Understanding Immunopathogenesis of Hepatitis B Virus

描述（由申请方提供）：B型肝炎病毒（HBV）是一种嗜肝DNA病毒，是人类急性和慢性肝炎的主要原因。全球有3亿人慢性感染HBV，使HBV成为最常见的人类病原体之一。HBV复制不是致细胞病变的，有证据表明肝脏病理是免疫介导的。因此，了解急性和慢性B型肝炎病毒感染的发病机制要求了解这些过程背后的免疫反应。天然嗜肝DNA病毒感染仅发生在人类和其他远系繁殖的物种中，其免疫系统特征不佳且难以研究。该提案旨在使用一种新的乙型肝炎病毒感染转基因小鼠模型来确定参与急性和慢性乙型肝炎病毒感染免疫发病机制的机制，包括了解先天免疫应答在这些疾病过程中的作用。我们希望在确定这些疾病过程的潜在机制时，我们将能够设计特异性免疫疗法来预防和治疗HBV相关肝病。我们的具体目标是：1.目的：1.探讨非经典NKT细胞介导原发性HBV感染转基因小鼠急性实验性肝炎的机制。检验我们的原发性HBV感染模型中非经典NKT细胞和/或NK细胞的早期活化可以显著影响我们的疾病模型中肝炎的慢性期的假设;和3.建立B型肝炎病毒诱导非经典NKT细胞活化的体外模型，为进一步研究非经典NKT细胞活化机制奠定基础。

DESCRIPTION (provided by applicant): Hepatitis B Virus (HBV) is a hepadnavirus that is a major cause of acute and chronic hepatitis in humans. Three hundred million people globally are chronically infected with HBV, making HBV one of the most common human pathogens. HBV replication is not cytopathic, and evidence has shown that hepatic pathology is immune-mediated. Thus, understanding the pathogenesis of acute and chronic hepatitis B virus infection mandates understanding the immune responses underlying these processes. Natural hepadnaviral infections occur only in humans and other outbred species whose immune systems are poorly characterized and difficult to study. This proposal seeks to use a new transgenic mouse model of hepatitis B virus infection to identify mechanisms involved in immunopathogenesis of acute and chronic hepatitis B virus infection, including understanding the role of the innate immune response in these disease processes. It is our hope that in identifying mechanisms underlying these disease processes, we will be able to design specific immunotherapies to prevent and treat HBV-related liver disease. Our specific aims are: 1. To determine the mechanism by which non-classical NKT cells mediate acute experimental hepatitis in our transgenic mouse model of primary HBV infection; 2. To test the hypothesis that the early activation of non-classical NKT cells and/or NK Cells in our model of primary HBV infection can significantly influence the chronic phase of hepatitis in our disease model; and 3. To develop an in vitro model of non-classical NKT cell activation in response to Hepatitis B virus, which will establish a fundamental experimental system for identifying the mechanisms of non-classical NKT cell activation.