Role of immature DC in host defense against HCV

描述（由申请人提供）：丙型肝炎病毒（HCV）是美国最常见的慢性病毒性肝炎原因，是发病率和死亡率的重要原因。针对HCV衍生抗原的T细胞反应被认为在HCV介导疾病的发病机制中很重要，参与了有利的临床结果以及器官损伤。HCV反应性T细胞的效应功能障碍被认为是导致HCV感染持续存在的原因。事实上，HCV感染被认为会导致ARC功能障碍，APC-T细胞相互作用异常，以及存在功能障碍的病毒特异性T细胞。外周循环的未成熟树突状细胞（DC）亚群（MDC和PDC或髓细胞和浆细胞样DC）已成为形成T细胞免疫的关键APC。扩大的MDC功能障碍已在HCV感染中得到证实。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宿主防御机制的重要信息，并为HCV感染治疗药物的合理设计奠定基础。我们将研究HCV感染导致DC成熟能力改变的假设，表现为加工和呈递抗原的能力受损，免疫调节细胞因子的分泌不足，初始和效应记忆T细胞免疫的激活受损，从而阻止感染的控制。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感染和健康对照者的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功能直接抑制剂的作用。

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.