Cellular Immune Failure in Acute Hepatitis C

急性丙型肝炎的细胞免疫衰竭

• 批准号: 7014306
• 负责人: STUART C RAY
• 金额: $ 22.81万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014306
• 关键词: T lymphocyte; acute disease /disorder; biomarker; cellular immunity; chronic disease /disorder; cooperative study; hepatitis C; hepatitis C virus; host organism interaction; human subject; immune response; leukocyte activation /transformation; patient oriented research; virus cytopathogenic effect

The purpose of this project is to test the hypothesis that hepatitis C virus (HCV) infection persists due to arrested development of CDS T cell-mediated antiviral responses during the ransition from acute to chronic phase by CD4 dependent mechanisms. During the previous funding period we have developed an infrastructure to obtain large numbers of peripheral blood mononuclear cells (PBMC) from acutely-infected individuals, and used overlapping peptides encompassing the entire HCV polyprotein to characterize IFNgamma-mediated immune responses. Most subjects responded to multiple epitopes, with peak recognition around 6 months then decreasing during the following 12-18 months. New specificities were not detected after the first 6 months, despite ongoing amino acid replacements. Amino acid replacements in T cell epitopes frequently represent escape mutants, and most epitopes develop amino acid replacements. We therefore propose to investigate the mechanisms of cellular immune failure during the transition between acute and chronic infection. Aim 1: To define molecular markers of CD8+ T lymphocyte failure in PBMC from persons with acute HCV infection. We will determine the timing and breadth of response, measure cell-surface and intracellular markers of CDS phenotype and maturation. We will correlate these findings with responses in lymphocytes obtained from livers in a well-characterized subset of volunteers to assess the degree of compartmentalization. Aim 2: To define the role of CD4 T cells in modulating CDS T cell responses to acute HCV infection. The number, phenotype, and compartmentalization of CD4 cells will be investigated. Measures will include TH1/TH2 cytokine expression, cell surface markers of phenotype and regulation, and the temporal relationship of these markers versus CDS function determined in aim 1. The proposed studies will be synergistic with a well-characterized prospective cohort of active injection drug users (see clinical core) from whom clinical, histologic, and virologic information will also be obtained.

本项目的目的是验证丙型肝炎病毒(HCV)感染持续存在的假设，这是由于CDS T细胞介导的抗病毒反应在从急性期向慢性期的转变过程中，通过CD4依赖机制而停止发展。在之前的资助期间，我们开发了一套基础设施，从急性感染者身上获得大量外周血单个核细胞(PBMC)，并使用包含整个丙型肝炎病毒多蛋白的重叠多肽来表征IFNGamma介导的免疫反应。大多数受试者对多个表位有反应，峰值识别率约为6 月，然后在接下来的12-18个月内减少。尽管正在进行氨基酸替换，但在前6个月后没有检测到新的特异性。T细胞表位中的氨基酸替换通常代表逃逸突变，并且大多数表位都发生氨基酸替换。因此，我们建议研究急性和慢性感染过渡过程中细胞免疫衰竭的机制。目的1：确定急性丙型肝炎患者外周血中CD8+T淋巴细胞衰竭的分子标志物。我们将确定反应的时间和广度，测量CDS表型和成熟的细胞表面和细胞内标志物。我们将把这些发现与从具有良好特征的志愿者亚群的肝脏中获得的淋巴细胞的反应相关联，以评估 分隔化。目的：探讨CD4T细胞在调节CDS T细胞对急性丙型肝炎病毒感染应答中的作用。将调查CD4细胞的数量、表型和区隔。措施将包括TH1/TH2细胞因子的表达，表型和调节的细胞表面标记，以及这些标记与目标1中确定的CDS功能的时间关系。拟议的研究将与特征良好的预期活跃注射吸毒者队列(见临床核心)协同进行，临床、组织学和病毒学信息也将从这些队列中获得。