dnTGF Beta RII Mice and PBC

dnTGF Beta RII 小鼠和 PBC

基本信息

批准号：
8909120
负责人：
MERRILL E GERSHWIN
金额：
$ 50.23万
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/8909120
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 Health 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 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 Transforming Growth Factor beta 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 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-ß receptor II gene under control of the promoter for CD4 (dnTGF-ßRII). 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-ßRII 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-ßRII 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-ß 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-ßRII 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）：原发性胆汁性肝硬化（PBC）是一种胆道特异性自身免疫性疾病，其特征是汇管束的淋巴细胞浸润、抗线粒体抗体（AMA）和胆道上皮的选择性破坏，尽管PBC通常被认为是一种自身免疫性疾病。疾病，并且在定义晚期自身免疫效应物（自身抗体、T 细胞和 B/T在 PBC 患者中，此类数据尚未转化为新疗法。人类 PBC 存在较长的无症状临床前阶段，因此，导致胆道损伤的最早事件在很大程度上尚不清楚。我们的实验室将利用一种独特的 PBC 小鼠模型，即在 CD4 启动子控制下表达显性失活 TGF-β 受体 II 基因的小鼠。 (dnTGF-ßRII)。这些小鼠出现了严重的炎症性胆道疾病，并且 AMA 外显率达到 100%。我们在当前资助期间取得的进展带来了重要的、新颖的、在某些情况下令人惊讶的结果，使我们能够解决三个关键领域的问题。有可能定义导致耐受破坏、胆管炎和肝纤维化的免疫病理学，首先，CD8 T 细胞介导胆道病理学，更重要的是，KLRG1+ 效应子。 CD8 T 细胞亚群在肝脏中积累，但仅在存在缺陷的 dnTGF-ßRII Tregs 的情况下进行。我们的目标是定义 KLRG1+ 表型、其转移疾病的能力以及 Treg 介导的对该关键细胞亚群的控制机制。其次，我们已经证明，dnTGF-ßRII 小鼠中 IL-12p35 的缺失不仅会导致门静脉炎症和胆管损伤，还会导致具有独特细胞因子的纤维化我们将利用这一观察结果并连续监测这些事件，以确定功能失调的 TGF-β 信号传导过程中病理性细胞因子的来源，以及确定 IL-17 信号传导在异常过程中如何被细胞因子交叉调节。通过利用除独特骨骼外缺乏 IL-17A、IL-17F、IL-22、IL-23p19 或 IL-17RA 的转基因 dnTGF-ßRII 小鼠的慢性免疫反应最后，我们发表的数据表明，microRNA 失调在自身反应性 CD8 T 细胞介导的胆道病理学中发挥着重要作用，我们现有的模型和新提出的方法将使我们能够纠正这种失调并测试纠正的 miRNA 生物合成的效果。我们认为，该提案的结果将深入了解 CD8 效应器介导的损伤的作用机制，并将提供开发生物网络的机会。最早的免疫介导的纤维化事件以及最终关于微小RNA在自身免疫性胆管炎中的作用的关键机制信息，我们相信这些数据将有可能确定治疗靶向的新途径。