Defining the intrahepatic immune response to hepatitis C virus

描述(申请人提供)：感染丙型肝炎病毒(丙型肝炎病毒)会导致大多数感染者的持续性肝病，丙型肝炎病毒相关的终末期肝病现在是美国肝脏移植的主要适应症。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。我们最近发表的工作表明，在慢性感染的人类患者中，肝内丙型肝炎病毒特异性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细胞是肝脏浸润性人群的特征。因此，我们推测，在丙型肝炎病毒感染的自然过程中，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，是肝内抗原提呈细胞(APC)调节和损害抗病毒T细胞反应，从而促进病毒持续存在。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。已知这一过程对肝纤维化的形成很重要，但对HSC作为APC的重要性以及APC功能在丙型肝炎病毒感染过程中如何改变知之甚少。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。因此，本文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。

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.