INNATE AND ADAPTIVE MICROBIAL IMMUNITY IN IBD

总体说明 炎症性肠病（IBD）仍然是复杂的疾病，但在过去的十年中，IBD的实验模型已经推进了我们对其发病机制中重要的一些细胞和分子机制的理解。这些模型已经表明，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致病性应答，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，先天性和适应性免疫应答与微生物群及其产物的相互作用是主要焦点。我们已经从微生物、小鼠和人类来源中收集了新的工具、技术和试剂，这些工具、技术和试剂使得要解决的实质性问题和要回答的有趣假设成为可能。在这些资源中有一组免疫显性微生物抗原， 特别是细菌鞭毛蛋白，其已显示在多种小鼠模型和克罗恩病患者亚组中刺激免疫应答。在Charles Elson博士的指导下，我们将使用鞭毛蛋白作为C3 H和B6小鼠对微生物群的先天性和适应性免疫反应的探针，将首次确定对微生物抗原的免疫反应的表位扩散是否发生在IBD中，并与其进展有关，并将确定致病性T细胞在结肠炎小鼠中的位置和方式。 由Robin Lorenz博士领导，我们将使用mdr 1alpha敲除模型来定义宿主上皮细胞和其他先天免疫细胞如何检测和响应微生物群。由凯西韦弗博士领导，我们将使用新的转基因细胞因子报告小鼠系来研究适应性T细胞对微生物群的反应，特别是IL-23与IL-12，IL-17与IFN γ在建立致病性和调节性T细胞反应之间的平衡中的作用。博士领导 位于加利福尼亚州洛杉矶的Cedars-Sinai医学中心的Stephan Targan将领导利用大量患者材料来定义对CBiM鞭毛蛋白有反应的克罗恩病患者的先天性和适应性免疫反应，以及他们的临床表型和基因型，以检验这些患者代表不同患者亚群的假设。这项研究将提供行政支持和协调，并在U.A.B.的动物模型。这将集中生产实验性结肠炎小鼠，提供中央病理学分析，并产生供使用的转基因小鼠的储备。这旨在加速从基础实验室到诊所的信息传输，反之亦然。长期目标是增加我们对IBD的基本机制的理解，以便为患者制定更好的诊断和治疗策略。

DESCRIPTION, OVERALL The inflammatory bowel diseases (IBD) remain complex disorders, but over the past decade experimental models of IBD have advanced our understanding of some of the cellular and molecular mechanisms important in their pathogenesis. These models have shown that CD4 T cells are the effector cells mediating disease in most instances, that the enteric bacterial flora drives this pathogenic response, and that the innate immune system (epithelium, dendritic cells, macrophages) is a critical link between these two elements. Thus, the interaction of the innate and adaptive immune response with the microbiota and their products is the major focus. We have assembled novel tools, technologies, and reagents from microbial, mouse, and human sources that make possible substantive questions to be addressed and interesting hypotheses to be answered. Among these resources is a panel of immunodominant microbial antigens, particularly bacterial flagellins, which have been shown to stimulate immune responses in multiple mouse models and in a subset of patients with Crohn's disease. Directed by Dr. Charles Elson, we will use flagellins as probes of the innate and adaptive immune response to the microbiota in C3H and B6 mice, will define for the first time whether epitope spreading of the immune response to microbial antigens occurs in IBD and is related to its progression, and will define where and how pathogenic T cells are sensitized in colitic mice. Headed by Dr. Robin Lorenz, we will use the mdr1alpha knockout model to define how the host epithelium and other innate immune cells detect and respond to the microbiota. Headed by Dr. Casey Weaver, we will use novel transgenic cytokine reporter mouse lines to study the adaptive T cell response to the microbiota and particularly the roles IL-23 versus IL-12, and IL-17 versus IFNgamma play in establishing the balance between pathogenic and regulatory T cell responses. Led by Dr. Stephan Targan, located at Cedars-Sinai Medical Center in Los Angeles, CA, will lead the utilization of a large panel of patient materials to define the innate and adaptive immune response in patients with Crohn's disease who are reactive to CBiM flagellin, as well as their clinical phenotypes and genotypes, to test the hypothesis that these patients represent a distinct patient subset. This research will provide administrative support and coordination, and an Animal Model 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 mice for use. This is designed to accelerate the transfer of information discovered from basic labs to the clinic and vice versa. The long-term goal is to increase our understanding of the fundamental mechanisms of IBD in order to develoo better diaanostic and therapeutic strateaies for patients.