Development of mouse model of chronic lung allograft dysfunction to evaluate immune regulation

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K19558
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Kyoto University
• Principal Investigator: Tanaka Satona 京都大学, 医学研究科, 助教 (80847517)
• Co-Investigator(Kenkyū-buntansha): 伊達 洋至 京都大学, 医学研究科, 教授 (60252962) ; 山田 義人 京都大学, 医学研究科, 特定病院助教 (80375691)
• Project Period (FY): 2022-06-30 – 2024-03-31
• Keywords: 肺移植 / 慢性期移植肺機能不全 / 細胞性拒絶 / 線維化 / 二次リンパ組織

Outline of Final Research Achievements

We developed a murine model of chronic lung allograft dysfunction (CLAD) and transplanted left lungs from BALB/c donors into B6 recipients that were treated with intermittent cyclosporine and methylprednisolone postoperatively. In this model, the lung allograft developed acute cellular rejection on day 15 which, by day 30 after transplantation, progressed to severe pleural and peribronchovascular fibrosis with lymphocyte infiltration. This model reflects restrictive type of CLAD. Using secondary lymphoid organ - deficient mice as recipients, we found that secondary lymphoid organs were necessary for progression from acute cellular rejection to allograft fibrosis. sICAM-1 elevation in bronchoalveolar lavage fluid was characteristics in this model. We uncovered a critical role for recipient secondary lymphoid organs in the development of CLAD and identified a possible predictive marker for CLAD.

Free Research Field

呼吸器外科

Academic Significance and Societal Importance of the Research Achievements

肺移植臨床で経験する線維化主体の慢性期移植肺機能不全(RAS: restrictive allograft dysfunction)を反映するマウス肺移植モデルを開発し、細胞性拒絶から線維化への進行メカニズムの一端を明らかにした。さらに、慢性期移植肺機能不全発症を予測するマーカーの候補を同定した。本研究成果は、肺移植後の長期予後改善を妨げ、いまだ有効な治療がない慢性期移植肺機能不全に対する発症予測と新たな治療ターゲットの開発に貢献しうる。