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，T细胞介导的免疫反应被认为在丙型肝炎病毒（HCV）感染的发病机制中发挥着重要作用；然而，在此过程中新疗法（例如 siRNA）的分子基础和潜在宿主靶点尚未得到很好的探索。 我们假设 B7 共刺激分子是肝脏中 HCV 特异性 T 细胞激活和延长存活所必需的，因此是疾病发病机制的关键。 将使用两种互补的方法在新开发的肝脏特异性转基因小鼠模型中检验这一假设。 首先，将产生两只在肝脏中表达结构或全长HCV蛋白和CD86/B7.2分子的双基因转基因小鼠。 将表征肝脏 HCV 特异性和非特异性 T 细胞、NK 细胞和巨噬细胞，并将这些动物的肝损伤与单一转基因动物的肝损伤进行比较。 为了进一步检查 HCV 特异性 T 细胞是否可以在肝脏中启动以及共刺激信号是否是疾病发生和持续所必需的，我们接下来将生成在转基因诱导后表达肝内 HCV 和 CD86/B7.2 分子的条件双基因小鼠。 由于 HCV 特异性 T 细胞在这些小鼠中本质上被启动，因此后一种模型更接近地模拟 HCV 感染者中发生的情况。 还将通过流体动力学基因传递技术研究CD80/B7.1和CD40在HCV发病机制中的功能。 我们将致力于确定肝内 IFN-( 和 CC 趋化因子的动力学产生及其与 HCV 定向肝损伤的相关性。这些研究将提供有关 HCV 发病机制中共刺激分子的重要信息，并可能有助于制定针对 HCV 的未来策略阻止特定候选人。