dnTGF Beta RII Mice and PBC

描述（由申请人提供）：原发性胆汁性肝硬化（PBC）是一种胆道特异性自身免疫性疾病，其特征是淋巴细胞浸润门静脉束，抗线粒体抗体（AMAs）和胆道上皮的选择性破坏。尽管PBC通常被认为是一种模式自身免疫性疾病，并且在定义PBC患者的晚期自身免疫效应物（自身抗体、T细胞和B/T自身表位）方面取得了重大进展，但这些数据尚未转化为新的治疗方法。人类PBC有一个延长的沉默临床前阶段，因此，导致胆道损伤的最早事件在很大程度上是未知的。这种发病与临床症状之间的差距，使人们无法理解导致自我容忍被打破的原因。我们的实验室将利用独特的小鼠PBC模型，小鼠在CD4启动子（dnTGF-ß ß ß rii）的控制下表达显性阴性TGF-ß受体II基因。这些小鼠发展为严重的炎症性胆道疾病和100%的ama外显率。在目前的资助期内，我们取得了重要的、新颖的、在某些情况下令人惊讶的结果，使我们能够解决三个关键领域的问题，这些领域有可能定义导致耐受性破坏、胆管炎和肝纤维化的免疫病理学。首先，CD8 T细胞介导胆道病理，更重要的是，KLRG1+效应CD8 T细胞亚群在肝脏中积聚，但仅在存在缺陷的dnTGF-ßRII Tregs的情况下。我们的目标是确定KLRG1+表型，其转移疾病的能力，以及treg介导的对这一关键细胞亚群的控制机制。其次，我们发现dnTGF-ßRII小鼠IL-12p35的缺失不仅会导致门脉炎症和胆管损伤，还会导致一种不同的细胞因子纤维化

DESCRIPTION (provided by applicant): Primary biliary cirrhosis (PBC) is a biliary specific autoimmune disease characterized by lymphocytic infiltrates of portal tracts, anti-mitochondrial antibodies (AMAs) and selected destruction of the biliary epithelium. Although PBC is often considered a model autoimmune disease and there have been significant advances in defining the late stage autoimmune effectors (autoantibodies, T cells, and B/T autoepitopes) in PBC patients, such data has not been translated to new therapies. There is an extended silent preclinical phase in human PBC and, as such, the earliest events that lead to biliary damage are largely unknown. This gap between onset and clinical symptoms has frustrated efforts to understand the events that lead to breach of self-tolerance. Our laboratories will take advantage of a unique murine model of PBC, mice that express a dominant-negative TGF-ß receptor II gene under control of the promoter for CD4 (dnTGF-ßRII). These mice develop a robust inflammatory biliary disease and 100% penetrance of AMAs. Our progress during the current period of funding has led to important, novel and in some cases surprising results that allow us to address three critical areas that have the potential to define the immunopathology leading to breach of tolerance, cholangitis and hepatic fibrosis. First, CD8 T cells mediate biliary pathology and, more importantly, the KLRG1+ effector CD8 T cell subset accumulates in the liver, but only in the presence of defective dnTGF-ßRII Tregs. Our goal will be to define the KLRG1+ phenotype, its ability to transfer disease, and the mechanism of Treg-mediated control of this critical cell subset. Second, we have shown that deletion of IL-12p35 in dnTGF-ßRII mice leads not only to portal inflammation and bile duct damage, but also to fibrosis with a distinct cytokine profile. We will take advantage of this observation and serially monitor these events to define the sources of pathologic cytokines in the course of dysfunctional TGF-ß signaling as well as define how IL-17 signaling is cross-regulated by cytokines in the course of a chronic immune response by taking advantage of transgenic dnTGF-ßRII mice that lack IL-17A, IL-17F, IL-22, IL- 23p19 or IL-17RA in addition to unique bone marrow chimeric mouse models. Finally, our published data show that microRNA dysregulation plays a major role in autoreactive CD8 T cell mediated biliary pathology. Our existing models and novel proposed methods will allow us to correct this dysregulation and to test the effect of corrected miRNA biosynthesis on T cell activation status, and, more importantly, on immunopathology. We submit that the results of this proposal will provide insight into the mechanisms of action of CD8 effector mediated damage, will provide the opportunity to develop a biologic network of the earliest immune mediated fibrotic events and finally critical mechanistic information on the role of micro- RNA in autoimmune cholangitis. Importantly, we believe these data will potentially identify new pathways for therapeutic targeting.