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: 7038202
• 负责人: Young S. Hahn
• 金额: $ 23.48万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038202
• 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（由申请方提供）：丙型肝炎病毒（HCV）感染人体后，通过逃避宿主免疫监视，可显著有效地建立持续性感染。HCV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。在我们之前的研究中，我们证明了HCV核心蛋白，病毒感染过程中产生的第一个蛋白，通过与Fas相互作用，增加Fas介导的凋亡途径，具有抑制抗病毒CTL活性的免疫调节功能。为了研究HCV核心蛋白免疫调节的分子机制和肝损伤的免疫发病机制，我们通过在T细胞中定向表达HCV核心蛋白来建立了一种CD 2/核心转基因小鼠模型，因为T细胞支持HCV感染和病毒复制。在这些CD 2/core转基因小鼠中，与人类慢性丙型肝炎相似，肝脏门脉道中大量淋巴细胞浸润明显沿着伴有严重的免疫失调。此外，在OVA特异性CD 4 + T细胞中核心蛋白的表达通过在OVA 323 -339肽注射后促进核心TCR小鼠中淋巴细胞向肝脏的募集而诱导严重的肝损伤。基于这些发现，我们推测肝脏浸润性T细胞的FasL可能是通过促进FasL介导的促凋亡和炎症反应作为旁观者杀伤机制诱导肝损伤的原因。为了验证这一假设，并进一步研究肝脏浸润性T细胞对肝细胞损伤的分子机制，我们将首先探讨肝脏浸润性T淋巴细胞对肝细胞损伤的机制。其次，我们将描述核心TCR小鼠中T细胞活化和肝脏浸润T细胞分化的状态。最后，我们将分析肝脏浸润性T细胞对肝细胞炎症激活的调节。本研究为阐明Fas/FasL诱导的炎症反应致肝损伤的发病机制提供了新的信息，并为合理设计新型肝损伤治疗药物提供了依据。