INNATE AND ADAPTIVE IMMUNITY IN IBD

IBD 的先天免疫和适应性免疫

基本信息

批准号：
8545796
负责人：
CHARLES O ELSON
金额：
$ 122.5万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-10 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8545796
关键词：
Address Adjuvant Affect American Anaerobic Bacteria Animal Model Antibiotics Antibodies Antigens Aryl Hydrocarbon Receptor Autoantigens Autoimmune Diseases Autoimmunity Automobile Driving B-Lymphocytes Bacteria Biological Models Biology CD4 Positive T Lymphocytes Cataloging Catalogs Cells Chronic Disease Colitis Communities Complex Crohn&apos s disease Data Defect Dendritic Cells Development Diagnostic Disease Disease remission Disease susceptibility Effector Cell Elements Enteral Epithelial Epithelial Cells Epithelium Experimental Animal Model Experimental Models Family Flagellin Gene Expression Gene Mutation Genes Genetic Genetic Variation Goals Head Health Health Care Costs Homeostasis Host resistance Human Human Microbiome IL2RA gene Immune Immune response Immune system Immunoglobulin G Individual Induced Mutation Infection Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Interleukin-10 Interleukin-17 Interleukin-2 Intestines Knock-out Lamina Propria Lead Learning Link Literature Los Angeles Maintenance Mediating Medical center Membrane Memory Metabolism Microbe Modeling Molecular Morbidity - disease rate Mouse Strains Mucosal Immunity Mucous Membrane Multi-Drug Resistance Mus Mutant Strains Mice Natural History Natural Immunity Nervous system structure Organ Participant Pathogenesis Pathologic Pathway interactions Patients Pattern recognition receptor Phase Play Predisposition Production Pump Regulation Regulatory T-Lymphocyte Reporter Reporting Research Robin bird Role Serological Shapes Staging Susceptibility Gene T-Lymphocyte T-Lymphocyte Subsets TGFB1 gene Techniques Technology Testing Therapeutic Tissues Toll-like receptors Tretinoin Ulcerative Colitis United States United States National Institutes of Health Variant Vascular System Work Xenobiotics adaptive immunity base cell type chemokine cost cytokine emergency service responder expression cloning genetic profiling genome wide association study improved insight interest interleukin-22 interleukin-23 intestinal homeostasis macrophage microbial microbiome novel pathogen patient population programs prototype receptor response sensor tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): The inflammatory bowel diseases (IBD) involve complex abnormalities in the innate and adaptive immune response to the Intestinal microbiota. Data from experimental models has found that CD4 T cells are the effector cells mediating disease in most instances, that the enteric bacterial flora drives this pathologic response, and that the innate immune system (epithelium, dendritic cells, macrophages) is a critical link between these two elements. Thus, the major focus of this Program Project is on the interaction of the innate and adaptive immune responses with the microbiota and its products and on the genes that affect these interactions. The Program Project will be directed by Dr. Charles Elson and will consist of four Projects and two Cores. Project 1, headed by Dr. Elson, will use flagellins as probes of the normal T cell homeostatic response in the intestine. Studies will address the hypothesis that CD4 T cell effector subsets in the intestine maintain homeostasis by a number of different pathways that can compensate for one another, that these pathways have limits beyond which intestinal inflammation results, and that homeostasis can be restored by augmentation of regulatory T cells. Project 2, headed by Dr. Robin Lorenz, will use the mdr1a knockout model to address the hypothesis that the absence of the mdr1a encoded membrane pump leads to dysfunctional handling of xenobiotics, which results in abnormal development and function in cell types that express the aryl hydrocarbon receptor resulting in spontaneous. Project 3 will be headed by Dr. Casey Weaver who will continue his studies on Th17 cells in the intestine and their role in IBD and will use novel cytokine reporter and other mutant mouse lines to test the hypothesis that Th17 and "Th1-like" cells cooperate to sustain intestinal inflammation to intestinal microbiota antigens in IBD, that both cell types emerge from a common early Th17 developmental pathway, and that IL-23-dependent memory Th17 cells are required for sustained IBD pathogenesis. Project 4 is led by Dr. Stephan Targan at Cedars-Sinai Medical Center in Los Angeles, CA. This Project will continue to utilize a large panel of patient materials to define the Innate and adaptive Immune response in patients with Crohn's disease who have seroreactivity to CBir1 flagellins to test the hypothesis that immune response to CBIr1 flagellin defines a population of patients with genetic variations of the IL-23, IL-17, and IL-22 pathways, as well as variations in TL1A gene expression, resulting In a severe disease course in IBD. These Projects will be supported by an Administrative Core which will provide administrative support and coordination, and an Animal Model Core at U.A.B. which will centralize the production of mice with experimental colitis, provide for a central pathologic analysis, and generate stocks of genetically-modified stocks of mice for use in the Projects. The long-term goal is to increase our understanding of the fundamental mechanisms of IBD in order to develop better diagnostic and therapeutic strategies for patients.

描述（由申请人提供）：炎症性肠病（IBD）涉及对肠道微生物群的先天性和适应性免疫反应的复杂异常。来自实验模型的数据发现，在大多数情况下，CD4 T 细胞是介导疾病的效应细胞，肠道菌群驱动这种病理反应，而先天免疫系统（上皮细胞、树突状细胞、巨噬细胞）是这些细胞之间的关键联系。两个要素。因此，该计划项目的主要重点是先天性和适应性免疫反应与微生物群及其产物的相互作用，以及影响这些相互作用的基因。该计划项目将由 Charles Elson 博士指导，由四个项目和两个核心组成。由 Elson 博士领导的项目 1 将使用鞭毛蛋白作为肠道中正常 T 细胞稳态反应的探针。研究将提出这样一种假设：肠道中的 CD4 T 细胞效应子亚群通过许多可以相互补偿的不同途径维持体内平衡，这些途径有限制，超过这些限制就会导致肠道炎症，并且可以通过增强调节性来恢复体内平衡。 T 细胞。由 Robin Lorenz 博士领导的项目 2 将使用 mdr1a 敲除模型来解决以下假设：mdr1a 编码膜泵的缺失会导致外源物质处理功能障碍，从而导致表达芳基的细胞类型发育和功能异常碳氢化合物受体产生自发性。项目 3 将由 Casey Weaver 博士领导，他将继续研究肠道中的 Th17 细胞及其在 IBD 中的作用，并将使用新型细胞因子报告基因和其他突变小鼠系来检验 Th17 和“Th1 样”细胞的假设IBD 中肠道微生物群抗原协同维持肠道炎症，这两种细胞类型均来自共同的早期 Th17 发育途径，并且 IL-23 依赖性记忆 Th17 细胞是持续 IBD 所必需的发病机制。项目 4 由加利福尼亚州洛杉矶 Cedars-Sinai 医疗中心的 Stephan Targan 博士领导。该项目将继续利用大量患者材料来定义对 CBir1 鞭毛蛋白有血清反应性的克罗恩病患者的先天性和适应性免疫反应，以检验对 CBIr1 鞭毛蛋白的免疫反应定义了具有以下遗传变异的患者群体的假设： IL-23、IL-17 和 IL-22 通路以及 TL1A 基因表达的变异，导致 IBD 的严重病程。这些项目将得到提供行政支持和协调的行政核心以及 U.A.B. 的动物模型核心的支持。它将集中生产患有实验性结肠炎的小鼠，提供中央病理分析，并产生用于项目的转基因小鼠库存。长期目标是增加我们对 IBD 基本机制的了解，以便为患者制定更好的诊断和治疗策略。