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

原发性胆汁性肝硬化小鼠模型中自身免疫的发病机制

• 批准号: 7082343
• 负责人: MERRILL E GERSHWIN
• 金额: $ 59.19万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082343
• 关键词: NOD mouse; autoimmunity; chromosome disorders; developmental immunology; disease /disorder model; flow cytometry; gene expression; genetic mapping; genetic strain; genetic susceptibility; genetically modified animals; histopathology; immunogenetics; immunopathology; liver cirrhosis; model design /development; molecular cloning; pathologic process

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.

描述（由申请人提供）：原发性胆汁性肝硬化（PBC）是一种神秘的肝脏特异性自身免疫性疾病，其特征是抗线粒体抗体和肝内胆管的进行性破坏。目前还没有 PBC 的动物模型，研究依赖于人类临床标本，由于疾病发病的神秘性，无法在早期阶段识别患者，因此问题变得更加复杂。在其他自身免疫性疾病中，信息丰富的动物模型促进了免疫过程的剖析。我们提出了一种联合方法，利用 3 个校区的优势来研究 2 种新型自身免疫性胆道疾病小鼠模型，即第 3 号和第 4 号染色体上具有 B6/B10 衍生区域的 NOD.c3c4 同类小鼠以及一种称为 2445 的新品系。与NOD.c3c4相比，2445在3号和4号染色体上的B6/B10间隔显着减少，这将有利于定位克隆疾病不可或缺的基因。两种品系的小鼠均出现进行性汇管淋巴细胞浸润、肉芽肿、抗线粒体抗体和终末期胆道疾病。我们的目标是利用 NOD.c3c4、菌株 2445 和对照对免疫系统进行详细的个体发育分析，以确定特定谱系对疾病过程的影响的动力学。将进行的研究反映了人类原发性胆汁性胆管炎，包括对先天、体液和细胞免疫系统的分析，包括肝淋巴亚群和免疫组织化学，以确定每个成分对疾病发病机制的发育阶段。我们还将使用现有的同源菌株以及将产生的新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 受体的过继转移策略将定义肝病发展所需的致病效应细胞。我们认为，该模型不仅可以增强我们对 PBC 的理解，而且可以增强我们对自身免疫的理解。 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得到了密切再现。最后，由于这种 PBC 小鼠模型在病理学和免疫学上与人类 PBC 相似，因此它开启了对起始事件进行判别分析并最终研究治疗干预措施的可能性。