Cellular Immune Response to Acute HCV Infection

对急性 HCV 感染的细胞免疫反应

• 批准号: 7919765
• 负责人: ANDREA L COX
• 金额: $ 18.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919765
• 关键词: Acute; Adoptive Transfer; Agonist; Antibodies; Biological Assay; Blocking Antibodies; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell membrane; Cells; Cellular biology; Characteristics; Chronic; Classification; Clinical; Data; Epitopes; Failure; Goals; Human; Immune; Immune response; Immune system; Immunodeficient Mouse; Immunotherapy; Impairment; In Vitro; Infection; Infection Control; Investigation; Knowledge; Longitudinal Studies; Lymphocyte; Molecular; Mus; Mutation; Outcome; Patients; Persons; Phenotype; Play; Production; Role; Sampling; Specimen; System; T-Lymphocyte; T-Lymphocyte Epitopes; Viral; Virus; Virus Diseases; arm; base; cohort; comparative; cytokine; cytotoxic; functional disability; in vivo; longitudinal analysis; novel; receptor

The primary objective of Project 1 is to define the mechanisms of functional impairment of HCV-specific CDS T cells associated with viral persistence. While viral escape mutations within T cell epitopes occur in HCV immune evasion, a significant proportion of CDS T cells in chronically infected subjects recognize HCV epitopes that do not demonstrate escape mutations. It is thus likely that functional impairment of CDS cells specific for nonescaped epitopes is an additional important factor in HCV persistence. We propose that a comprehensive comparative analysis of HCV-specific CDS T cell phenot5TDe and function among patients who clear HCV infection versus those who do not, and between T cells recognizing epitopes that undergo substitution and those that do not will reveal specific molecular and cellular mechanisms of T cell unresponsiveness relevant to viral persistence. Specifically, we aim l)To perform a set of in vitro fiinctional analyses assessing the capacity of HCV specific CDS T cells of various previously characterized phenotj^jes to produce relevant effector cj^okines and to perform killer functions and 2)To develop and characterize an in vivo cj^otoxic lymphocyte (CTL) assay for functional analysis of tetramer+ HCV specific CDS cells using adoptive transfer into an established NOD/SCID/--/- system. This will allow us to directly analyze the in vivo functional effects of antibodies and/or cytokines targeted at potentially relevant cell membrane receptors on human HCV specific CDS T cells. Using specific antagonist antibodies, candidate molecular determinants of CDS T cell unresponsiveness will be interrogated in this novel in vivo system in which human T cells from patients are adoptively transferred into receptive immunodeficient mice. Outcomes of this interrogation will have direct translational relevance to the immunotherapy of chronic HCV infection as well as enhancing understanding of T cell impairment associated with persistent infection. Results of studies of humoral immune responses from Project 2 will be integrated to expand knowledge of the interplay between humoral and cellular immune responses to HCV in humans. We have already demonstrated that we can obtain the critical specimens required for this investigation and will be able to conduct unique longitudinal studies of adaptive immune responses in acute HCV.

项目1的主要目标是确定与病毒持久性相关的hcv特异性CDS T细胞功能损伤的机制。虽然T细胞表位内的病毒逃逸突变发生在HCV免疫逃逸中，但慢性感染受试者中相当大比例的CDS T细胞识别不表现出逃逸突变的HCV表位。因此，非逃逸表位特异性CDS细胞的功能损伤可能是HCV持续存在的另一个重要因素。我们建议对清除HCV感染的患者与未清除HCV感染的患者，以及识别表位进行替代的T细胞与未识别表位的T细胞之间的HCV特异性CDS T细胞表型5tde和功能进行全面的比较分析，以揭示与病毒持久性相关的T细胞无反应性的特定分子和细胞机制。具体来说，我们的目标是1)进行一系列体外功能性分析，评估各种先前表征的表型的HCV特异性CDS T细胞产生相关效应因子和执行杀伤功能的能力；2)通过过继转移到已建立的NOD/SCID/- /-系统中，开发和表征一种体内cj毒性淋巴细胞（CTL）测定，用于分析四聚体+ HCV特异性CDS细胞的功能。这将使我们能够直接分析针对潜在相关细胞膜受体的抗体和/或细胞因子对人类HCV特异性CDS T细胞的体内功能影响。使用特异性拮抗剂抗体，CDS T细胞无反应性的候选分子决定因素将在这个新的体内系统中被询问，在这个系统中，来自患者的人类T细胞被过继转移到接受性免疫缺陷小鼠中。这项研究的结果将与慢性丙型肝炎病毒感染的免疫治疗直接相关，并增强对持续感染相关的T细胞损伤的理解。项目2的体液免疫反应研究结果将被整合，以扩大人类对HCV的体液和细胞免疫反应之间相互作用的知识。我们