Mechanisms of T cell dysfunction in Hepatitis C virus persistence

丙型肝炎病毒持续存在中 T 细胞功能障碍的机制

• 批准号: 7442182
• 负责人: HENRY Thomas RADZIEWICZ
• 金额: $ 12.83万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7442182
• 关键词: 5-(6)-carboxyfluorescein diacetate succinimidyl ester; Accounting; Activities of Daily Living; Acute Hepatitis C; Adverse effects; Antigen Presentation; Antigen-Presenting Cells; Antigens; Antiviral Response; Apoptosis; Attenuated; Award; B-Lymphocytes; Binding; Biological Assay; Blocking Antibodies; CD28 gene; CD4 Positive T Lymphocytes; CD80 gene; CD8B1 gene; Cells; Cellular Immunity; Chimeric Proteins; Chronic; Chronic Hepatitis; Cirrhosis; Class; Commit; Communicable Diseases; Communication; Cultured Cells; Data; Dendritic Cells; Development; Differentiation Antigens; Disease Progression; Down-Regulation; Environment; Evaluation; Extracellular Domain; Failure; Family; Fibrosis; Frequencies; Functional disorder; Funding; Genome; Genotype; Goals; HIV; HIV Infections; HLA-A2 Antigen; HLA-DR Antigens; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; IL7R gene; Immune; Immune response; Immunohistochemistry; Immunology; In Vitro; Individual; Infection; Inflammatory; Interferons; Ligands; Link; Liver; Liver Function Tests; Liver diseases; Lung; Lymphocytic choriomeningitis virus; Measures; Mediating; Medicine; Modeling; Monoclonal Antibody HuM291; Muromonab-CD3; Mus; Mutation; Pathogenesis; Pathway interactions; Patients; Persons; Phenotype; Play; Polymerase Chain Reaction; Predisposition; Primary carcinoma of the liver cells; Production; Protein Overexpression; Psoriasis vulgaris; Regulation; Research; Rheumatoid Arthritis; Ribavirin; Role; SELL gene; Scientist; Score; Serum; Signal Transduction; Signaling Molecule; Site; Spleen; Staining method; Stains; System; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Tendon Transfer; Testing; Time; Tissues; United States; Universities; Vaccine Research; Viral; Viral Load result; Viral Proteins; Viral hepatitis; Viremia; Virus; Virus Diseases; Work; annexin A5; antiretroviral therapy; base; career; cytokine; enzyme linked immunospot assay; exhaust; exhaustion; functional restoration; hepatoma cell; improved; improved functioning; intrahepatic; liver biopsy; liver function; liver infection; liver transplantation; medical specialties; member; monocyte; mouse model; peripheral blood; programs; receptor; response; virus core

DESCRIPTION (provided by applicant): Henry Radziewicz is a highly motivated scientist at Emory University with a specialty in Infectious Diseases Medicine, whose overall goal is to develop an independent scientific career with a research program focused on understanding the pathogenesis of chronic viral infections such as hepatitis C virus (HCV). Why does the adaptive immune response to HCV fail in the majority of infected persons? His immediate goal is to receive funding through a research career award (K08) that will enable sufficient protected time for didactics and research to enable this development. His long-term goal is to discover and test better treatments of chronic viral illness with the improved understanding of their pathogenesis. HCV infects 150-200 million persons and causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. It has become the major cause of liver transplantation in the United States. Current therapies for HCV are very difficulty to tolerate due to disabling side-effects, require prolonged treatment, and are only successful in approximately half of treated patients for the major genotype in the US. Better therapies are needed. Recently, several new members of the B7/CD28 family of co-inhibitory molecules have been discovered, and may play important roles in modulating the immune responses to chronic viral infections. One pair of molecules, PD-1 and its ligand PD-L1 has demonstrated a critical role in the immune response to chronic murine LCMV infection. Blockade of PD-1/PD-L1 enhanced the response of exhausted T cells in this model, and treated mice were able to clear infection from serum, liver, and lung. We hypothesize that an inability to clear HCV viremia in the majority of infected patients is due to overexpression of the PD-1/PD-L1 co-inhibitory system. In conjunction with a research career award, Henry would like to evaluate this system in humans with chronic HCV, and to test if inhibiting this system improves the function of HCV specific CD8+ T cells. Guided by top scientists, Arash Grakoui and Rafi Ahmed, Henry's proposed 4-year program will include one year of didactics in basic immunology and signal transduction, followed by three lab-based, research concentrated years. Emory University is committed to help Henry reach his goal of becoming a top scientist, and the environment at Emory and the Vaccine Research Center is a wonderful environment for a young scientist to flourish.

描述(申请人提供)：Henry Radziewicz是埃默里大学传染病医学专业的一名上进心很强的科学家，他的总体目标是发展一项独立的科学生涯，开展一项专注于了解丙型肝炎病毒(HCV)等慢性病毒感染的发病机制的研究计划。为什么大多数感染者对丙型肝炎病毒的适应性免疫反应失败？他的直接目标是通过研究事业奖(K08)获得资金，这将使教学和研究有足够的受保护时间，以实现这一发展。他的长期目标是发现和测试更好的治疗慢性病毒疾病的方法，并提高对其发病机制的了解。丙型肝炎病毒感染1.5亿-2亿人，并导致慢性肝炎、肝硬变和肝细胞癌。它已经成为美国肝移植的主要原因。目前的丙型肝炎病毒治疗方法由于副作用大，难以耐受，需要长期治疗，而且在美国主要基因型别的治疗患者中，仅有大约一半有效。需要更好的治疗方法。最近，B7/CD28共抑制分子家族的几个新成员被发现，它们可能在调节慢性病毒感染的免疫反应中发挥重要作用。一对分子PD-1及其配体PD-L1在小鼠慢性LCMV感染的免疫应答中发挥了关键作用。在该模型中，阻断PD-1/PD-L1可增强耗尽T细胞的反应，并能清除血清、肝脏和肺中的感染。我们假设，在大多数感染患者中，无法清除丙型肝炎病毒血症是由于PD-1/PD-L1共抑制系统的过度表达。亨利希望结合一项研究事业奖，评估慢性丙型肝炎患者的这一系统，并测试抑制这一系统是否能改善丙型肝炎病毒特异性CD8+T细胞的功能。在顶尖科学家阿拉什·格拉库伊和拉菲·艾哈迈德的指导下，亨利提出的为期4年的计划将包括一年的基础免疫学和信号转导教学，然后是三年以实验室为基础的研究重点年。埃默里大学致力于帮助亨利实现成为顶尖科学家的目标，埃默里和疫苗研究中心的环境是年轻科学家茁壮成长的绝佳环境。