Immunogenetic control of autoimmune biliary disease

自身免疫性胆道疾病的免疫遗传学控制

• 批准号: 10265581
• 负责人: William M Ridgway
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265581
• 关键词: Affect; Age; Alcoholic Hepatitis; Animal Disease Models; Animal Model; Antibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Biliary; Biliary Atresia; Biology; Cellular Immunity; Characteristics; Cholangitis; Chromosome 1; Clinic Visits; Clinical; Common bile duct structure; Complement; Complex; Congenic Mice; DNA Sequence Alteration; Data; Development; Disease; Down-Regulation; Event; Genetic; Genetic Predisposition to Disease; Goals; Grant; Granuloma; Hepatic; Hepatitis C; Human; Human Characteristics; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunogenetics; Immunotherapeutic agent; Immunotherapy; Inflammation; Innate Immune System; Insulin-Dependent Diabetes Mellitus; Intrahepatic bile duct; Liver; Liver Failure; Liver diseases; Mediating; Medical; Mission; Mitochondria; Modeling; Mouse Strains; Mus; Mutate; Myeloid-derived suppressor cells; Onset of illness; Organ; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Play; Primary biliary cirrhosis; Reaction; Regulator Genes; Rheumatoid Arthritis; Role; S100A9 gene; Sampling; Science; Sjogren' s Syndrome; Specimen; Symptoms; System; T-Lymphocyte; TNF gene; Testing; Thyroiditis; Time; Tissues; Tumor-infiltrating immune cells; Veterans; autoreactive T cell; base; bile duct; cholangiocyte; congenic; genetic approach; human disease; immunopathology; insight; liver inflammation; liver transplantation; macrophage; military veteran; mouse model; new therapeutic target; novel; novel therapeutics; polycystic liver disease; primary sclerosing cholangitis

Primary biliary cholangitis (PBC) is an incurable autoimmune biliary disease (“ABD”) in which the immune system destroys bile ducts by targeting cholangiocytes. Many immune based therapies have been applied to PBC, but none have been successful and the disease is currently incurable. Progress in finding new therapies for PBC has been blocked because the clinical symptoms of disease often arise many years after initiation of disease; thus data derived from human patients has not permitted fundamental insights into the immunopathogenesis of the disease. Fundamental new insights that can generate new therapeutic targets require information about the earliest pathogenesis of PBC, which must come from animal models of disease. We developed the first spontaneous animal model of PBC: NOD.ABD mice that develop autoimmune biliary disease remarkably similar to human including 1) anti-mitochondrial antibodies highly specific for human PBC; 2) disease transferable by autoreactive T cells; and 3) immunohistopathology highly characteristic of PBC with granuloma formation, T cell infiltrates in the biliary lining, and destructive cholangitis. Recently we discovered a novel genetic mutation in NOD ABD. Understanding how this novel genetic system controls the aberrant cholangiocyte: immune system interaction which drives ABD is the goal of the current grant. Here we have constructed a novel congenic mouse (NOD.Abd3) that allows us to mechanistically analyze the very earliest basis of disease. We also show that a genetic background which enhances autoimmunity (the NOD genetic background, which predisposes to many autoimmune conditions including T1D, Sjogren’s syndrome, and thyroiditis) must be present. This complex genetic etiology is similar to human disease. Therefore our unique model offers new insights into basic immunopathology relevant to human PBC and other cholangiopathies. We propose 3 aims: Aim 1: Determine the genetic basis of NOD autoimmune biliary disease. We show that disease in congenic NOD.Abd3 mice requires a region on chromosome 1, “Abd3”, which includes a 1.0 Mb B6 interval (“B6-Abd3”) as well as mutated Pkhd1del36-67 upstream of it. Our hypothesis is that early expression of aberrant Pkhd1 in cholangiocytes breaks immune tolerance to cholangiocytes. We can prove/disprove this hypothesis by sophisticated genetic approaches. Aim 2: Determine the role of early cholangiocyte “ductular reaction” in NOD.Abd3 pathogenesis. By 4 weeks of age, NOD.Abd3 bile ducts show massive immune infiltration which then ascends into intrahepatic bile ducts. Our hypothesis is that the aberrant immune response is due to an early “ductular reaction” of NOD.Abd3 cholangiocytes, which stimulates the innate immune system. Aim 3: Mechanistic role of myeloid derived suppressor cells (MDSCs) and activated macrophages in NOD.Abd3 and human PBC pathogenesis. The immune system is required for clinical ABD in our model. We hypothesize that the Abd3 genetic region alters macrophage function/subset ratios. We will test the role of macrophages in both murine disease and human PBC liver samples. These studies are relevant to specific, incurable biliary diseases that affect Veterans, and are also important due to the central role hepatic immunity/inflammation plays in many liver diseases (e.g. alcoholic hepatitis, hepatitis C) that are common in Veteran populations. Our studies will produce insights into the basic biology of autoimmune cholangitis and liver inflammation/tolerance, and identify new therapeutic targets for these intractable conditions.

