DEFINING THE INTRAHEPATIC IMMUNE RESPONSE TO HEPATITIS C VIRUS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在大多数感染丙型肝炎病毒的人中，感染丙型肝炎病毒会导致持续性肝病，而丙型肝炎病毒相关的终末期肝病现在是美国肝移植的主要适应症。许多研究强调了T细胞反应对病毒清除的重要性，并将持续感染归因于T细胞反应不足。然而，在持续性的丙型肝炎病毒感染中，导致免疫失败的因素尚不清楚。我们推测，在丙型肝炎病毒感染的自然过程中，病毒持久性是肝内免疫反应不足的直接结果，更具体地说，是肝内抗原提呈细胞(APC)调节和损害抗病毒T细胞反应，从而促进病毒持久性。肝星状细胞(HSC)是一种新型的肝内APC，在肝脏损伤或感染时会发生显著的表型和功能变化。我们的初步工作表明，当HSC被激活时，免疫刺激功能向免疫抑制功能转变。建议的工作将集中在HSC及其在共刺激或共抑制分子背景下通过病毒抗原提呈来调节T细胞免疫的能力，以及丙型肝炎病毒对这一过程的影响。我们将剖析HSC和T细胞、HSC和丙型肝炎病毒之间的配对关系，同时结合所有这三个因素来确定这种三方交互作用对丙型肝炎病毒感染结局的影响。我们期望发现HSC在丙型肝炎病毒感染时肝内T细胞功能障碍中发挥作用，从而促进持续感染。

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.