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: 6347296
• 负责人: William Mason
• 金额: $ 7.89万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347296
• 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.

乙肝病毒的短暂和慢性感染涉及每一个人 肝脏中的肝细胞并触发免疫反应，导致 发炎。暂时性疾病和慢性病之间的区别在于 前者突然停止，通常没有明显症状，而 ALTER可能会持续一生。因此，一个主要的问题涉及到 在恢复过程中起作用的宿主反应。使用土拨鼠肝炎 以土拨鼠的病毒感染为模型，我们发现 免疫系统能够通过以下方式迅速清除肝脏中的病毒 既涉及细胞杀伤又涉及细胞治愈的机制。从长远来看 我们现在的研究目标是确定免疫反应是如何 (内源性免疫反应)实现了这一结果，以及 基于这种形态，免疫疗法可能被设计用于治疗 慢性感染的治疗。 为了实现这一目标，我们将：1)克隆土拨鼠T细胞标志并 已知在抗病毒免疫反应中起中介作用的细胞因子；ii) 描述慢性感染和感染期间的内源性免疫反应 在短暂感染的过程中，特别是在 关键清除阶段和III)检查治愈的可能性 通过特定细胞因子的时间表达而引起的慢性感染 肝脏中，包括土拨鼠干扰素和肿瘤坏死因子α。 因此，已经设计了实验，以获得全面的 一过性感染的关键恢复期图片，在 参考个别肝细胞、肝细胞内的病毒感染 周转与内源性免疫反应。据预计， 这些研究的结果将揭示细胞因子表达的变化 一过性感染中的T细胞反应导致病毒的开始 以及提供了为什么慢性感染未能 安全。从我们的结果中获得的信息将被用于 重组腺病毒载体抗病毒策略的研究进展 允许慢性肝病患者肝脏中免疫介质的表达 被感染的动物。