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Molecular and immunological analysis to clarify the pathogenesis of macrophage activation syndrome toward a developing interleukin18-targeted treatment strategy

Research Project

Project/Area Number 18K07786
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionTokyo Medical and Dental University (2020)
Kanazawa University (2018-2019)

Principal Investigator

Shimizu Masaki  東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座講師 (10401902)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsマクロファージ活性化症候群 / 全身型若年性特発性関節炎 / インターロイキン18 / インターロイキン1β / モデルマウス / バイオマーカー
Outline of Final Research Achievements

We developed a new mouse model of MAS using continuous infusion with IL-1β and/or IL-18. IL-1β and IL-18 play distinct roles in MAS. Furthermore, sustained elevation of IL-18 was necessary to develop MAS. From the comparison of serum cytokine profiles in patients with MAS in different background rheumatic diseases, the pathogenesis of MAS associated with s-JIA might be different from other diseases. Serum IL-18 levels might be useful for the differentiation s-JIA from other diseases, the assessment of disease activity and also for diagnosis of remission in s-JIA.

Academic Significance and Societal Importance of the Research Achievements

本研究により、まだ未解明であったMAS病態におけるIL-1βとIL-18の役割に関する理解が進み、現在までの有効な治療が確立していないMASに対して、IL-1βおよびIL-18両方の制御が必要であることが判明し、今後の治療開発に向け意義のある成果となった。また、臨床症状の組み合わせによって診断されるため他の炎症性疾患との鑑別が困難な全身型JIAおよびMASの診断、病勢評価、寛解判定に対する客観的指標として血清IL-18値が非常に有用であることが判明し、今後の保険収載に向けた基礎資料として意義のある成果となった。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (17 results)

All 2021 2020 2019 2018

All Journal Article (9 results) (of which Peer Reviewed: 9 results) Presentation (8 results) (of which Int'l Joint Research: 3 results,  Invited: 3 results)

  • [Journal Article] Clinical significance of interleukin-18 for the diagnosis and prediction of disease course in systemic juvenile idiopathic arthritis2021

    • Author(s)
      Mizuta M, Shimizu M, Inoue N, Ikawa Y, Nakagishi Y, Yasuoka R, Iwata N, Yachie A.
    • Journal Title

      Rheumatology

      Volume: - Issue: 5 Pages: 2421-2426

    • DOI

      10.1093/rheumatology/keaa634

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Macrophage activation syndrome in systemic juvenile idiopathic arthritis2021

    • Author(s)
      Masaki Shimizu
    • Journal Title

      Immunological Medicine

      Volume: -

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comparison of serum biomarkers for the diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis during tocilizumab therapy.2020

    • Author(s)
      Irabu H, Shimizu M, Kaneko S, Inoue N, Mizuta M, Nakagishi Y, Yachie A.
    • Journal Title

      Pediatric Research

      Volume: in press Issue: 6 Pages: 934-939

    • DOI

      10.1038/s41390-020-0843-4

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comparison of serum cytokine profiles in macrophage activation syndrome complicating different background rheumatic diseases in children2020

    • Author(s)
      Mizuta Mao、Shimizu Masaki、Irabu Hitoshi、Usami Masaaki、Inoue Natsumi、Nakagishi Yasuo、Wada Taizo、Yachie Akihiro
    • Journal Title

      Rheumatology

      Volume: 60 Issue: 1 Pages: 231-238

    • DOI

      10.1093/rheumatology/keaa299

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comparison of serum biomarkers for the diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.2019

    • Author(s)
      Takakura M, Shimizu M, Irabu H, Sakumura N, Inoue N, Mizuta M, Nakagishi Y, Yachie A.
    • Journal Title

      Clinical Immunology

      Volume: in press Pages: 108252-108252

    • DOI

      10.1016/j.clim.2019.108252

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Extensive serum biomarker analysis in patients with macrophage activation syndrome associated with systemic lupus erythematosus.2019

