Development of an animal model for autoimmune hepatitis

描述(申请人提供)：我们的目标是发展一种新的自身免疫性肝炎(AIH)动物模型。AIM是一种严重的免疫不良反应，困扰肝脏，导致实质进行性破坏。到目前为止，还没有有效的动物模型可以反映人类AIH的临床和病理特征，并允许研究其病因学和免疫病理学。AIH的一个特征是存在肝/肾微粒体抗体，该抗体将细胞色素P450亚型2D6(CYP2D6)识别为主要的靶标自身抗原。因此，目的是通过感染嗜肝病毒(腺病毒)来打破CYP2D6小鼠的靶器官(肝脏)对转基因表达的靶抗原(人CYP2D6)的耐受性，确保局部炎症和大量触发抗原(人CYP2D6)的传递。从初步实验中我们知道，这种方法会导致CYP2D6转基因小鼠的持续性肝损伤，其特征是淋巴细胞浸润、肝纤维化和高滴度的抗CYP2D6抗体。除了作为研究AIH的新模型的明显益处外，CYP2D6小鼠还可以被用作研究纤维蛋白形成和由细胞色素P450家族成员介导的药物诱导的自身免疫性疾病的一般机制的原理证明，如氟烷肝炎(CYP2E1)或普鲁卡因胺诱导的狼疮(CYP2D6)。 目的1：自身免疫性肝炎模型的建立及特性研究目的2：自身免疫性肝损伤的机制；目的3：评价消除自身免疫性肝炎的可能治疗方法。

DESCRIPTION (provided by applicant): Our goal is to develop a novel animal model for autoimmune hepatitis (AIH). AIM is a severe adverse immune reaction afflicting the liver, resulting in the progressive destruction of the parenchyma. To date no valid animal model is available that reflects the clinical and pathological features of human AIH and allows to study its etiology and immunopathology. A hallmark of AIH is the presence of liver/kidney microsomal antibodies that recognize the cytochrome P450 isoform 2D6 (CYP2D6) as a major target autoantigen. Thus, it is the objective to break tolerance to a transgenically expressed target antigen (human CYP2D6) in the target organ (liver) of CYP2D6-mice by infection of a liver-tropic virus (adenovirus), ensuring local inflammation and delivery of large quantities of the triggering antigen (human CYP2D6). From preliminary experiments we know that this approach results in persistent liver damage in CYP2D6-mice, which is characterized by lymphocyte infiltration, hepatic fibrosis, and high titer anti-CYP2D6 antibodies. In addition to its obvious benefit as a novel model to study AIH, the CYP2D6 mouse may also be used as a proof of principle for studying general mechanisms involved in fibrinogenesis and in drug-induced autoimmune diseases that are mediated by members of the cytochrome P450 family, such as Halothane hepatitis (CYP2E1) or procainamide-induced lupus (CYP2D6). Aim 1: Development and characterization of the CYP2D6-mouse model for autoimmune hepatitis Aim 2: Mechansims of autoimmune liver damage in the CYP2D-mouse model; Aim 3: Evaluation of possible treatments to abrogate autoimmunity in the CYP2D6-mouse model.