PATHOBIOLOGY OF ACUTE AND CHRONIC HEPADNAVIRUS INFECTIONS

急性和慢性肝炎病毒感染的病理学

• 批准号: 6102246
• 负责人: William Mason
• 金额: $ 42.8万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-25 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102246
• 关键词: Hepadnaviridae; T lymphocyte; acute disease /disorder; biopsy; cell cycle; cellular immunity; chronic disease /disorder; cytokine; disease /disorder model; gene expression; hepatitis B virus group; hepatocellular carcinoma; host organism interaction; immunocytochemistry; in situ hybridization; infection; interferon gamma; liver cells; marmots; molecular cloning; pathologic process; tissue /cell culture; tumor necrosis factor alpha; virus DNA; virus infection mechanism; virus load; virus related neoplasm /cancer

Transient and chronic infections by a hepatitis B virus involve every hepatocyte in the liver and trigger an immune response that leads to inflammation. A difference between transient and chronic disease is that the former suddenly ceases, often without overt symptoms, whereas the alter may persist for life. A major question thus concerns the nature of the host responses that play a role in recovery. Using woodchuck hepatitis virus infection of woodchucks as a model for HBV, we have found that the immune system is able to rapidly eliminate virus from the liver by mechanisms that involve both cell killing and cell curing. The long term objective of our research is now to determine how the immune response (endogenous immune response) achieved this outcome and how an immunotherapy might be designed, based on this formation, for the treatment of chronic infections. Towards this objective, we will i) clone woodchuck T-cell markers and cytokines known to act as mediators in antiviral immune responses; ii) characterize the endogenous immune response during chronic infections and during the course of a transient infection and, in particular, during the critical clearance phase and iii) examine the possibility of curing chronic infections through the temporal expression of specific cytokine sin the liver, including woodchuck interferon gamma and TNF alpha. Accordingly, experiments have been designed to obtain a comprehensive picture of the critical recovery phase of a transient infection, in reference to viral infection within individual hepatocytes, hepatocyte turnover and the endogenous immune response. It is anticipated that the results from these studies will reveal how changes in cytokine expression and T-cell responses in transient infections lead to the start of virus clearance, as well as providing clues as to why chronic infections fail to clear. Information gained from our results will be exploited for the development of anti-viral strategies using recombinant adenovirus vectors that permit expression of immunological mediators in livers in chronically infected animals.

B型肝炎病毒的短暂和慢性感染涉及每一个 肝脏中的肝细胞并引发免疫反应， 炎症暂时性疾病和慢性疾病的区别在于， 前者突然停止，往往没有明显的症状，而 改变可能会持续一生。因此，一个主要问题涉及到 在恢复过程中发挥作用的宿主反应。用土拨鼠肝炎 作为HBV模型的土拨鼠病毒感染，我们发现， 免疫系统能够迅速消除病毒从肝脏通过 涉及细胞杀伤和细胞治愈的机制。长期 我们研究的目的是确定免疫反应是如何 （内源性免疫反应）实现了这一结果， 免疫疗法可能会被设计，基于这种形成， 治疗慢性感染。 为了实现这一目标，我们将i）克隆土拨鼠T细胞标记物， 已知在抗病毒免疫应答中充当介体的细胞因子; ii） 表征慢性感染期间的内源性免疫应答， 在短暂感染的过程中，特别是在 关键清除阶段和iii）检查固化的可能性 通过特异性细胞因子的暂时表达的慢性感染 包括土拨鼠干扰素γ和TNF α。 因此，设计了实验以获得全面的 短暂感染的关键恢复阶段的图片， 提及单个肝细胞内的病毒感染，肝细胞 周转和内源性免疫反应。预计该 这些研究的结果将揭示细胞因子表达的变化 和T细胞的反应导致病毒的开始 清除，以及提供线索，为什么慢性感染未能 清楚从我们的结果中获得的信息将被用于 使用重组腺病毒载体的抗病毒策略的开发 允许免疫介质在肝脏中表达， 被感染的动物