Development of an animal model for autoimmune hepatitis

描述（由申请人提供）：我们的目标是开发一种新的自身免疫性肝炎（AIH）动物模型。AIM是一种严重的影响肝脏的不良免疫反应，导致肝脏实质的进行性破坏。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，并允许研究其病因和免疫病理学。AIH的一个标志是存在肝/肾微粒体抗体，该抗体识别细胞色素P450异构体2D6 （CYP2D6）作为主要的靶自身抗原。因此，目的是通过感染嗜肝病毒（腺病毒）打破CYP2D6小鼠靶器官（肝脏）中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）的递送。从初步实验中我们知道，这种方法会导致cyp2d6小鼠持续肝损伤，其特征是淋巴细胞浸润、肝纤维化和高滴度抗cyp2d6抗体。除了作为研究AIH的新模型的明显益处外，CYP2D6小鼠还可以作为研究纤维蛋白生成和药物性自身免疫性疾病的一般机制的原理证明，这些疾病是由细胞色素P450家族成员介导的，如氟烷肝炎（CYP2E1）或普鲁卡因酰胺诱导的狼疮（CYP2D6）。

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.