Defining the intrahepatic immune response to hepatitis C virus

描述（由申请人提供）：丙型肝炎病毒（HCV）感染导致大多数感染个体的持续性肝病，HCV相关终末期肝病现在是美国肝移植的主要指征。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。我们最近发表的工作表明，慢性感染的人类患者的肝内HCV特异性T细胞反应并不反映外周血中的反应，事实上，表型耗尽的T细胞表征了肝脏浸润人群。因此，我们假设在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。这一过程是已知的肝纤维化的重要性，但很少有人知道的重要性，HSC的APC和APC功能是如何改变在HCV感染。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。因此，这里提出的工作将集中在HSC和他们的能力，通过病毒抗原呈递的背景下，共刺激或共抑制分子和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，从而促进持续感染。

DESCRIPTION (provided by applicant): 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 recently published work showing that the intrahepatic HCV-specific T cell response in chronically infected human patients does not mirror the response in the peripheral blood and that, in fact, phenotypically exhausted T cells characterize the liver infiltrating population. Accordingly, 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. This process is known to be important for liver fibrogenesis, but little is known of the importance of HSC as APCs and how APC function is changed during HCV infection. Our preliminary work indicates a transition from immunostimulatory to immunoinhibitory function upon activation of HSC. Thus, the 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 and therefore promote persistent infection.