Understanding Immunopathogenesis of Hepatitis B Virus

描述(申请人提供)：乙肝病毒(乙肝病毒)是一种肝炎病毒，是人类急性和慢性肝炎的主要原因。全球有3亿人慢性感染乙肝病毒，使其成为人类最常见的病原体之一。乙肝病毒的复制不是细胞病变，而且有证据表明肝脏的病理是由免疫介导的。因此，要了解急性和慢性乙肝病毒感染的发病机制，就必须了解这些过程背后的免疫反应。自然的肝炎病毒感染只发生在人类和其他近亲繁殖的物种中，这些物种的免疫系统特征不佳，难以研究。这项建议试图使用一种新的乙肝病毒感染的转基因小鼠模型来识别急性和慢性乙肝病毒感染的免疫发病机制，包括了解先天免疫反应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，我们将能够设计出特定的免疫疗法来预防和治疗乙肝病毒相关的肝病。我们的具体目标是：1.在我们的转基因小鼠乙肝病毒感染模型中，确定非经典NKT细胞介导急性实验性肝炎的机制；2.检验在我们的疾病模型中，非经典NKT细胞和/或NK细胞的早期激活可以显著影响疾病模型中慢性肝炎的假说；以及3.建立非经典NKT细胞对乙肝病毒的体外激活模型，为研究非经典NKT细胞激活的机制奠定基础。

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.