DEFINING THE INTRAHEPATIC IMMUNE RESPONSE TO HEPATITIS C VIRUS

定义对丙型肝炎病毒的肝内免疫反应

• 批准号: 8357563
• 负责人: Arash Grakoui
• 金额: $ 3.29万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357563
• 关键词: Antigen Presentation; Antigen-Presenting Cells; Antiviral Agents; Failure; Functional disorder; Funding; Grant; Hepatic Stellate Cell; Hepatitis C; Hepatitis C virus; Immune; Immune response; Immunity; Individual; Infection; Injury to Liver; Liver diseases; National Center for Research Resources; Outcome; Play; Population; Primates; Principal Investigator; Process; Research; Research Infrastructure; Resources; Role; Source; Staging; T cell response; T-Lymphocyte; United States; United States National Institutes of Health; Viral; Viral Antigens; Work; cost; intrahepatic; liver transplantation; novel; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Infection with hepatitis C virus (HCV) results in persistent liver disease in the majority of infected individuals and HCV-associated end-stage liver disease is now the leading indication for liver transplantation in the United States. Many studies have highlighted the importance of the T cell response for viral clearance and attributed persistent infection to an insufficient T cell response. However, in persistent HCV infection the factors leading to immune failure are not clear. We postulate that in the natural course of HCV infection, viral persistence is a direct result of the inadequacy of the intrahepatic immune response and more specifically, that intrahepatic antigen presenting cells (APCs) modulate and impair the antiviral T cell response thereby contributing to viral persistence. Hepatic stellate cells (HSC) are a novel population of intrahepatic APC that undergo dramatic phenotypic and functional changes in response to liver injury or infection. Our preliminary work indicates a transition from immunostimulatory to immunoinhibitory function upon activation of HSC. Work proposed here will focus on HSC and their ability to modulate T cell immunity through viral antigen presentation in the context of costimulatory or coinhibitory molecules and the influence that HCV has on this process. We will dissect the pair-wise relationships between HSC and T cells, HSC and HCV, while bringing together all three factors to determine the impact of this tripartite interaction on the outcome of HCV infection. We expect to find that HSC play a role in the intrahepatic T cell dysfunction during HCV infection, promoting persistent infection.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 丙型肝炎病毒（HCV）感染会导致大多数感染者出现持续性肝脏疾病，而丙型肝炎病毒相关的终末期肝脏疾病现在是美国肝移植的主要适应症。许多研究强调了T细胞应答对病毒清除的重要性，并将持续感染归因于T细胞应答不足。然而，在持续性HCV感染中，导致免疫失败的因素尚不清楚。 我们推测，在HCV感染的自然过程中，病毒持续存在是肝内免疫应答不足的直接结果，更具体地说，肝内抗原呈递细胞（APC）调节和损害抗病毒T细胞应答，从而导致病毒持续存在。肝星状细胞（HSC）是一种新型的肝内APC细胞群，其在肝损伤或感染时发生显著的表型和功能变化。 我们的初步工作表明，从免疫刺激到免疫抑制功能的HSC激活后的过渡。这里提出的工作将集中在HSC和他们的能力，通过病毒抗原的共刺激或共抑制分子的背景下，HCV对这一过程的影响，调节T细胞免疫。我们将剖析HSC和T细胞，HSC和HCV之间的成对关系，同时将所有三个因素结合在一起，以确定这种三方相互作用对HCV感染结果的影响。我们期望发现HSC在HCV感染时肝内T细胞功能障碍中发挥作用，促进持续感染。