Immune Costimulatory Molecules in HCV Pathogenesis

HCV 发病机制中的免疫共刺激分子

• 批准号: 6741223
• 负责人: JIAREN SUN
• 金额: $ 15.1万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2005-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6741223
• 关键词: CD antigens; CD40 molecule; T lymphocyte; cellular immunity; chemokine; disease /disorder model; genetically modified animals; hepatitis C; hepatitis C virus; immunomodulators; interferon gamma; laboratory mouse; leukocyte activation /transformation; pathologic process

DESCRIPTION (provided by applicant): T cell-mediated immune responses have long been proposed to play an important role in the pathogenesis of hepatitis C virus (HCV) infection; however, the molecular basis and potential host targets for novel therapeutics (e.g. siRNA) during this process are not well explored. We hypothesize that the B7 co-stimulatory molecules are required for activation and prolonged survival of HCV specific T cells in the liver and thus key to disease pathogenesis. Two complementary approaches will be used to test this hypothesis in newly developed, liver-specific transgenic mouse models. First, two bigenic transgenic mice that express the structural or full-length HCV proteins and CD86/B7.2 molecules in the liver will be generated. Hepatic HCV-specific and -nonspecific T cells, NK cells and macrophages will be characterized and liver injuries in these animals will be compared with those in single transgenics. To further examine whether HCV-specific T cells can be primed in the liver and whether co-stimulatory signals are necessary for disease initiation and perpetuation, we will next generate conditional bigenic mice that express intrahepatic HCV and CD86/B7.2 molecules upon transgene induction. As HCV-specific T cells are primed intrinsically in these mice, this latter model mimics more closely what occurs in HCV-infected persons. The functions of CD80/B7.1 and CD40 in HCV pathogenesis will also be studied through a hydrodynamic gene delivery technology. Effort will be directed at defining the kinetic production of intrahepatic IFN-( and CC chemokines and its correlation to HCV-directed liver injury. These studies would provide important information on co-stimulatory molecules in HCV pathogenesis and may aid in devising future strategies targeted at blocking specific candidates.

描述（由申请人提供）：长期以来一直认为T细胞介导的免疫应答在丙型肝炎病毒（HCV）感染的发病机制中发挥重要作用;然而，尚未充分探索该过程中新型治疗剂（例如siRNA）的分子基础和潜在宿主靶点。 我们假设B7共刺激分子是激活和延长肝脏中HCV特异性T细胞存活所必需的，因此是疾病发病机制的关键。 两种互补的方法将被用来测试这一假设在新开发的，肝脏特异性转基因小鼠模型。 首先，将产生在肝脏中表达结构或全长HCV蛋白和CD 86/B7.2分子的两个双基因转基因小鼠。 肝脏HCV特异性和非特异性T细胞，NK细胞和巨噬细胞的特点和肝损伤在这些动物将与那些在单一的转基因比较。 为了进一步研究HCV特异性T细胞是否可以在肝脏中引发以及共刺激信号是否是疾病起始和延续所必需的，我们接下来将产生在转基因诱导后表达肝内HCV和CD 86/B7.2分子的条件性双基因小鼠。 由于HCV特异性T细胞在这些小鼠中固有地引发，后一种模型更接近地模拟HCV感染者中发生的情况。 通过流体动力学基因递送技术，还将研究CD 80/B7.1和CD 40在HCV发病机制中的功能。 我们将致力于确定肝内IFN-β和CC趋化因子的动态产生及其与HCV介导的肝损伤的相关性。 这些研究将提供重要的信息，共刺激分子在HCV发病机制，并可能有助于制定未来的战略，有针对性地阻止特定的候选人。