Cyclophilin D is a novel therapeutic target in ANCA vasculitis

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08581
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Hokkaido University
• Principal Investigator: Nakazawa Daigo 北海道大学, 大学病院, 助教 (60724135)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 腎炎 / ANCA関連血管炎 / 好中球

Outline of Final Research Achievements

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease characterized by necrotizing vasculitis. Dysregulated neutrophil extracellular traps (NETs) contribute to the development of necrosis in AAV, however, the specific therapy based on NETs physiology remains to be established. The authors discovered the therapeutic target molecule, Cyclophilin D (CypD), by analyzing the transcriptome profiling of ANCA-induced NETs using RNA sequencing. Animal studies revealed that genetic deficiency of CypD in murine AAV models ameliorated vascular necrosis via the regulation of NETs and endothelial injury. These findings suggest that the CypD might become a novel and specific therapeutic target of vascular necrosis in autoimmune vasculitis.

Free Research Field

腎臓病

Academic Significance and Societal Importance of the Research Achievements

抗好中球細胞質抗体 (ANCA) 関連血管炎は、外来微生物の侵入を阻止する好中球を異常に活性化する自己抗体であるANCAが何らかの機序で作られます。そのANCAにより活性化された好中球が体中の毛細血管で暴走し、腎臓や肺の毛細血管に壊死を引き起こして急激な腎不全や肺出血をきたす難病の一つです。治療は強力な免疫抑制薬が必要ですが、免疫力を低下させることで感染症による副作用が多いことが課題であり、本研究では免疫を抑制せずに好中球の暴走を阻止する治療の開発を目的としてCyclophilinDという標的を見つけ、治療効果を動物モデルで検証しました。今後は患者さんへの応用が期待されます。