Mouse model of chronic viral hepatitis

描述(由申请人提供)：技术概述：慢性病毒性肝炎是全世界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组织损伤的主要原因。急性免疫性肝损伤的动物模型比比皆是，但需要一种复制慢性病毒性肝炎的关键特征的模型：肝损伤、纤维化、免疫衰竭和病原体的持久性。我们已经开发了一种有希望的新模型，在这种模型中，持续感染腺相关病毒载体将靶抗原表达至少8个月，而外源性T细胞会造成组织损伤并激活星状细胞。抗原和T细胞长期共存会导致T细胞功能障碍。尽管该模型基于复制缺陷载体，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极佳载体。与小鼠嗜肝病毒不同，载体模型不太可能需要适应性来禁用肝脏免疫；因此，我们可以分离地研究肝细胞抗原的免疫反应。利用这一模型，在目标1中，我们将测试急性和慢性免疫性炎症过程中肝细胞损伤的机制。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交叉启动而导致的CD4+T细胞缺乏激活的假设。在特定的目标4中，我们将诱发慢性复发性肝炎，并测试反复的炎症循环是否会导致持续的星状细胞激活和肝纤维化。复制慢性肝损伤、星状细胞激活和免疫功能障碍的模型将最有价值地产生有助于现有抗病毒疗法作用机制的机械性研究以及新疗法的合理设计的范例。 与公众健康相关：免疫系统在抗击肝炎病毒方面很重要，但在此过程中，免疫细胞会对肝脏造成损害。我们已经开发出一种全新的小鼠模型，它将有可能区分免疫损伤的途径和对抗入侵者的途径。这将为肝炎的新型治疗开辟道路。

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.