Mechanistically based therapeutic strategies in murine primary biliary cholangitis

小鼠原发性胆汁性胆管炎的机制治疗策略

基本信息

批准号：
10337052
负责人：
MERRILL E GERSHWIN
金额：
$ 39.74万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-10 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337052
关键词：
3&apos Untranslated Regions Acetates Address Amylose Animal Model Antibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Bile Acids Biology Butyrates CCR6 gene CXCR3 gene Cell Compartmentation Cells Cholangitis Coin Collaborations Colon Complement Data Defect Development Diabetes Mellitus Diet Disease Elements Enzymes Epigenetic Process Excision Female Fibrosis Future Genes Goals Hepatology Histones Human Immune Immune Tolerance Immunology Inbred NOD Mice Individual Inflammation Interferon Receptor Interferon Type I Interferons Interleukin-12 Lead Link Liver Liver diseases Maize Mediating Modeling Molecular Biology Monoclonal Antibodies Mus Natural History Paper Pathogenicity Pathology Pathway Analysis Pathway interactions Persons Pilot Projects Play Portal vein structure Prevention Primary biliary cirrhosis Pruritus Publishing Receptor Signaling Refractory Regulation Regulatory T-Lymphocyte Resources Role Severity of illness Sex Bias Signal Pathway Signal Transduction Starch Structure of germinal center of lymph node TLR7 gene Therapeutic United States National Institutes of Health Volatile Fatty Acids Work X Chromosome X Inactivation alternative treatment autoreactive B cell autoreactivity base comparative efficacy dietary editorial experience genome wide association study gut microbiome gut microbiota immunoregulation inhibitor innovation metabolomics molecular pathology multidisciplinary novel strategies prevent restoration small molecule treatment response treatment strategy

项目摘要

Summary The treatment of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases. We propose to challenge this void with our multidisciplinary team with expertise in metabolomics, immunology, molecular biology and pathology. We submit that our use of ARE–/– mice are a powerful new model as mice recapitulate human PBC with female predominance, AMAs, portal inflammation, increased total bile acids, itching, fibrosis and elevated female expression of type I interferon (IFN), required for TLR7 mediated function. We will first propose an entirely new approach to treat autoimmunity, in which depletion of pathogenic immune cells in combination with gut microbiome metabolite therapy restores tolerance. Autoimmune liver diseases are ideal for such therapies because the liver is situated upstream from the colon. Indeed, if pathogenic cell removal, followed by tolerogenic diets work in PBC (our Aim 1), it should lead to trials in other autoimmune diseases. Th1 or Th17 cell removal is a radical new approach, and it is important to complement this with understanding of individual Th1 or Th17/Tfh/germinal centre pathway molecules, to understand whether Th1 or Th17 biology underpins PBC. We will address pathway involvement by downregulating effector function by modulating TLR7 and altering germinal center function (Aim 2) and/or directly addressing IFN receptor signaling (Aim 3). These goals are based on our data, and unique resources that directly target the mechanisms of autoimmune cholangitis. Our group has a wealth of published/unpublished data including extensive experience in modulating autoimmunity by diet and metabolites. Hence our three goals are firstly to eliminate pathogenic cells through antibody depletion of Th1 (CXCR3 mAb), or Th17 and Tfh (CCR6 mAb), followed by immune restoration/regulation with beneficial bacterial metabolites that boost Tregs and promote tolerance. This step involves use of HAMS (high amylose maize starch) diets that produce very large amounts of gut butyrate or acetate. This approach has worked spectacularly well in our hands for diabetes in the NOD mouse. Our second goal is to modulate TLR7, critical for GC formation, and prevent disease in female ARE–/– mice; TLR7 is highly expressed in female ARE–/– mice. These data may lead to future opportunities using small molecules that target TLR7 signaling. In our third and final aim we propose that inhibition of type I IFN receptor signaling will be therapeutic. We know that deletion of the type I IFN receptor in ARE–/– mice reduces disease severity. Thus, we will block the IFN receptor with a mAb and JAK/STAT signaling with a JAK inhibitor. Collectively we submit that this proposal is innovative, likely to lead to better therapeutic approaches, and has importance not only in PBC but generically in other autoimmune diseases.

概括原发性胆管炎（PBC）的治疗落后于其他自身免疫性疾病。我们建议与我们的多学科团队一起挑战这一空白，具有代谢组学，免疫学，分子的专业知识生物学和病理学。我们认为，随着小鼠的概括女性PBC具有女性占主导地位，AMA，门户注射，总胆汁酸增加，瘙痒，纤维化 TLR7介导的功能所需的I型干扰素（IFN）的女性表达升高。我们将首先提案是一种全新的治疗自身免疫性的方法，其中致病性免疫细胞耗尽与肠道微生物组代谢物治疗结合恢复了公差。自身免疫性肝病是理想的选择这种疗法是因为肝脏位于结肠上游。确实，如果去除病原细胞，则遵循通过PBC的耐受性饮食（我们的目标1），应导致其他自身免疫性疾病的试验。 Th1或Th17 切除细胞是一种根本的新方法，重要的是要了解个人 TH1或TH17/TFH/生发中心途径分子，以了解Th1或Th17生物学的基础 PBC。我们将通过调制TLR7并更改来解决途径参与，通过下调效应子功能生发中心功能（AIM 2）和/或直接解决IFN受体信号传导（AIM 3）。这些目标是基于我们的数据以及直接针对自身免疫性胆管炎机制的独特资源。我们的集团拥有大量已发表/未发表的数据，包括在调节自身免疫方面的丰富经验通过饮食和代谢产物。因此，我们的三个目标首先是通过抗体部署消除致病细胞的 TH1（CXCR3 mAb）或Th17和TFH（CCR6 mAb）的属构成，然后进行免疫修复/调节，有益细菌代谢产物，可提高Treg并促进耐受性。此步骤涉及使用火腿（高直链淀粉）玉米淀粉）饮食可产生大量的肠道丁酸或醋酸盐。这种方法有效在我们手中，在点头小鼠的糖尿病手中非常好。我们的第二个目标是调节TLR7，对 GC形成并预防雌性的疾病是 - / - 小鼠； TLR7在雌性中高度表达 - / - 小鼠。这些数据可能会使用针对TLR7信号传导的小分子导致未来的机会。在我们的第三和最终目标我们建议抑制I型IFN受体信号传导将是理论。我们知道删除的 I型IFN受体是 - / - 小鼠降低了疾病的严重程度。那，我们将用mAb阻止IFN受体和JAK抑制剂的JAK/STAT信号。我们共同提出，该提议具有创新性，可能会领导更好的治疗方法，不仅在PBC中，而且在其他自身免疫性中都具有重要意义疾病。