原发性胆汁性胆管炎（PBC）是一种无法治愈的自身免疫性胆道疾病（“ABD”），其中 免疫系统通过针对胆管细胞来破坏胆管。许多基于免疫的 已经对 PBC 进行了治疗，但没有成功，该疾病正在 目前无法治愈。寻找 PBC 新疗法的进展一直受阻，因为 疾病的临床症状通常在发病多年后出现；由此得出数据 来自人类患者的研究尚未允许对免疫发病机制有基本的了解 这种疾病。可以产生新治疗靶点的基本新见解需要 有关PBC最早发病机制的信息，必须来自于动物模型 疾病。我们开发了第一个自发性 PBC 动物模型：NOD.ABD 小鼠 发展出与人类非常相似的自身免疫性胆道疾病，包括 1) 抗线粒体疾病 对人类 PBC 具有高度特异性的抗体； 2）可通过自身反应性T细胞转移的疾病；和 3) 免疫组织病理学具有 PBC 的高度特征，伴有肉芽肿形成、T 细胞浸润 胆道内壁和破坏性胆管炎。最近我们发现了一种新的基因突变 在NOD ABD。了解这种新颖的遗传系统如何控制异常胆管细胞： 驱动 ABD 的免疫系统相互作用是当前资助的目标。在这里我们有 构建了一种新型同源小鼠（NOD.Abd3），它使我们能够机械地分析 疾病的最早基础。我们还表明，遗传背景可以增强 自身免疫（NOD 遗传背景，易导致许多自身免疫性疾病 必须存在 T1D、干燥综合征和甲状腺炎等疾病。这个综合体 遗传病因与人类疾病相似。因此，我们独特的模型提供了新的见解 深入了解与人类 PBC 和其他胆管病相关的基础免疫病理学。我们建议3 目的： 目标 1：确定 NOD 自身免疫性胆道疾病的遗传基础。我们展示 同源 NOD.Abd3 小鼠的疾病需要 1 号染色体上的一个区域“Abd3”，该区域 包括 1.0 Mb B6 间隔（“B6-Abd3”）及其上游突变的 Pkhd1del36-67。我们的 假设胆管细胞中异常 Pkhd1 的早期表达会破坏免疫系统 对胆管细胞的耐受性。我们可以通过复杂的遗传来证明/反驳这个假设 接近。目标 2：确定早期胆管细胞“导管反应”在 NOD.Abd3 发病机制。 4 周龄时，NOD.Abd3 胆管显示出强大的免疫能力 浸润，然后上升至肝内胆管。我们的假设是，异常的 免疫反应是由于 NOD.Abd3 胆管细胞的早期“导管反应”， 刺激先天免疫系统。目标 3：骨髓来源的机制作用 NOD.Abd3 和人 PBC 中的抑制细胞 (MDSC) 和活化巨噬细胞 发病。在我们的模型中，免疫系统是临床 ABD 所必需的。我们假设 Abd3 遗传区域改变巨噬细胞功能/亚群比率。我们将测试角色 小鼠疾病和人类 PBC 肝脏样本中的巨噬细胞。 这些研究与影响退伍军人的特定的、无法治愈的胆道疾病有关，并且是 由于肝免疫/炎症在许多肝脏中发挥着核心作用，因此也很重要 退伍军人中常见的疾病（例如酒精性肝炎、丙型肝炎）。我们的 研究将深入了解自身免疫性胆管炎和肝脏的基本生物学 炎症/耐受性，并确定这些棘手病症的新治疗靶点。