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Novel therapeutic strategy of polymyositis targeting muscle fiber death

Research Project

Project/Area Number 19K23839
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0803:Pathology, infection/immunology, and related fields
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Kamiya Mari  東京医科歯科大学, 医学部附属病院, 特任助教 (20844377)

Project Period (FY) 2019-08-30 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords炎症性筋疾患 / 細胞死 / 筋傷害 / DAMPs / 多発性筋炎
Outline of Research at the Start

多発性筋炎(PM)は自己免疫性の炎症性筋疾患であり、細胞傷害性Tリンパ球(CTL)による筋傷害が病態の中心と考えられている。既存の免疫細胞を標的とする治療法では感染症などの副作用が問題となる一方で筋炎抑制効果が不十分である例が存在する現状から、我々はPMの病態における筋細胞の役割に注目した。CTLにより傷害され、細胞死に至った筋は様々な炎症介在因子を放出し更なる炎症を誘導すると考えられ、筋細胞死がPMの新たな治療標的となると考えたが、PMの筋細胞死機序は不明である。PMの筋細胞死機序と、その制御がもたらす効果を解明するために、培養細胞や動物モデル、そしてPM筋組織を用いた検証を行う。

Outline of Final Research Achievements

We clarified that the pattern of cell death of muscle fibers in polymyositis (PM) is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of PM patients and models of PM in vitro and in vivo. While apoptosis is an anti-inflammatory cell death, necroptosis is known as one of inflammatory forms of cell death, as necroptotic cells release inflammatory mediators such as damaged molecular patterns (DAMPs) and cytokines. Treatment with a necroptosis inhibitor ameliorated myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles in murine model of PM. Thus, targeting necroptosis in muscle cells is a promising strategy for treating PM providing an alternative to current therapies directed at leukocytes.

Academic Significance and Societal Importance of the Research Achievements

多発性筋炎(PM)の既存治療は副腎皮質ステロイド薬や免疫抑制薬であるが、これらは免疫細胞を標的とした治療であり、感染症を合併するほどの免疫抑制状態を誘導してすら筋炎を抑制できない例や、筋炎抑制に長期間を要し筋力低下が更に進行する例が存在することが臨床的問題であり、PMに対する免疫抑制療法の限界と考えざるを得ない。
我々は本研究において、筋の細胞死の制御が、PMの新たな治療戦略として期待されることを示した。
筋の細胞死を直接の標的とする治療は、既存治療とは全く異なる仕組みを介した治療であり、既存の治療で炎症が抑制できない症例や、治療開始後も筋力低下が更に進行する症例への有効性が期待できる。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report

Research Products

(7 results)

All 2021 2020 2019

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (6 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] A new in vitro model of polymyositis reveals CD8+ T cell invasion into muscle cells and its cytotoxic role2020

    • Author(s)
      Kamiya Mari、Mizoguchi Fumitaka、Takamura Akito、Kimura Naoki、Kawahata Kimito、Kohsaka Hitoshi
    • Journal Title

      Rheumatology.

      Volume: 59 Pages: 224-232

    • DOI

      10.1093/rheumatology/kez248

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] HMGB1 is highly expressed in injured muscle fibers and accelerates inflammation and muscle injury in inflammatory myopathies.2021

    • Author(s)
      Mari Kamiya, Shinsuke Yasuda, Fumitaka Mizoguchi
    • Organizer
      65th Annual General Assembly and Scientific Meeting of the Japan College of Rheumatology 2021.04.27
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Targeting necroptosis in muscle cells ameliorates inflammatory myopathies.2020

    • Author(s)
      Mari Kamiya, Kimito Kawahata, Hitoshi Kohsaka , Fumitaka Mizoguchi.
    • Organizer
      64th Annual General Assembly and Scientific Meeting of the Japan College of Rheumatology
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 炎症性筋疾患においてHMGB1は傷害筋線維に発現し筋炎の病態の悪化に寄与する2020

    • Author(s)
      神谷 麻理、王 登莉、保田 晋助、西堀 正洋、溝口 史高.
    • Organizer
      第48回日本臨床免疫学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Necroptosis阻害は実験的多発性筋炎モデルにおいて筋細胞死と炎症細胞浸潤を抑制し筋力を改善させる2019

    • Author(s)
      神谷 麻理、川畑 仁人、上阪 等、溝口 史高
    • Organizer
      第47回日本臨床免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Necroptosis阻害は実験的多発性筋炎モデルにおいて筋細胞死と炎症介在因子の放出、炎症細胞浸潤を抑制し筋力を改善させる2019

    • Author(s)
      神谷 麻理、川畑 仁人、上阪 等、溝口 史高
    • Organizer
      第5回JCRベーシックリサーチカンファレンス
    • Related Report
      2019 Research-status Report
  • [Presentation] Inhibition of Necroptosis Suppresses Muscle Cell Death and Inflammatory Infiltrate, and Improves Muscle Strength in Experimental Polymyositis2019

    • Author(s)
      Mari Kamiya, Fumitaka Mizoguchi, Kimito Kawahata, Hitoshi Kohsaka
    • Organizer
      2019 ACR/ARP Annual meeting
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-09-03   Modified: 2022-01-27  

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