Pathological and therapeutic roles of semaphorin in refractory vasculitis

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16146
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Osaka University
• Principal Investigator: Nishide Masayuki 大阪大学, 医学系研究科, 招へい教員 (80812255)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ANCA関連血管炎 / セマフォリン / 好中球 / 好酸球

Outline of Final Research Achievements

We focused on two diseases, ANCA-associated vasculitis (AAV) and Eosinophilic chronic rhinosinusitis (ECRS). We developed a passive transfer model of acute AAV, using purified monoclonal anti-MPO antibody taken from MPO-deficient mice immunized with recombinant mouse MPO. Mice exhibited glomeruli vasculitis and elevated proteinuria.Serum soluble SEMA4D levels were elevated in patients with ECRS and positively correlated with disease severity. Cell surface expression of SEMA4D on eosinophils from patients was reduced, which was due to MMP-mediated cleavage of membrane SEMA4D. Soluble SEMA4D enabled eosinophil trans-endothelial migration, and treatment with anti-SEMA4D antibody ameliorated eosinophilic infiltration in sinus tissues in the ECRS animal model. Semaphorins are thus potentially usuful as clinical markers and therapeutic targets for autoimmune vascular diseases.

Free Research Field

臨床免疫学

Academic Significance and Societal Importance of the Research Achievements

本研究を通して、難病である血管炎モデルマウスの作成に着手し、好中球・好酸球を活性化させる免疫たんぱく質「セマフォリン」について研究を行いました。その結果、難病の血管炎、鼻ポリープを形成するアレルギー性疾患に対して、セマフォリンを標的とする治療が有効であることを突き止めました。