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: 6746042
• 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/6746042
• 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)：丙型肝炎病毒(丙型肝炎病毒)在人类中的感染通过逃避宿主免疫监视而显著有效地建立持续感染。丙型肝炎病毒持续感染是肝细胞癌和自身免疫性疾病发生的主要危险因素。在我们前期的研究中，我们证明了病毒感染过程中产生的第一种蛋白--丙型肝炎病毒核心蛋白具有免疫调节功能，通过与Fas相互作用增加Fas介导的细胞凋亡途径来抑制抗病毒的CTL活性。为了探讨丙型肝炎病毒核心蛋白免疫调节的分子机制和肝损伤的免疫发病机制，我们利用T细胞支持丙型肝炎病毒感染和病毒复制的特点，通过引导T细胞表达丙型肝炎病毒核心蛋白建立了CD2/核心转基因小鼠模型。在这些CD2/core转基因小鼠中，与人类慢性丙型肝炎相似，肝门管内有大量淋巴细胞浸润，并伴有严重的免疫失调。此外，OVA特异的CD4+T细胞中核心蛋白的表达通过促进OVA323-339肽注射后CORE-TCR小鼠的淋巴细胞向肝脏的募集而导致严重的肝损伤。基于这些发现，我们推测肝脏浸润性T细胞的FasL可能通过促进FasL介导的促凋亡和炎症反应而作为旁观者杀伤机制而导致肝损伤。为了验证这一假说，进一步研究肝脏浸润性T细胞损伤肝细胞的分子机制，我们将首先探讨肝脏浸润性T细胞损伤肝细胞的机制。其次，我们将表征CORE-TCR小鼠肝脏浸润性T细胞的T细胞活化和分化状态。最后，我们将分析肝脏浸润性T细胞对肝细胞炎性激活的调节。本研究将为Fas/FasL诱导的炎症反应所致肝损伤的发病机制提供新的有用的信息，并为合理设计新型肝损伤治疗药物提供依据。