Immunogenetic Control of Autoimmune Liver Disease

自身免疫性肝病的免疫遗传学控制

• 批准号: 8762395
• 负责人: William M Ridgway
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762395
• 关键词: Address; Adoptive Transfer; Alcoholic Hepatitis; Alleles; Animal Disease Models; Animal Model; Antigens; Autoantibodies; Autoimmune Process; Biliary; Biological Models; Bone Marrow; Breeding; CD4 Positive T Lymphocytes; CD8 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chromosomes; Clinical; Congenic Mice; Congenic Strain; Data; Dependence; Development; Disease; Disease model; Effector Cell; Environment; Etiology; Event; Female; Future; Genes; Grant; Hepatic; Human; Immune; Immune system; Immunity; Immunogenetics; In Vitro; Inbred NOD Mice; Inflammatory; Injury; Interferon Type II; Lead; Liver; Liver diseases; Mediating; Medical; Memory; Mission; Modeling; Mus; Mutation; Non obese; Oxidoreductase; Pathogenesis; Pathogenicity; Pathology; Penetrance; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Play; Population; Primary biliary cirrhosis; Process; Production; Publishing; Pyruvate Dehydrogenase Complex; Regulatory T-Lymphocyte; Role; Science; Specificity; Splenocyte; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Time; Work; base; biliary tract; cytokine; diabetic; human disease; in vivo; insight; intrahepatic; liver inflammation; liver injury; male; mouse model; novel; novel therapeutics; pathogen; prevent; research study; response

DESCRIPTION (provided by applicant): We have produced several Nonobese diabetic (NOD) congenic strains (generically designated "NOD.ABD" mice) that develop spontaneous, autoimmune biliary disease (ABD) and anti-pyruvate dehydrogenase complex (PDC) autoantibodies, and serve as a model of human primary biliary cirrhosis (PBC). They provide a much needed model system for determining early immunogenetic mechanisms of PBC, which is critically important because the human disease has a long "silent" phase. We have now produced a novel congenic mouse, termed NOD.Abd3, with a 1.0 megabase chromosome one B6 interval on the NOD background; this strain develops severe, spontaneous ABD with 100% penetrance in male and female mice. This grant will study immunological mechanisms of disease in NOD.Abd3 mice. Our preliminary data show that ABD can be transferred by NOD.ABD, but not NOD, CD8+ cells, implicating NOD.Abd3 CD8 cells in pathogenesis. Our preliminary data also show that the adaptive immune system is central to the ABD disease process. Finally, co- transfer of ABD T regulatory cells prevented CD8 cell mediated ABD in scid recipients. This grant will dissect the immunological basis for this enhanced pathogenicity of NOD.ABD CD8 cells, and protective capacity of NOD.Abd3 Tregs, through the following specific aims: Aim #1. Mechanism of CD8+ T cell mediated autoimmune biliary disease. We have demonstrated that NOD.ABD, but not NOD, CD8+ T cells are sufficient to transfer biliary pathology to ABD-scid recipients. This aim dissects major mechanisms of CD8+ T cell mediated disease, using 1) transfer and bone marrow chimeric studies; 2) an exhaustive analysis of CD8+ T cell marker expression in NOD.ABD mice; and 3) a thorough analysis of CD8+ T cell cytokine expression in vitro, and in vivo following adoptive transfer. Aim #2. T helper dependence and antigen specificity of intrahepatic NOD.ABD CD8 T cells. This aim will address two major issues: 1) Are the NOD CD8 T cell responses CD4+ T cell dependent or independent? 2) Are intrahepatic CD8 T cells antigen specific? We will test these issues by studying ABD with and without either CD4 or CD8 cells and by restricting the CD8+ T cell repertoire and assessing effect on disease. Aim #3: Role of T regulatory cells in ABD. We have shown that co-transfer of NOD.Abd3 splenic Tregs can prevent disease in our adoptive transfer model. Why don't NOD.Abd3 Tregs prevent spontaneous disease in vivo? We will exhaustively study the phenotype of hepatic vs. peripheral Tregs and demonstrate the functional role of Tregs in ABD by employing transfer and depletion studies. These studies are important and significant because they will allow us to study mechanisms of immune mediated biliary damage that previously could not be studied due to a lack of a spontaneous animal model of disease. Understanding early mechanisms of altered biliary immunity will lead to new hypotheses regarding the etiology and treatment of human autoimmune biliary disease.

描述（由申请人提供）： 我们已经产生了几种非肥胖糖尿病（NOD）同类品系（一般称为“NOD.ABD”小鼠），其产生自发性自身免疫性胆道疾病（ABD）和抗丙酮酸脱氢酶复合物（PDC）自身抗体，并用作人原发性胆汁性肝硬化（PBC）的模型。它们为确定PBC的早期免疫遗传机制提供了急需的模型系统，这是至关重要的，因为人类疾病具有长的“沉默”阶段。我们现在已经产生了一种新的同源小鼠，称为NOD.Abd3，在NOD背景上具有1.0兆碱基的染色体1个B6间隔;该品系在雄性和雌性小鼠中发展严重的自发ABD，具有100%的突变率。该基金将研究NOD.Abd3小鼠疾病的免疫机制。我们的初步数据表明，ABD可以通过NOD.ABD，而不是NOD，CD 8+细胞转移，暗示NOD. Abd 3 CD 8细胞在发病机制中。我们的初步数据还表明，适应性免疫系统是ABD疾病过程的核心。最后，ABD调节性T细胞的共转移防止了scid受体中CD 8细胞介导的ABD。这项资助将通过以下具体目标来剖析NOD.ABD CD 8细胞的这种增强的致病性的免疫学基础，以及NOD. Abd 3 T细胞的保护能力：目标1。CD 8 + T细胞介导自身免疫性胆道疾病的机制我们已经证明，NOD、ABD，而不是NOD、CD 8 + T细胞足以将胆道病变转移到ABD-scid受体。本研究旨在通过以下方法剖析CD 8 + T细胞介导疾病的主要机制：1）转移和骨髓嵌合研究; 2）NOD.ABD小鼠中CD 8 + T细胞标志物表达的详尽分析; 3）过继转移后体外和体内CD 8 + T细胞细胞因子表达的全面分析。目标2。肝内NOD.ABD CD 8 T细胞的辅助性T细胞依赖性和抗原特异性这一目标将解决两个主要问题：1）NOD CD 8 T细胞反应是CD 4 + T细胞依赖性的还是独立的？2)肝内CD 8 T细胞是抗原特异性的吗？我们将通过研究有和没有CD 4或CD 8细胞的ABD以及通过限制CD 8 + T细胞库和评估对疾病的影响来测试这些问题。目的#3：调节性T细胞在ABD中的作用。我们已经证明，NOD.Abd3脾THBE的共转移可以在我们的过继转移模型中预防疾病。为什么NOD.Abd3 TdR不能预防体内自发性疾病？我们将详尽地研究肝脏与外周THBE的表型，并通过转移和耗竭研究证明THBE在ABD中的功能作用。这些研究是重要和有意义的，因为它们将使我们能够研究免疫介导的胆道损伤的机制，以前无法研究，由于缺乏自发的动物模型的疾病。了解胆道免疫改变的早期机制将导致关于人类自身免疫性胆道疾病的病因和治疗的新假设。