Long-term immune evaluation and novel therapeutic strategy using lymphocyte activating factor in elderly with sepsis

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K18323
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55060:Emergency medicine-related
• Research Institution: Kobe University
• Principal Investigator: Masafumi Saito 神戸大学, 医学研究科, 特命助教 (80826321)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 敗血症 / 高齢者 / IL-15 / 免疫抑制

Outline of Final Research Achievements

Although Interleukin-15 (IL-15) significantly improved the survival rate in a septic mouse model, its effect on the immune mechanism of aged septic mice was still unknown. Therefore, we established repeated infection models by using cecal slurry injection to induce sepsis in young and old mice and investigated the effects of IL-15 for long-term immune exhaustion. In the repeated infection model, the 50-day survival rate was 91% in the young group, 69% in the old group, and 100% in the young and old groups treated with IL-15. Although the percentage of program death-1 (PD-1)-expressed CD4+/CD8+ T cells and regulatory T cells (Treg) in peripheral blood was significantly increased in the aged group compared with the young group. When administered IL-15 with aged septic mice, this phenotype of T cells were significantly decreased in the peripheral blood during 50 days.

Free Research Field

救急医学

Academic Significance and Societal Importance of the Research Achievements

現在、敗血症患者の多くは高齢者であり、生命予後は極めて悪い。既知の研究から、生命予後の悪化は敗血症に伴う強烈な免疫抑制と長期化が原因と考えられてきたが、免疫抑制の期間やそのメカニズムは不明であった。本研究において、高齢マウスでは若齢マウスと比較して、免疫応答を抑制するPD-1陽性T細胞やTregの血中での割合が持続的に高値を示すことが明らかとなった。それに対して、IL-15を投与することで、高齢マウスの生命予後を改善し、免疫を賦活化することが示された。この結果から、IL-15が高齢者敗血症の新規の治療ターゲットとなり、二次感染のリスク低減にも寄与する可能性が示された。