dnTGF Beta RII Mice and PBC

dnTGF Beta RII 小鼠和 PBC

基本信息

批准号：
8749065
负责人：
MERRILL E GERSHWIN
金额：
$ 51.63万
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：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8749065
关键词：
Address Anabolism Antibodies Area Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocyte Epitopes Belief Bile fluid Biliary Biogenesis Bone Marrow CD8B1 gene Cells Cholangitis Chronic Clinical Data Detection Disease Dissection Dominant-Negative Mutation Down-Regulation Effector Cell Epithelium Event Fibrosis Funding Genes Goals Grant Human Immune Immune response In Vitro Inflammation Inflammatory Interleukin-17 Kupffer Cells Laboratories Lead Learning Liver Liver Fibrosis Liver diseases Lymphocytic Infiltrate Mediating Methods MicroRNAs Mitochondria Modeling Molecular Monitor Mus Mutant Strains Mice Pathogenicity Pathologic Pathology Pathway interactions Patients Penetrance Phase Phenotype Play Population Primary biliary cirrhosis Procollagen-Proline Dioxygenase Production Proteins Publishing Regulation Regulatory T-Lymphocyte Role Sclerosing Cholangitis Self Tolerance Signal Pathway Signal Transduction Source Staging Symptoms T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Intervention Transgenic Organisms Translating Up-Regulation Wild Type Mouse base bile duct biliary tract cell injury cytokine immunopathology in vivo insight interleukin-12 subunit p35 interleukin-22 mouse model novel pre-clinical promoter public health relevance receptor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Primary biliary cirrhosis (PBC) is a biliary specific autoimmune disease characterized by lymphocytic infiltrates of portal tracts, anti-mitochondrial antibodies (AMAs) and selected destruction of the biliary epithelium. Although PBC is often considered a model autoimmune disease and there have been significant advances in defining the late stage autoimmune effectors (autoantibodies, T cells, and B/T autoepitopes) in PBC patients, such data has not been translated to new therapies. There is an extended silent preclinical phase in human PBC and, as such, the earliest events that lead to biliary damage are largely unknown. This gap between onset and clinical symptoms has frustrated efforts to understand the events that lead to breach of self-tolerance. Our laboratories will take advantage of a unique murine model of PBC, mice that express a dominant-negative TGF-? receptor II gene under control of the promoter for CD4 (dnTGF-?RII). These mice develop a robust inflammatory biliary disease and 100% penetrance of AMAs. Our progress during the current period of funding has led to important, novel and in some cases surprising results that allow us to address three critical areas that have the potential to define the immunopathology leading to breach of tolerance, cholangitis and hepatic fibrosis. First, CD8 T cells mediate biliary pathology and, more importantly, the KLRG1+ effector CD8 T cell subset accumulates in the liver, but only in the presence of defective dnTGF-?RII Tregs. Our goal will be to define the KLRG1+ phenotype, its ability to transfer disease, and the mechanism of Treg-mediated control of this critical cell subset. Second, we have shown that deletion of IL-12p35 in dnTGF-?RII mice leads not only to portal inflammation and bile duct damage, but also to fibrosis with a distinct cytokine profile. We will take advantage of this observation and serially monitor these events to define the sources of pathologic cytokines in the course of dysfunctional TGF-? signaling as well as define how IL-17 signaling is cross-regulated by cytokines in the course of a chronic immune response by taking advantage of transgenic dnTGF-?RII mice that lack IL-17A, IL-17F, IL-22, IL- 23p19 or IL-17RA in addition to unique bone marrow chimeric mouse models. Finally, our published data show that microRNA dysregulation plays a major role in autoreactive CD8 T cell mediated biliary pathology. Our existing models and novel proposed methods will allow us to correct this dysregulation and to test the effect of corrected miRNA biosynthesis on T cell activation status, and, more importantly, on immunopathology. We submit that the results of this proposal will provide insight into the mechanisms of action of CD8 effector mediated damage, will provide the opportunity to develop a biologic network of the earliest immune mediated fibrotic events and finally critical mechanistic information on the role of micro- RNA in autoimmune cholangitis. Importantly, we believe these data will potentially identify new pathways for therapeutic targeting.

描述（由申请人提供）：原发性胆汁肝硬化（PBC）是一种胆道特异性的自身免疫性疾病，其特征是门户区域的淋巴细胞浸润，抗中性抗体（AMAS）和胆汁上皮的选定破坏。尽管PBC通常被认为是一种模型自身免疫性疾病，并且在定义PBC患者的晚期自身免疫性效应子（自身抗体，T细胞和B/T自动放量）方面取得了重大进展，但此类数据尚未转化为新疗法。在人类PBC中存在一个扩展的无声临床前阶段，因此，导致胆道损伤的最早事件在很大程度上是未知的。发作和临床症状之间的这种差距使人们沮丧地努力了解导致违反自我耐受的事件。我们的实验室将利用一种独特的PBC鼠模型，即表达主导性阴性TGF-的小鼠？受体II基因在CD4启动子（DNTGF-？rii）的控制下。这些小鼠会出现强大的炎症性胆道疾病和AMA的100％渗透率。我们在当前资金期间的进步导致了重要的，新颖的和在某些情况下令人惊讶的结果，这使我们能够解决有可能定义免疫病理学的三个关键领域，从而违反了耐受性，胆管炎和肝纤维化。首先，CD8 T细胞介导胆道病理学而且，更重要的是，KLRG1+效应子CD8 T细胞子集积累在肝脏中，但仅在存在有缺陷的DNTGF-？RII Treg的情况下。我们的目标是定义KLRG1+表型，转移疾病的能力以及Treg介导的该关键细胞子集的控制机制。其次，我们已经证明了dntgf-？rii小鼠中IL-12p35的删除不仅导致门户炎症和胆管损伤，而且还导致纤维化具有独特的细胞因子轮廓。我们将利用这一观察结果并串行监测这些事件，以定义功能障碍TGF-的病理细胞因子来源？信号传导以及在慢性免疫反应过程中如何通过利用缺乏IL-17A，IL-17F，IL-22，IL-22，IL-23p19或IL-17RA的转基因DNTGF-？RII小鼠来定义IL-17信号传导如何被细胞因子交叉调节。最后，我们发表的数据表明，microRNA失调在自动反应性CD8 T细胞介导的胆道病理学中起主要作用。我们现有的模型和新颖的方法将使我们能够纠正这种失调，并测试校正的miRNA生物合成对T细胞激活状态的影响，更重要的是，对免疫病理学的影响。我们认为，该提案的结果将洞悉CD8效应介导的损伤的作用机理，将为开发最早的免疫介导的纤维化事件的生物网络提供机会，最后关于微RNA在自身免疫性胆管炎中的作用的关键机理信息。重要的是，我们认为这些数据可能会确定用于治疗靶向的新途径。