INNATE AND ADAPTIVE IMMUNITY IN IBD

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应答的复杂异常。来自实验模型的数据已经发现，在大多数情况下，CD 4 T细胞是介导疾病的效应细胞，肠道细菌植物群驱动这种病理反应，并且先天免疫系统（上皮细胞、树突细胞、巨噬细胞）是这两种元素之间的关键联系。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。该计划项目将由查尔斯·埃尔森博士指导，将包括四个项目和两个核心。由Elson博士领导的项目1将使用鞭毛蛋白作为肠道正常T细胞稳态反应的探针。研究将解决以下假设：肠道中的CD 4 T细胞效应子亚群通过许多不同的途径维持稳态，这些途径可以相互补偿，这些途径具有超出肠道炎症结果的限制，并且稳态可以通过增强调节性T细胞来恢复。由Robin Lorenz博士领导的项目2将使用mdr 1a敲除模型来解决以下假设：mdr 1a编码的膜泵的缺失导致外源性物质的功能障碍，这导致表达芳香烃受体的细胞类型的发育和功能异常，从而导致自发性。项目3将由凯西韦弗博士领导，他将继续研究肠道中的Th 17细胞及其在IBD中的作用，并将使用新的细胞因子报告基因和其他突变小鼠系来测试以下假设：Th 17和“Th 1样”细胞合作维持IBD中肠道微生物群抗原的肠道炎症，这两种细胞类型来自共同的早期Th 17发育途径，IL-23依赖性记忆Th 17细胞是持续IBD发病所必需的。项目4由加州洛杉矶Cedars-Sinai医疗中心的Stephan Targan博士领导。本项目将继续利用大量患者材料来确定对CBir 1鞭毛蛋白具有血清反应性的克罗恩病患者的先天性和适应性免疫应答，以检验对CBIr 1鞭毛蛋白的免疫应答定义了具有IL-23、IL-17和IL-22途径遗传变异以及TL 1A基因表达变异的患者群体的假设，导致IBD的严重病程。这些项目将由一个提供行政支持和协调的行政核心和一个位于U.A.B.的动物模型核心提供支持。这将集中生产实验性结肠炎小鼠，提供中央病理分析，并产生用于项目的转基因小鼠种群。长期目标是增加我们对IBD基本机制的理解，以便为患者制定更好的诊断和治疗策略。

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.