Antigen-independent CD8 T cell-induced Hepatitis

抗原非依赖性 CD8 T 细胞诱导的肝炎

• 批准号: 6674948
• 负责人: ROBERT H PIERCE
• 金额: $ 10.92万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6674948
• 关键词: CD95 molecule; Kupffer's cell; T cell receptor; apoptosis; cytokine; cytotoxic T lymphocyte; cytotoxicity; hepatitis; immune tolerance /unresponsiveness; immunopathology; laboratory mouse; leukocyte activation /transformation

DESCRIPTION (provided by applicant): This proposal outlines a career development program with the goal of developing a successful academic career in Pathology. The principal investigator (PI) is an Assistant Professor with a tenuretrack appointment in Pathology at the University of Rochester School of Medicine (UR). He is a diplomat of the American Board of Pathology and possesses significant clinical and teaching experience. This Mentored Clinical Scientist Award (KO8) proposal will facilitate the acquisition of basic research expertise in the area of liver immuno- pathology through a 5 year educational and research program focusing on the mechanism of antigen-independent CD8 T cell -induced liver damage. The liver appears to play a unique role in the elimination of CD8 T lymphocytes undergoing activation-induced apoptosis. Our current understanding of this mechanism of T cell clearance is based largely on the work of Dr. Crispe, the PI's Mentor, using mouse models expressing transgenic T cell receptors (TCR). Binding of target peptide to these transgenic T cells causes a clonal expansion, resulting in their selective uptake by the liver and subsequent death. As a consequence of this ongoing lymphocyte apoptosis in the liver, serum transaminase levels increase, indicating hepatocyte injury in the absence of hepatocyte expression of target antigen. Recent work in the PI's laboratory has demonstrated hepatitis, consisting of cellular infiltrates containing both CD8 T celland Kupffer cells both in the transgenic TCR model as well as in influenza infection. These data suggest that this phenomenon may represent a general response to expanded CD8 T cell populations and a common pathway of liver injury, which may have significant clinical implications. This study will investigate the mechanism of this novel antigen-independent CD8 T cell-induced hepatitis. Dr. Crispe is one of the leaders in the emerging area of liver-specific immunobiology and has an excellent track record as a mentor. In addition, a career development advisory committee consisting of 3 additional senior scientists will provide advice and guidance to the PI. Overall, the UR provides an outstanding setting by providing both excellent facilities and by fostering an atmosphere of support and collaboration. This structured and mentored program will facilitate the PI's evolution to independence as an investigator, culminating in a future RO1 application in the area of liver immunopathology.

描述（由申请人提供）：该提案概述了职业发展计划，目标是在病理学领域发展成功的学术生涯。主要研究者（PI）是罗切斯特大学医学院（UR）病理学终身教职助理教授。他是美国病理学委员会的外交官，拥有丰富的临床和教学经验。该指导临床科学家奖（KO8）提案将通过一项为期5年的教育和研究计划，重点关注抗原非依赖性CD8 T细胞诱导的肝损伤机制，促进获得肝脏免疫病理学领域的基础研究专业知识。 肝脏似乎在消除经历活化诱导的细胞凋亡的CD8 T淋巴细胞中发挥独特的作用。我们目前对这种T细胞清除机制的理解主要基于PI导师Crispe博士的工作，使用表达转基因T细胞受体（TCR）的小鼠模型。靶肽与这些转基因T细胞的结合引起克隆扩增，导致它们被肝脏选择性摄取并随后死亡。由于肝脏中这种持续的淋巴细胞凋亡，血清转氨酶水平升高，表明在靶抗原的肝细胞表达不存在的情况下肝细胞损伤。PI实验室的最新研究表明，在转基因TCR模型和流感感染中，肝炎均由含有CD8 T细胞和枯否细胞的细胞浸润组成。这些数据表明，这种现象可能代表了对扩增的CD8 T细胞群的一般反应和肝损伤的共同途径，这可能具有重要的临床意义。本研究将探讨这种新的抗原非依赖性CD8 T细胞诱导肝炎的机制。Crispe博士是肝脏特异性免疫生物学新兴领域的领导者之一，作为导师有着出色的记录。此外，由另外3名高级科学家组成的职业发展咨询委员会将为PI提供建议和指导。总的来说，乌拉圭回合提供了一个出色的设置，既提供优良的设施，并通过培养支持和合作的气氛。这种结构化和指导性的计划将促进PI作为研究者独立发展，最终在肝脏免疫病理学领域的未来RO1应用中达到高潮。