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: 8050079
• 负责人: Arash Grakoui
• 金额: $ 35.92万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050079
• 关键词: Animal Model; Antigen Presentation; Antigen-Presenting Cells; Antiviral Agents; Apoptosis; Area; Biological Assay; Biological Models; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Communication; Cell physiology; Cells; Cessation of life; Chronic; Cirrhosis; Data; Dependence; Development; Disease Progression; Eragrostis; Event; Experimental Models; Failure; Family; Flow Cytometry; Functional disorder; Future; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune; Immune response; Immunity; Individual; Infection; Infectious hepatitides; Injury to Liver; Investigation; Kinetics; Knockout Mice; Liver; Liver Fibrosis; Liver diseases; Mediating; Modeling; Molecular; Mus; Outcome; Patients; Perisinusoidal Space; Phenotype; Play; Population; Positioning Attribute; Primary carcinoma of the liver cells; Process; Production; Proteins; Publishing; Refractory; Regulatory T-Lymphocyte; Role; Sampling; Signal Transduction; Specimen; Staging; Stimulus; T cell differentiation; T cell response; T-Lymphocyte; Therapeutic; Tretinoin; United States; Viral; Viral Antigens; Viral Proteins; Virus; Virus Diseases; Work; cytokine; exhaust; in vitro Model; in vivo; inhibitor/antagonist; interest; intrahepatic; liver transplantation; novel; peripheral blood; programs; prophylactic; public health relevance; response; small molecule

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. PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV)-induced chronic liver disease with associated cirrhosis and hepatocellular carcinoma is now the leading indication for liver transplantation in the United States. There are currently an estimated 170 million HCV carriers worldwide and nearly 3 million in the U.S. (~2% of the population). We are seeking to elucidate and understand the mechanisms by which the host immune response fails in the majority of those infected and to future efforts to develop prophylactic and/or therapeutic HCV eradication strategies.

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和与HCV相关的终末期肝病，现在是美国肝移植的主要指标。许多研究强调了T细胞反应对病毒清除率的重要性，并将持续感染归因于T细胞反应不足。但是，在持续的HCV感染中，导致免疫失效的因素尚不清楚。我们最近发表了研究表明，肝内HCV特异性T细胞反应在慢性感染的人类患者中不能反映出外周血中的反应，实际上，表型耗尽的T细胞表征了肝脏浸润的人群。因此，我们假设在HCV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，肝内抗原呈递细胞（APCS）调节并损害了抗病毒T细胞反应，从而导致病毒持久性。肝星状细胞（HSC）是肝内APC的新型人群，在肝损伤或感染的响应中经历了急剧的表型和功能变化。该过程对肝纤维发生很重要，但知之甚少，HSC作为APC的重要性以及在HCV感染期间如何改变APC功能。我们的初步工作表明在激活HSC后，从免疫刺激到免疫抑制功能的过渡。因此，此处提出的工作将集中在HSC及其在cot刺或共抑制分子的背景下通过病毒抗原表现来调节T细胞免疫的能力，以及HCV对此过程的影响。我们将剖析HSC和T细胞，HSC和HCV之间的成对关系，同时将所有三个因素汇总在一起，以确定该三方相互作用对HCV感染结果的影响。我们希望发现HSC在HCV感染过程中在肝内T细胞功能障碍中起作用，因此促进持续感染。 公共卫生相关性：乙型肝炎病毒（HCV）诱导的慢性肝病与肝硬化和肝细胞癌相关的癌症现在是美国肝移植的主要指标。目前，全球估计有1.7亿辆HCV航空公司，在美国有近300万辆（占人口的约2％）。我们正在寻求阐明和了解大多数感染者中宿主免疫反应失败的机制，以及未来开发预防性和/或治疗性HCV消除策略的努力。