Role of immature DC in host defense against HCV

描述（由申请人提供）：丙型肝炎病毒（HCV）是美国慢性病毒性肝炎的最常见原因，也是发病率和死亡率的重要原因。针对HCV衍生抗原的T细胞应答被认为在HCV介导的疾病的发病机制中是重要的，参与有利的临床结果以及器官损伤。已经提出HCV反应性T细胞的效应子功能障碍有助于HCV感染的常见持续性。事实上，已经提出HCV感染导致ARC功能障碍、异常APC-T细胞相互作用以及功能障碍的病毒特异性T细胞的存在。外周循环的未成熟树突状细胞（DC）亚群（MDC和PDC或髓样和浆细胞样DC）已成为塑造T细胞免疫的关键APC。已在HCV感染中显示了扩增的MDC的功能障碍。对HCV感染过程中MDC和PDC功能以及T细胞反应性的进一步了解可能揭示对宿主防御机制的重要见解，并为HCV感染的适当治疗设计奠定基础。我们将调查的假设，HCV感染的结果在改变DC的能力，经历成熟，表现在一个受损的处理和呈递抗原的能力，和免疫调节细胞因子的分泌缺陷，和幼稚和效应记忆T细胞免疫，反过来又阻止控制感染的激活受损。此外，HCV感染可能影响T细胞对正常功能DC的反应性。为了验证这一假设，我们将确定HCV感染对DC表型和功能的影响，通过表征HCV感染和健康对照受试者中的T细胞反应性来确定HCV对T细胞的影响，以及HCV核心蛋白作为DC功能的直接抑制剂的影响。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis in the United States, and is a significant cause of morbidity and mortality. The T cell response directed at HCV derived antigens is thought to be important in the pathogenesis of HCV mediated disease, participating in favorable clinical outcome as well as in organ damage. Effector dysfunction of HCV reactive T cells has been proposed to contribute to the common persistence of HCV infection. In fact, HCV infection has been proposed to result in ARC dysfunction, abnormal APC-T cell interactions, and for the presence of dysfunctional virus specific T cells. Peripherally circulating immature dendritic cell (DC) subpopulations (MDC and PDC or myeloid and plasmacytoid DC) have emerged as key APC in shaping T cell immunity. Dysfunction in expanded MDC has been shown in HCV infection. An improved understanding of MDC and PDC function, and T cell responsiveness, during HCV infection may reveal important insight into host defense mechanisms, and lay the foundation for appropriate design of therapeutics in HCV infection. We will investigate the hypothesis that HCV infection results in altered DC ability to undergo maturation, manifesting in an impaired ability to process and present antigen, and a deficit in secretion of immune regulatory cytokines, and impaired activation of naive and effector memory T cell immunity that in turn prevents control of the infection. In addition HCV infection may affect T-cell responsiveness to normal functioning DC. To test this hypothesis we will determine the impact of HCV infection on DC phenotype and function, the impact of HCV on T cells by characterizing T cell responsiveness in HCV infected and healthy control subjects, and the effects of HCV core protein as a direct inhibitor DC function.