Reveal of the pathogenesis of MPO-ANCA-associated vasculitis and development of novel therapeutic strategies

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02958
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Hokkaido University
• Principal Investigator: Ishizu Akihiro 北海道大学, 保健科学研究院, 教授 (60321957)
• Co-Investigator(Kenkyū-buntansha): 益田 紗季子 北海道大学, 保健科学研究院, 講師 (10763617) ; 外丸 詩野 北海道大学, 大学病院, 准教授 (20360901) ; 中沢 大悟 北海道大学, 大学病院, 助教 (60724135)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: MPO-ANCA / MPO-ANCA関連血管炎 / 好中球 / 好中球細胞外トラップ / Fc受容体 / 分解抵抗性 / モノクローナル抗体

Outline of Final Research Achievements

MPO-ANCA binds to MPO at the Fab portion and to the Fc receptor at the Fc portion. Patients with ANCA, in which stimulation from the Fc receptor predominated, had significantly greater renal damage and significantly more frequent renal death than patients with ANCA, in which stimulation from antigens predominated.
Degradation-resistant neutrophil extracellular traps (NETs) play an important role in the pathogenesis of MPO-ANCA-associated vasculitis (MPO-AAV). Five candidate proteins were extracted to contribute to impaired degradation of NETs, and a monoclonal antibody inhibiting the activity was prepared for one of them. Furthermore, the inhibitory effect of the antibody on the formation of degradation-resistant NETs was confirmed in vitro and in vivo.

Free Research Field

病理学

Academic Significance and Societal Importance of the Research Achievements

MPO-ANCAを抗原刺激優位型とFc受容体刺激優位型に分類することにより、MPO-ANCA関連血管炎（MPO-AAV）患者のうち、腎予後不良群を抽出することが可能となる。このことは患者の層別化につながり、個々の患者により適した医療を提供する根拠となる。
MPO-AAVに対する標準治療は確立されつつあるが、治療選択肢は必ずしも多いとは言えない。本研究で見出した好中球細胞外トラップに分解抵抗性をもたらすタンパクの活性を阻害するモノクローナル抗体は、MPO-AAVの新規治療薬シーズとなる。