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Mechanism of autoimmune hepatitis development in a novel mouse model

新型小鼠模型中自身免疫性肝炎发生的机制

基本信息

批准号：
9516717
负责人：
KONSTANTINA ALEXANDROPOULOS
金额：
$ 38.03万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-20 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9516717
关键词：
Affinity Alleles Animals Antibiotic Therapy Antibiotics Antibodies Antigen Presentation Antigen Targeting Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Hepatitis Autoimmune Responses Autoimmunity Bacteria Binding CCR9 gene CD4 Positive T Lymphocytes Cell Adhesion Molecules Clinical Data Development Disease Endothelial Cells Etiology Exhibits Functional disorder Germ-Free Gnotobiotic HLA Antigens Hepatitis Histologic Histopathology Home environment Homing Human Human Characteristics Immune Immune response Immunize Immunodeficient Mouse Immunoglobulins Immunologics Impairment In Vitro Infiltration Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Infiltrate Inflammatory Response Interphase Knockout Mice Lead Liver Liver diseases Lobular Maintenance Major Histocompatibility Complex Mediating Methods Modeling Mucous Membrane Mus Pathogenesis Pathology Patients Peripheral Plasma Cells Play Population Predisposition Primary biliary cirrhosis Process Production Proteins Regulatory T-Lymphocyte Relapse Role Self Tolerance Sequence Homology Steroids Stromal Cells Structure of thymic cortex Surface Symptoms T-Cell Activation T-Lymphocyte T-cell diversity Testing Thymic epithelial cell Thymus Gland Time Tissues To autoantigen Up-Regulation autoreactive T cell base cellular targeting central tolerance chemokine experimental study gut microbiota insight intrahepatic knockout animal liver inflammation liver transplantation microbial microbiota microbiota profiles mouse model normal microbiota novel novel therapeutics peripheral tolerance primary sclerosing cholangitis receptor recruit response screening thymocyte ubiquitin ligase

项目摘要

SUMMARY. Autoimmune hepatitis (AIH) is an inflammatory liver disease of unknown etiology. The inflammatory response is thought to be orchestrated by CD4+ T lymphocytes recognizing liver self- antigens. The identification of susceptibility HLA-DRB1 (*0401 and *0301) alleles within the human leukocyte antigen (HLA) region suggested that faulty antigen presentation by these alleles and ensuing T cell activation may play a role in the pathogenesis of AIH. We recently generated a mouse model, Traf6TEC, displaying impaired antigen presentation in the thymus due to depletion of medullary thymic epithelial cells (mTECs). Expression of tissue restricted antigens (TRAs) by mTECs and presentation of these self-antigens to developing thymocytes leads to elimination of autoreactive T cells and suppression of autoimmunity. Conditional depletion of mTECs in Traf6TEC mice associated with spontaneous development of autoimmune hepatitis (AIH) that recapitulated the known histopathological and immunological hallmarks of human AIH. More recently we found that antibiotic treatment reduced AIH histopathology in Traf6TEC mice implicating the gut microbiota in AIH development. We also found increased production of regulatory T cells and T cells expressing the gut-homing receptors 47 and CCR9 in the gut and liver of Traf6TEC mice accompanied by increased expression of endothelial-cell adhesion molecules and chemokines in the liver. These results establish a connection between the gut microbiota and development of AIH in this mouse model and additionally recapitulate similar evidence observed in the clinical setting of other liver autoimmune diseases. Based on our results to date, we propose the following hypothesis: mTEC depletion leads to production of autoreactive T cells that home to the liver and initiate inflammation through aberrant recognition of liver self-antigens. Changes in the microbiota of knockout animals lead to increased production of mucosal T cells that circulate to the liver and exacerbate AIH. To examine this hypothesis we will: 1) Determine the contributions of autoreactive T cells vs. the gut microbiota in AIH development/maintenance and identify liver self-antigens targeted by autoreactive T cells; 2) Elucidate the mechanism of gut-mediated induction and/or exacerbation of AIH; and 3) Define the microbiota profile of Traf6TEC and how it differs from normal microbiota and identify a signature/bacterial species that associate with AIH pathology. Elucidation of the mechanisms that regulate of AIH development may lead to much-needed novel therapeutic strategies to better manage and perhaps treat this disease. These experiments may also define a common mechanism underling the development of other liver autoimmune diseases irrespective of their ultimate cellular targets.

总结。自身免疫性肝炎（AIH）是一种病因不明的炎症性肝病。的