New mouse model of rare lung disease and novel therapy with macrophages

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K21750
• Research Category: Fund for the Promotion of Joint International Research (Home-Returning Researcher Development Research)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Jichi Medical University
• Principal Investigator: SUZUKI Takuji 自治医科大学, 医学部, 准教授 (80344670)
• Project Period (FY): 2017 – 2019
• Keywords: 呼吸器疾患 / 肺胞蛋白症 / ノックアウトマウス / マクロファージ

Outline of Final Research Achievements

Hereditary pulmonary alveolar proteinosis (hPAP) is rare genetic diseases caused by GM-CSF receptor alpha or beta gene (CSF2RA or CSF2RB, respectively) mutation. hPAP with CSF2RA gene mutation has been difficult to study due to the unavailability of a mouse model with Csf2ra gene mutation. We demonstrated the Csf2ra gene deficient mice are the faithful model of human hPAP with CSF2RA gene mutations. The characteristics of the Csf2ra gene deficient mice including lung histology, macrophage phenotype and function, bronchoalveolar lavage fluid appearance, gene expression profiles and PAP biomarkers showed similar abnormality as hPAP patients with CSF2RA gene mutations. We also demonstrated that pulmonary macrophage transplantation therapy is effective and safe in Csf2ra gene deficient mice. These results strongly support the potential utility of the new disease model mice and the feasibility of novel cell therapy for the patients with this specific genetic lung disease.

Academic Significance and Societal Importance of the Research Achievements

これまで存在しなかったヒトCSF2RA遺伝子変異による遺伝性肺胞蛋白症の有効な疾患モデルが確立されたことで、その病態解析および生物学的解析を行えるという学術的意義がある。また、新規治療法の開発といったトランスレーショナルな研究を行うことにより、患者さんへ治療法を還元していくという社会的意義がある。

Free Research Field

呼吸器内科