Strategy for the Development of a Novel Treatment for Severe Interstitial Pneumonia Complicated by Autoimmune Myositis

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08478
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Dokkyo Medical University
• Principal Investigator: Kurasawa Kazuhiro 獨協医科大学, 医学部, 特任教授 (30282479)
• Co-Investigator(Kenkyū-buntansha): 有馬 雅史 獨協医科大学, 医学部, 教授 (00202763) ; 大和田 高義 獨協医科大学, 医学部, 講師 (30456016) ; 田中 彩絵 獨協医科大学, 医学部, 助教 (30743067)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: interstitial pneumonia

Outline of Final Research Achievements

Pulmonary disease associated with collagen disease is the most important complication in terms of prognosis. In particular, interstitial pneumonia (ILD), a complication of anti-MDA5 antibody-positive dermatomyositis, is a rapidly progressive disease with a poor prognosis, and no treatment has been established. Although it has been reported that increased production of multiple inflammatory cytokines and macrophage activation may be involved in ILD, the pathogenesis is not fully understood. We established a model of rapidly progressive hyperinflammatory ILD in mice with macrophage-specific deficiency of ADAR1, a double-stranded RNA editing enzyme. This study revealed that dysfunction of ADAR1 in macrophages induces hyperfunction of MDA5, which is deeply involved in the progression of severe lung inflammation due to hyperimmune and inflammatory responses.

Free Research Field

Rheumatology

Academic Significance and Societal Importance of the Research Achievements

本研究は自己免疫疾患で発症する間質性肺炎の急速に難治化する過程に誘導されるサイトカインスト―ムにおいて，特に重要とされるマクロファージの活性化に注目し，ヒト臨床研究と遺伝子改変マウスを利用した動物実験を行った．その結果，過剰炎症性肺炎の難治性病態におけるマクロファージのADAR1機能の異常に病理的意義が見出された．この点において学術的意義があると思われる．また，間質性肺炎の難治化メカニズムの解明を目的とした本研究は，予後が極めて不良の抗MDA5抗体陽性間質性肺炎の病態の解明および、その根治的治療の開発に向けた基盤的研究である点において社会的意義があると思われる．