INNATE AND ADAPTIVE MICROBIAL IMMUNITY IN IBD

说明，总体 炎症性肠病(IBD)仍然是一种复杂的疾病，但在过去的十年中，IBD的实验模型促进了我们对其发病机制的一些重要的细胞和分子机制的理解。这些模型表明，在大多数情况下，CD4T细胞是介导疾病的效应细胞，肠道细菌菌群驱动这种致病反应，天然免疫系统(上皮细胞、树突状细胞、巨噬细胞)是这两个要素之间的关键纽带。因此，天然免疫和获得性免疫反应与微生物区系及其产物的相互作用是研究的重点。我们从微生物、老鼠和人类来源收集了新的工具、技术和试剂，使解决实质性问题和回答有趣的假设成为可能。在这些资源中有一组免疫优势微生物抗原， 特别是细菌鞭毛蛋白，已被证明在多种小鼠模型和克罗恩病患者的子集中刺激免疫反应。在Charles Elson博士的指导下，我们将使用鞭毛蛋白作为C3H和B6小鼠对微生物区系的先天和获得性免疫反应的探针，将首次确定对微生物抗原的免疫反应的表位扩散是否在IBD中发生，并与其进展相关，并将确定致病T细胞在哪里以及如何在结肠炎小鼠中致敏。由Robin Lorenz博士领导，我们将使用mdr1pha基因敲除模型来定义宿主上皮和其他先天性免疫细胞如何检测和响应微生物区系。在Casey Weaver博士的领导下，我们将使用新型转基因细胞因子报告鼠系来研究T细胞对微生物区系的适应性反应，特别是IL-23和IL-12，以及IL-17和IFNGamma在建立致病T细胞反应和调节T细胞反应之间的平衡中所起的作用。由Dr。 位于加利福尼亚州洛杉矶Cedars-Sinai医疗中心的Stephan Targan将领导利用大量的患者材料来确定对CBIM鞭毛蛋白有反应的克罗恩病患者的先天和获得性免疫反应，以及他们的临床表型和基因类型，以检验这些患者代表一个独特的患者亚群的假设。这项研究将提供行政支持和协调，以及亚利桑那大学的动物模型，该模型将集中生产实验性结肠炎小鼠，提供中央病理分析，并产生可供使用的转基因小鼠种群。这是为了加速将发现的信息从基础实验室传输到临床，反之亦然。我们的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。

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.