Role of Fas/FasL interaction in liver damage

Fas/FasL 相互作用在肝损伤中的作用

• 批准号: 6884074
• 负责人: Young S. Hahn
• 金额: $ 24.05万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6884074
• 关键词: CD95 molecule; IP 10 protein; RNase protection assay; apoptosis; cell differentiation; cell line; cytotoxic T lymphocyte; cytotoxicity; enzyme linked immunosorbent assay; gene expression; genetically modified animals; helper T lymphocyte; hepatitis C virus; immunomodulators; immunotoxicity; in situ hybridization; inflammation; laboratory mouse; leukocyte activation /transformation; liver cells; messenger RNA; monocyte chemoattractant protein 1; nuclear factor kappa beta; nucleocapsid

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection in humans is remarkably efficient in the establishment of persistent infection by evading host immune surveillance. HCV persistent infection is a major risk factor for the development of hepatocellular carcinoma and autoimmune disease. In our prior studies, we demonstrated that HCV core protein, a first protein produced during viral infection contains the immunomodulatory function to suppress anti-viral CTL activity through its interaction with Fas to increase the Fas-mediated apoptotic pathway. To dissect the molecular mechanism of immune modulation by HCV core and immunopathogenesis of liver damage, we have developed a murine model of CD2/core transgenic mice by directing the expression of HCV core protein in T cells because T cells support HCV infection and replication of virus. In these CD2/core transgenic mice, similar to chronic hepatitis C in humans, massive lymphocytic infiltration was notable in the portal tract of liver along with profound immune dysregulation. In addition, the expression of core protein in OVA-specific CD4+ T cells induces severe liver damage by facilitating recruitment of lymphocytes to liver in core-TCR mice upon OVA323-339 peptide injection. Based on these findings, we hypothesize that FasL of liver-infiltrating T cells may be responsible for inducing liver damage as a bystander killing mechanism by promoting FasL-mediated pro-apoptotic and inflammatory responses. In order to test this hypothesis and further investigate the molecular mechanism of hepatocyte damage by liver-infiltrating T cells, we will first explore the mechanism of hepatocyte damage by liver-infiltrating T lymphocytes. Secondly, we will characterize the status of T cell activation and differentiation of liver-infiltrating T cells in core-TCR mice. Lastly, we will analyze the regulation of hepatocyte inflammatory activation by liver-infiltrating T cells. The studies proposed here will provide new and useful information on the pathogenesis of liver damage by Fas/FasL-induced inflammatory response and will help to provide a basis for the rational design of novel therapeutic agents to liver damage.

描述（由申请人提供）：通过逃避宿主的免疫监测，人类乙型肝炎病毒（HCV）感染在建立持续感染方面非常有效。 HCV持续感染是肝细胞癌和自身免疫性疾病发展的主要危险因素。在先前的研究中，我们证明了HCV核心蛋白是在病毒感染过程中产生的第一种蛋白质，包含免疫调节功能，通过与FAS相互作用来抑制抗病毒CTL活性，以增加FAS介导的凋亡途径。为了通过HCV核心剖析免疫调节的分子机制，并通过指导T细胞中HCV核心蛋白的表达来开发CD2/核心转基因小鼠的鼠模型，因为T细胞支持HCV感染和病毒的复制。在这些CD2/核心转基因小鼠中，类似于人类的慢性丙型肝炎，在肝脏的门户区域中很明显淋巴细胞浸润以及严重的免疫失调。此外，通过促进OVA323-339肽注射，核心蛋白在OVA特异性CD4+ T细胞中的表达可诱导严重的肝脏损伤。基于这些发现，我们假设肝脏浸润的T细胞的FASL可能是通过促进FASL介导的促凋亡和炎症反应来诱导肝脏损害作为旁观者杀死机制的。为了检验这一假设并进一步研究肝脏浸润T细胞肝细胞损伤的分子机制，我们将首先探索肝脏浸润T淋巴细胞的肝细胞损伤机制。其次，我们将表征Core-TCR小鼠中T细胞激活和肝脏浸润T细胞的分化的状态。最后，我们将通过肝脏浸润T细胞分析肝细胞炎症激活的调节。此处提出的研究将提供有关FAS/FASL诱导的炎症反应对肝损害发病机理的新的有用信息，并将有助于为新型治疗剂的合理设计提供基础，从而为肝脏损伤提供理性设计。