Defining the intrahepatic immune response to hepatitis C virus

描述（由申请人提供）：丙型肝炎病毒（HCV）感染在大多数感染者中导致持续的肝脏疾病，HCV相关的终末期肝脏疾病现在是美国肝移植的主要指征。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HCV感染中，导致免疫功能衰竭的因素尚不清楚。我们最近发表的研究表明，慢性感染人类患者的肝内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细胞是肝脏浸润人群的特征。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反应不足的直接结果，更具体地说，肝内抗原呈递细胞（APCs）调节和损害抗病毒T细胞反应，从而促进病毒持续存在。肝星状细胞（HSC）是一种新型的肝内APC，在肝损伤或感染时发生显著的表型和功能变化。已知这一过程对肝纤维化很重要，但对HSC作为APC的重要性以及APC在HCV感染期间如何改变功能知之甚少。我们的初步工作表明，在激活HSC时，其功能从免疫刺激向免疫抑制转变。因此，本文提出的工作将集中于HSC及其在共刺激或共抑制分子背景下通过病毒抗原呈递调节T细胞免疫的能力，以及HCV对这一过程的影响。我们将剖析HSC和T细胞、HSC和HCV之间的成对关系，同时将这三个因素结合在一起，以确定这三方相互作用对HCV感染结果的影响。我们希望发现在HCV感染期间，HSC在肝内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.