Mouse model of chronic viral hepatitis

描述（由申请人提供）：技术摘要：慢性病毒性肝炎是世界范围内发病率和死亡率的主要原因，在这一疾病家族中，免疫系统被认为是造成大部分组织损伤的原因。急性免疫性炎症性肝损伤的动物模型很多，但需要一种能再现慢性病毒性肝炎关键特征的模型：肝损伤、纤维化、免疫功能衰竭和病原体的持久性。我们已经开发了一种很有前景的新模型，在这种模型中，腺相关病毒载体的持续感染引导目标抗原在肝细胞中表达至少8个月，而外源性T细胞引起组织损伤并激活星状细胞。抗原与T细胞长期共存导致T细胞功能障碍。虽然该模型是基于复制缺陷载体，但它是研究T细胞与仅在肝细胞中表达的抗原相互作用的绝佳载体。与小鼠嗜肝病毒不同的是，载体模型不太可能产生使肝脏免疫丧失功能的适应性；因此，我们可以对肝细胞抗原的免疫反应进行分离研究。使用该模型，在Aim 1中，我们将测试急性和慢性免疫炎症期间肝细胞损伤的机制。在目标2中，我们将测试星状细胞激活的机制。在目标3中，我们将测试载体持久性是由于缺乏CD4+ T细胞激活的假设，因为缺乏交叉启动。在Specific Aim 4中，我们将诱导慢性复发性肝炎，并测试反复的炎症周期是否导致持续的星状细胞活化伴肝纤维化。复制慢性肝损伤、星状细胞活化和免疫功能障碍的模型将最有价值，它将为现有抗病毒治疗的作用机制的机制研究和新疗法的合理设计提供有用的范例。

DESCRIPTION (provided by applicant): Technical summary: Chronic viral hepatitis is a major cause of morbidity and mortality worldwide, and in this family of diseases the immune system is believed to be responsible for the majority of the tissue damage. Animal models of acute immuno-inflammatory liver damage abound, but there is a need for a model that reproduces the key features of chronic viral hepatitis: liver injury, fibrosis, immune failure, and persistence of the pathogen. We have developed a promising new model, in which persistent infection with an Adeno-Associated Virus vector directs expression of the target antigen to hepatocytes for at least 8 months, while exogenous T cells cause tissue damage and activate stellate cells. Prolonged co-existence of the antigen and the T cells leads to T cell dysfunction. Although this model is based on a replication- defective vector, it is an excellent vehicle to study the interactions of T cells with antigen expressed exclusively in hepatocytes. Unlike murine hepatotropic viruses, the vector model in unlikely to entail adaptations to disable liver immunity; thus we can study the immune response to hepatocellular antigens in isolation. Using this model, in Aim 1 we will test the mechanism of hepatocellular injury during acute and chronic immune inflammation. In Aim 2, we will test the mechanisms of stellate cell activation. In Aim 3 we will test the hypothesis that vector persistence is due to the lack of CD4+ T cell activation, because of a lack of cross-priming. In Specific Aim 4, we will induce chronic relapsing hepatitis, and test whether repeated cycles of inflammation lead to sustained stellate cell activation with liver fibrosis. A model that reproduces chronic liver damage, stellate cell activation and immune dysfunction will be most valuable in generating paradigms useful for mechanistic investigations of the mechanism of action of existing anti-viral therapy, and for the rational design of new therapies. Relevance to public health: The immune system is important in fighting against hepatitis viruses, but in the process immune cells cause damage to the liver. We have developed an entirely new mouse model that will make it possible to distinguish the pathways of immune damage from those that fight invaders. This will open the way to new kinds of treatment for hepatitis.