HEPATITIS C TRANSGENIC MICE AS MODEL OF LIVER INJURY

丙型肝炎转基因小鼠作为肝损伤模型

• 批准号: 2679055
• 负责人: EMMETT Vance SCHMIDT
• 金额: $ 31.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-15 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2679055
• 关键词: apoptosis; cell migration; cellular immunity; cytokine; cytotoxic T lymphocyte; disease /disorder model; genetically modified animals; hepatitis C; hepatitis C virus; immunopathology; inflammation; laboratory mouse; liver disorder; passive immunization; pathologic process; tissue /cell culture; virus protein

DESCRIPTION: Hepatitis C virus is a leading cause of liver failure in the United States. A striking feature of this infection is the propensity to develop chronic infection and disease, with at least 50-60 percent of chronically infected individuals sustaining liver damage. However, the pathogenesis of hepatocellular damage in HCV is poorly understood. Infiltrates in chronic HCV infection are composed of numerous CD4+ and CD8+ cells, but their role in control of viremia or induction of tissue damage is not understood. In general, HCV exhibits few direct cytopathic effects and current models strongly suggest that liver disease in this infection is secondary to the host immune response. Moreover, transgenic mice developed in the PI's laboratories that express HCV structural proteins do not develop hepatitis. However, it does appear that some component of the cellular immune response helps limit HCV replication, since persons with depressed immunity often have higher viral titers and more rapid progression of HCV-related liver disease. The applicant's laboratories have previously characterized human HCV-specific cytolytic T lymphocytes (CTL). The investigators have shown that the immune response against HCV is polyclonal and multispecific in chronically infected individuals. Moreover, these cells produce cytokines that may be involved in both control of viral replication and recruitment of inflammatory cells. They propose that the CTL response against HCV is marked not only by apopotosis of infected hepatocytes, but also by production of cytokines that recruit other inflammatory cells and eventually lead to liver fibrosis. This hypothesis suggests that blockade of either the apoptosis or the cytokines produced might ameliorate HCV-induced liver damage. They propose to use the transgenic mouse that expresses the structural proteins of HCV model to study the mechanisms of liver damage in hepatitis C virus infection and test this hypothesis. The specific aims of this proposal include the following: 1) Develop a model for HCV hepatitis using adoptive transfer of cloned murine HCV-specific CTL into transgenic mice; 2) Define the mechanism of killing used by these HCV-specific CTL; 3) Determine whether expression of HCV structural proteins leads to modulation of immune responses in vivo; and 4) Characterize the cytokines produced by these CTL and their role in the recruitment of non-specific inflammatory cells to the liver. It is hoped that by defining the role of cellular immunity in the pathogenesis of chronic HCV hepatitis and liver damage, novel therapeutic strategies might be suggested for this infection.

描述：丙型肝炎病毒是肝衰竭的主要原因， 美国的 这种感染的一个显著特征是倾向于 患有慢性感染和疾病，至少有50- 60%的 慢性感染者肝脏受损。 但 对HCV肝细胞损伤的发病机制知之甚少。 慢性HCV感染者的补体由大量的CD 4+和CD 8+细胞组成， 细胞，但它们在控制病毒血症或诱导组织损伤中的作用是 不理解。 一般而言，HCV很少表现出直接的细胞病变作用， 目前的模型强烈表明，这种感染中的肝脏疾病是 继发于宿主免疫反应。 此外，转基因小鼠 在PI的实验室中，表达HCV结构蛋白的细胞不会产生 肝炎 然而，似乎细胞的某些成分 免疫反应有助于限制HCV复制，因为抑郁症患者 免疫力通常具有更高的病毒滴度和更快的进展， HCV相关性肝病 申请人的实验室以前 特征在于人HCV特异性溶细胞T淋巴细胞（CTL）。 的 研究人员已经表明，针对HCV的免疫应答是多克隆的， 并且在慢性感染个体中是多特异性的。 而且这些 细胞产生细胞因子，这些细胞因子可能参与病毒的控制， 炎性细胞的复制和募集。 他们建议， 抗HCV的CTL应答不仅表现为感染细胞的凋亡， 肝细胞，但也通过产生细胞因子，招募其他 炎症细胞，并最终导致肝纤维化。 这一假设 表明阻断细胞凋亡或细胞因子的产生 可能改善HCV引起的肝损伤。 他们建议使用 表达HCV模型结构蛋白的转基因小鼠， 丙型肝炎病毒感染与肝损害机制的研究 这个假设。 这项建议的具体目标包括： 1)利用克隆过继转移建立丙型肝炎模型 小鼠HCV特异性CTL转化为转基因小鼠; 2）确定 这些HCV特异性CTL所使用的杀伤; 3）确定 HCV结构蛋白导致体内免疫应答的调节;和 4)描述这些CTL产生的细胞因子及其在肿瘤发生中的作用。 非特异性炎症细胞向肝脏的募集。 希望 通过确定细胞免疫在疾病发病机制中的作用， 慢性HCV肝炎和肝损伤，新的治疗策略可能 建议用于这种感染。