The role of macrophages in chronic rejection after lung transplantation and regulatioon of macrophage activities by FROUNT inhibition

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08898
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: The University of Tokyo
• Principal Investigator: Sato Masaaki 東京大学, 医学部附属病院, 教授 (00623109)
• Co-Investigator(Kenkyū-buntansha): 漆山 博和 東京大学, 医学部附属病院, 助教 (20725303) ; 寺崎 泰弘 日本医科大学, 医学部, 准教授 (50332870) ; 寺島 裕也 東京大学, 医学部附属病院, 客員研究員 (90538729)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 肺移植 / 急性拒絶 / マクロファージ

Outline of Final Research Achievements

Macrophages contribute to post-transplant lung rejection. Disulfiram (DSF), an anti-alcoholic drug, has an anti-inflammatory effect and regulates macrophage chemotactic activity. We investigated DSF efficacy in suppressing acute rejection post-lung transplantation. A rat lung transplant model with minor histocompatibility antigen-mismatch was used. DSF (0.75 mg/h) monotherapy or co-solvent only as control was subcutaneously administered for 7 days (n = 10/group) without other immunosuppression. Grades of bronchial acute rejection, infiltration of immune cells positive for CD68 and CD3 were redused in the DSF geoup. The gene expression of chemokine ligand 2 and interleukin-6 were significantly lower in the DSF group. DSF can alleviate acute rejection post-lung transplantation by reducing macrophage accumulation around peripheral bronchi and suppressing pro-inflammatory cytokine expression.

Free Research Field

呼吸器外科学

Academic Significance and Societal Importance of the Research Achievements

抗アルコール薬として使われているDisulfiram (DSF)はその安全性が確立している。その抗炎症作用が肺移植においても、マクロファージの組織浸潤を制御することで急性拒絶を抑制する可能性が示唆された。肺移植後の予後を左右する拒絶反応の制御において、従来の免疫抑制療法に追加する形で効果が期待できる安全かつ安価な新規介入方法として期待される。