A comparative analysis of HAM/TSP using novel animal model and patients samples for understanding pathogenesis and identifying potential targets for future therapy.

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07541
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: Saito Mineki 川崎医科大学, 医学部, 教授 (40398285)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: HTLV-1 / HAM/TSP / 動物モデル / T細胞受容体 / 自己抗原特異的T細胞

Outline of Final Research Achievements

In HTLV-1 associated myelopathy (HAM), various autoantibodies are frequently detected in peripheral blood, and there are many cases of complications with other inflammatory diseases including autoimmune diseases. In this study, we generated double transgenic (Tg) mice by crossing the myelin oligodendrocyte glycoprotein -specific T-cell receptor-Tg mouse with mice expressing one of the two HTLV-1 viral regulatory genes (i.e., tax or HBZ) under control of a murine CD4-specific promoter/enhancer/silencer (2D2-Tax-Tg or 2D2-HBZ-Tg mouse). These mice spontaneously develop HAM-like lower limb paraplegia (HAM mice). Using both HAM mice and HAM patient specimens, we searched for host cell factors that reflect the pathophysiology. As a result, multiple host cell factors containing tax or HBZ target genes were identified. These factors can be new biomarkers and therapeutic target candidates that reflect the pathophysiology of HAM.

Free Research Field

ウイルス学、脳神経内科学

Academic Significance and Societal Importance of the Research Achievements

HTLV-1はマウスに感染しないため、従来HAMの小動物モデルは存在しなかった。我々が先行研究で独自に開発したHAM病態モデルマウスの病理学的・免疫学的解析結果は、HAM患者の特徴とよく一致しており、本マウスと患者検体との統合的な比較解析を通して新規治療標的や治療薬候補を探索することは、病態解析、発症予防・治療法の開発において極めて重要であり、学術的・社会的意義が大きい。今回の研究で、両者の病態に共通して関与する宿主細胞因子を同定できたことから、今後さらなる解析を通じて、HAMにおける慢性炎症形成の分子機構解明と新規発症予防法・治療法の開発に資する成果が得られる可能性がある。