Search for new treatments for influenza associated encephalopathy targeting innate immune mediators

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08278
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Okayama University
• Principal Investigator: TSUGE MITSURU 岡山大学, 医歯薬学域, 講師 (80625004)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 脳血管内皮細胞 / インフルエンザ脳症 / 脳浮腫 / 自然免疫 / サイトカイン / タイトジャンクション / 腫瘍壊死因子-α

Outline of Final Research Achievements

We investigated whether high mobility group box-1 (HMGB-1) monoclonal antibody could suppress the increase in vascular permeability of human primary cerebral vascular endothelial cells by tumor necrosis factor (TNF-α). After TNF-α stimulation, vascular permeability was significantly enhanced, and cell spindle-like deformation, increased intercellular space, increased F-actin formation, and decreased amount of VE-cadherin protein, which is a tight junction molecule, were observed. In the presence of anti-HMGB-1 antibody, vascular hyperpermeability was significantly suppressed, and the increase in intercellular space and the decrease in VE-cadherin protein were significantly suppressed. The concentrations of IL-6 and IP-10, which are inflammatory cytokines in the supernatant, increased by TNF-α stimulation were significantly suppressed in the presence of anti-HMGB-1 antibody.

Free Research Field

小児感染症

Academic Significance and Societal Importance of the Research Achievements

インフルエンザ脳症における脳浮腫・脳血管透過性亢進のメカニズムと自然免疫分子であるHMGB-1分子の関与について検討した。HMGB-1分子を中和するモノクローナル抗体によって、サイトカインによる脳血管内皮細胞の血管透過性亢進や細胞形態の変化、細胞間にあるタイトジャンクション分子と呼ばれる蛋白の減少を抑制することを明らかにした。インフルエンザ脳症の新規治療として抗HMGB-1モノクローナル抗体の有効性を説明しうる研究成果を得た。