Modulation of dendritic cell function in the pathogenesis of Inflammatory Bowel Diseases

炎症性肠病发病机制中树突状细胞功能的调节

• 批准号: 9349503
• 负责人: Fayez Khalaf Ghishan
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349503
• 关键词: Ablation; Adaptive Immune System; Address; Affect; American; Antigen Presentation; Antigens; Autoimmune Diseases; CD8-Positive T-Lymphocytes; CD8B1 gene; Celiac Disease; Cell Compartmentation; Cell physiology; Cells; Chronic; Clinical; Colitis; Complex; Crohn' s disease; Data; Dendritic Cells; Dendritic cell activation; Development; Dioxygenases; Disabled Homolog 2 Protein; Disabled Persons; Disease; Down-Regulation; Environment; FOXP3 gene; Genetic Predisposition to Disease; IL2RA gene; Immune; Immune Tolerance; Immune response; Immunity; Immunosuppressive Agents; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Innate Immune System; Interleukin-15; Intestines; Lead; Loeys-Dietz Syndrome; Mediating; Mediator of activation protein; Medical; Molecular; Mus; Mutation; Pathogenesis; Pathway interactions; Patients; Phase; Phenotype; Phosphorylation; Physiological; Play; Population; Process; Production; Property; Recurrent disease; Refractory; Regulatory T-Lymphocyte; Reporting; Research; Residencies; Resistance; Resistance development; Role; Shapes; Signal Transduction; Symptoms; System; T-Lymphocyte; TLR3 gene; TLR4 gene; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Ulcerative Colitis; Work; autoinflammatory; commensal microbes; cytokine; flexibility; functional disability; gastrointestinal; immunoregulation; improved; indoleamine; mouse model; novel; oral tolerance; receptor; response; tool

7. Project Summary/Abstract The development of resistance to immunomodulatory and tolerogenic effects of TGFβ in the immune cells is of key importance in the pathogenesis of auto-inflammatory disorders, including Inflammatory Bowel Diseases (IBD). While most effort has been directed towards understanding of such resistance in the cells of the adaptive immune system, similar phenomenon has not yet been described in the innate immune cells. Mucosal dendritic cells (DCs) play a crucial role in both immunity and tolerance, and by extension, in the pathogenesis of autoimmune disorders, including IBD. We provide new evidence to show that DC activation leads to a development of TGFβ resistance, and identify two putative mediators of this phenomenon – IL15/IL15Rα complex and DAB2 protein. We developed a mouse model mimicking DC-specific TGFβ resistance (TGFbR2ΔDC mice) in which we demonstrate severe consequences in form of gastrointestinal auto- inflammatory disorder. Both CD4+ and CD8+ T cells are required for the pathogenesis of colitis in TGFbR2ΔDC mice, which is accompanied with altered regulatory T cell compartment (Treg; expansion of CD4+CD25-FoxP3+ Tregs and reduction of CD8+CD103+ Tregs). With the developed mouse models and molecular tools, we will purse the hypothesis that DC activation by inflammatory and/or infectious insults result in elevated expression of IL15/IL15Rα complexes and downregulation of Dab2 that lead to TGFβ resistance in dendritic cells, a phenomenon resulting in impaired Treg development and function and an establishment of chronic intestinal inflammation. We propose to address this hypothesis in the following three specific aims: (1) To define the primary subset(s) of intestinal DCs affected with refractory TGFβ response during intestinal inflammation; (2) To characterize the mechanism responsible for the refractory response to TGFβ in activated DCs; (3) To define the phenotypic and functional impairment of CD4+ and CD8+ Treg phenotype and function that develops as a consequence of TGFβ resistance in dendritic cells. Our work will address a physiologically and clinically important, yet unexplored, phenomenon of TGFβ resistance acquired by activated dendritic cells. It will identify the molecular and cellular mechanisms responsible, and describe the consequences of such resistance in the context of autoinflammatory disorders.

7。项目摘要/摘要 TGFβ在免疫细胞中对免疫调节和耐受作用的抗性的发展是 自动炎症性疾病的发病机理的关键重要性，包括炎症性肠道疾病 （IBD）。虽然大多数努力是针对理解这种耐药性 自适应免疫系统，在先天免疫细胞中尚未描述类似现象。粘膜 树突状细胞（DC）在免疫和耐受性中都起着至关重要的作用，并扩展在发病机理中 包括IBD在内的自身免疫性疾病。我们提供了新的证据，以表明直流激活导致 TGFβ耐药性的发展，并确定了该现象的两个推定介体 - IL15/IL15Rα 复合和DAB2蛋白。我们开发了一个模拟DC特异性TGFβ电阻的小鼠模型 （TGFBR2ΔDC小鼠），其中我们以胃肠道自身的形式表现出严重的后果 炎症障碍。 CD4+和CD8+ T细胞都是TGFBR2ΔDC中结肠炎的发病机理所必需的 小鼠，伴随着改变的调节T细胞室（Treg； CD4+CD25-Foxp3+的扩展 Tregs和CD8+ CD103+ Tregs的还原）。使用开发的鼠标模型和分子工具，我们将 钱包假说，即通过炎症和/或感染侮辱激活直流导致升高 IL15/IL15Rα复合物的表达和DAB2的下调，导致TGFβ抗性 树突状细胞，这是一种现象，导致Treg发育和功能受损以及 建立慢性肠炎。我们建议在以下内容中解决这一假设 三个特定的目的：（1）定义了由难治性TGFβ影响的肠道DC的主要子集 肠炎期间的反应； （2）表征负责的机制 激活DC中对TGFβ的响应； （3）定义CD4+和CD8+的表型和功能障碍 树突状细胞中TGFβ耐药性而发展的Treg表型和功能。我们的工作 将解决TGFβ抗性的物理和临床上重要但出乎意料的现象 被活化的树突状细胞获取。它将确定负责的分子和细胞机制，以及 描述这种抵抗力在自发性疾病的背景下的后果。