Immunogenetic Control of Autoimmune Liver Disease

自身免疫性肝病的免疫遗传学控制

• 批准号: 8139557
• 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/8139557
• 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; Inflammation; 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; 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）： 我们已经培育了几种非肥胖糖尿病（NOD）同源品系（统称为“NOD.ABD”小鼠），它们产生自发的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，并作为人类原发性胆汁性肝硬化（PBC）的模型。它们为确定 PBC 的早期免疫遗传学机制提供了急需的模型系统，这一点至关重要，因为人类疾病有一个漫长的“沉默”阶段。我们现在已经培育出一种新型同源小鼠，称为 NOD.Abd3，其在 NOD 背景上具有 1.0 兆碱基的一号染色体 B6 间隔；该菌株会产生严重的、自发的 ABD，在雄性和雌性小鼠中外显率均为 100%。这笔资助将研究 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 转移，但不能通过 NOD、CD8+ 细胞转移，表明 NOD.Abd3 CD8 细胞参与发病机制。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 T 调节细胞的共转移阻止了 scid 受体中 CD8 细胞介导的 ABD。这笔资助将通过以下具体目标剖析 NOD.ABD CD8 细胞致病性增强的免疫学基础，以及 NOD.Abd3 Tregs 的保护能力：目标#1。 CD8+ T细胞介导的自身免疫性胆道疾病的机制。我们已经证明，NOD.ABD（而非 NOD）CD8+ T 细胞足以将胆道病理转移至 ABD-scid 受体。这一目标通过以下方式剖析 CD8+ T 细胞介导的疾病的主要机制：1) 转移和骨髓嵌合研究； 2) 对 NOD.ABD 小鼠中 CD8+ T 细胞标志物表达的详尽分析； 3) 对体外和过继转移后体内 CD8+ T 细胞细胞因子表达进行彻底分析。目标#2。肝内 NOD.ABD CD8 T 细胞的 T 辅助依赖性和抗原特异性。这一目标将解决两个主要问题：1）NOD CD8 T 细胞反应是 CD4+ T 细胞依赖性的还是独立的？ 2）肝内CD8 T细胞抗原是否具有特异性？我们将通过研究有或没有 CD4 或 CD8 细胞的 ABD、限制 CD8+ T 细胞库并评估对疾病的影响来测试这些问题。目标#3：T 调节细胞在 ABD 中的作用。我们已经证明，在我们的过继转移模型中，NOD.Abd3 脾 Tregs 的共同转移可以预防疾病。为什么 NOD.Abd3 Tregs 不能预防体内自发性疾病？我们将详尽地研究肝脏与外周 Tregs 的表型，并通过转移和耗竭研究来证明 Tregs 在 ABD 中的功能作用。这些研究非常重要，因为它们将使我们能够研究免疫介导的胆道损伤的机制，而以前由于缺乏自发的疾病动物模型而无法研究这些机制。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学和治疗的新假设。