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. 项目总结/摘要 免疫细胞对 TGFβ 的免疫调节和耐受作用产生抗性的发展具有重要意义。 在自身炎症性疾病（包括炎症性肠病）的发病机制中至关重要 （IBD）。虽然大多数努力都致力于了解细胞中的这种抵抗力 适应性免疫系统中，先天免疫细胞中尚未描述类似的现象。粘膜 树突状细胞 (DC) 在免疫和耐受性以及发病机制中发挥着至关重要的作用 自身免疫性疾病，包括 IBD。我们提供了新的证据表明 DC 激活会导致 TGFβ 耐药性的发展，并确定了这种现象的两个假定介质 – IL15/IL15Rα 复合物和 DAB2 蛋白。我们开发了一种模拟 DC 特异性 TGFβ 耐药性的小鼠模型 （TGFbR2ΔDC 小鼠），其中我们展示了胃肠道自动反应形式的严重后果 炎症性疾病。 CD4+ 和 CD8+ T 细胞都是 TGFbR2ΔDC 结肠炎发病机制所必需的 小鼠，伴随着调节性 T 细胞区室（Treg；CD4+CD25-FoxP3+ 的扩展）的改变 Tregs 和 CD8+CD103+ Tregs 的减少）。凭借开发的小鼠模型和分子工具，我们将 提出这样的假设：炎症和/或感染性损伤导致 DC 激活，从而导致 IL15/IL15Rα复合物的表达和Dab2的下调导致TGFβ抵抗 树突状细胞，一种导致 Treg 发育和功能受损的现象， 慢性肠道炎症的建立。我们建议在以下内容中解决这个假设 三个具体目标：(1) 定义受难治性 TGFβ 影响的肠道 DC 的主要亚群 肠道炎症期间的反应； (2) 表征耐火材料的机理 活化 DC 中对 TGFβ 的反应； (3) 定义CD4+和CD8+的表型和功能损伤 由于树突状细胞中 TGFβ 耐药性而产生的 Treg 表型和功能。我们的工作 将解决生理学和临床上重要但尚未探索的 TGFβ 耐药现象 由活化的树突状细胞获得。它将确定负责的分子和细胞机制，并且 描述在自身炎症性疾病的背景下这种抵抗的后果。