THE PATHOGENESIS OF AUTOIMMUNITY IN A MURINE MODEL OF PRIMARY BILIARY CIRRHOSIS

描述(申请人提供)：原发性胆汁性肝硬变(PBC)是一种神秘的、肝脏特有的自身免疫性疾病，其特征是抗线粒体抗体和进行性肝内胆管破坏。目前还没有PBC的动物模型，研究依赖于人类临床标本，这一问题因疾病发病的隐蔽性而变得更加复杂，这使得无法在早期阶段识别患者。在其他自身免疫性疾病中，提供信息的动物模型为免疫过程的剖析提供了便利。我们提出了一种联合方法，利用三个校区的优势来研究两种新的自身免疫性胆道疾病小鼠模型，NOD.C3C4同源小鼠，在第3和4号染色体上有B6/B10衍生区域，以及一种新的品系，称为2445。与NOD.C3C4相比，2445系显著缩短了3号和4号染色体上的B6/B10间隔，这将有助于疾病整合基因的定位克隆。两种品系的小鼠都会出现进行性门脉淋巴细胞性浸润性病变、肉芽肿、抗线粒体抗体和终末期胆道疾病。我们的目标是对免疫系统进行详细的个体发生分析，以确定特定谱系利用NOD.C3C4、2445菌株和对照对疾病过程做出贡献的动力学。将要进行的研究是那些反映人类PBC的研究，包括分析先天性、体液和细胞免疫系统，包括肝脏淋巴亚群和免疫组织化学，以确定每个组成部分在疾病发病机制中的发育阶段。我们还将利用目前可用的同源菌株以及将产生的新的同源菌株来定位克隆导致肝病的关键基因。基于这些数据，使用NOD.C3C4-和2445-SCID受体的采用转移策略将定义肝脏疾病发展所需的致病效应细胞。我们认为，这一模型不仅在提高我们对PBC的理解方面提供了巨大的潜力，而且在总体上也为自身免疫提供了巨大的潜力。PBC是一种典型的自身免疫性疾病，具有组织特异性影响，但具有恒定的非组织特异性自身反应性，这一特征在该模型中非常接近地再现。最后，由于PBC的小鼠模型在病理学和免疫学上与人类PBC相似，它为对启动事件进行判别分析和最终研究治疗干预措施打开了可能性。

DESCRIPTION (provided by applicant): Primary biliary cirrhosis (PBC) is an enigmatic, liver specific, autoimmune disease characterized by antimitochondrial antibodies and progressive destruction of intrahepatic bile ducts. There has not been an animal model of PBC and studies are dependent on human clinical specimens, a problem compounded by the cryptic nature of disease onset that prevents identification of patients in early stages. In other autoimmune diseases, the dissection of the immune process has been facilitated by informative animal models. We propose a consortium approach utilizing the strengths of 3 campuses to study 2 novel murine models of autoimmune biliary disease, the NOD.c3c4 congenic mouse with B6/B10 derived regions on chromosomes 3 and 4 as well as a new strain, called 2445. Line 2445 has significantly reduced B6/B10 intervals on chromosome 3 and 4 compared to NOD.c3c4, which will facilitate positional cloning of genes integral to disease. Both strains of mice develop progressive portal tract lymphocytic infiltrates, granulomas, anti-mitochondrial antibodies and terminal biliary disease. Our objectives are to perform a detailed ontogenetic analysis of the immune system to define the kinetics by which specific lineages contribute to disease process utilizing NOD.c3c4, strain 2445, and controls. The studies to be performed are those which mirror human PBC, including analysis of the innate, humoral and cellular immune systems, including liver lymphoid subpopulations and immunohistochemistry to identify the developmental stage each component contributes to disease pathogenesis. We will also positionally clone the genes critical for causing liver disease using currently available congenic strains as well as novel congenic strains that will be generated. Based upon this data, adoptive transfer strategies using NOD.c3c4- and 2445-scid recipients will define the pathogenic effector cells required for the development of liver disease. We submit that this model offers significant potential for not only enhancing our understanding of PBC, but also autoimmunity in general. PBC is the prototypic autoimmune disease with a tissue specific impact, but a constant non-tissue specific autoreactivity, features closely reproduced in this model. Finally, because this murine model of PBC is pathologically and immunologically similar to human PBC, it opens the possibility of discriminative analysis of initiating events and eventually study of therapeutic interventions.