume: 73 Issue: 1 Pages: 132-142

    • DOI

      10.1002/art.41457

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access

URL: 

Published: 2020-04-28   Modified: 2024-01-30  

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