    • Author(s)
      Usami M, Shimizu M, Mizuta M, Inoue N, Irabu H, Sakumura N, Nakagishi Y, Yachie A.
    • Journal Title

      Clinical Immunology

      Volume: 208 Pages: 108255-108255

    • DOI

      10.1016/j.clim.2019.108255

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Macrophage activation syndrome in neonates born to mothers with adult-onset Still's disease: Perinatal effect of maternal IL-18.2019

    • Author(s)
      Shimizu M, Kizawa T, Kato R, Suzuki T, Yachie A.
    • Journal Title

      Clin Immunol

      Volume: 207 Pages: 36-39

    • DOI

      10.1016/j.clim.2019.07.005

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Clinical significance of serum CXCL9 levels as a biomarker for systemic juvenile idiopathic arthritis associated macrophage activation syndrome.2019

    • Author(s)
      Mizuta M, Shimizu M, Inoue N, Nakagishi Y, Yachie A.
    • Journal Title

      Cytokine

      Volume: 119 Pages: 182-187

    • DOI

      10.1016/j.cyto.2019.03.018

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cytokine profile of macrophage activation syndrome associated with Kawasaki disease.2019

    • Author(s)
      Jinkawa A, Shimizu M, Nishida K, Kaneko S, Usami M, Sakumura N, Irabu H, Takakuwa M, Inoue N, Mizuta M, Ikawa Y, Fujita S, Yachie A.
    • Journal Title

      Cytokine.

      Volume: 119 Pages: 52-56

    • DOI

      10.1016/j.cyto.2019.03.001

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] サイトカインプロファイリング - どんな時にオーダーするのか?何が分かるのか?2020

    • Author(s)
      清水正樹
    • Organizer
      第123回 日本小児科学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 多面的サイトカイン解析からみた マクロファージ活性化症候群(MAS)の臨床的特徴.2020

    • Author(s)
      清水正樹
    • Organizer
      第64回 日本リウマチ学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Macrophage Activation Syndrome: Analysis of various Cytokines.2020

    • Author(s)
      Masaki Shimizu
    • Organizer
      22nd Asia-Pacific League of Associations for Rheumatology Congress
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Comparison of serum cytokine profile in macrophage activation syndrome among different background rheumatic diseases in children2019

    • Author(s)
      Mao Mizuta, Masaki Shimizu, Masaaki Usami, Naoto Sakumura, Hitoshi Irabu, Maiko Takakuwa, Natsumi Inoue, Yasuo Nakagishi, Akihiro Yachie
    • Organizer
      European congress of Rheumatology 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Comparison of serum biomarkers for the diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.2019

    • Author(s)
      Irabu H, Shimizu M, Takakura M, Sakumura N, Inoue N, Mizuta M, Nakagishi Y, Yachie A.
    • Organizer
      European congress of Rheumatology 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 多面的サイトカイン解析からみたマクロファージ活性化症候群(MAS)の臨床的特徴2019

    • Author(s)
      清水正樹
    • Organizer
      第63回日本リウマチ学会
    • Related Report
      2018 Research-status Report
  • [Presentation] マクロファージ活性化症候群における基礎疾患による血清サイトカインプロファイルの比較検討2018

    • Author(s)
      伊良部仁、清水正樹、水田麻雄、井上なつみ、宇佐美雅章、高桑麻衣子、作村直人、中岸保夫、谷内江昭宏
    • Organizer
      第28回日本小児リウマチ学会
    • Related Report
      2018 Research-status Report
  • [Presentation] 全身型若年性特発性関節炎に合併したマクロファージ活性化症候群における診断バイオマーカーの比較検討 ‐血清neopterin値の有用性‐2018

    • Author(s)
      高桑麻衣子、清水正樹、水田麻雄、井上なつみ、中岸保夫、谷内江昭宏
    • Organizer
      第28回日本小児リウマチ学会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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