INNATE AND ADAPTIVE MICROBIAL IMMUNITY IN IBD

描述（由申请人提供）： 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反应与微生物群及其产物的相互作用是该计划项目的主要重点。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，已显示其在多种小鼠模型和克罗恩病患者亚组中刺激免疫应答。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Charles Elson博士领导的项目1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IBD中是否发生对微生物抗原的免疫反应的表位扩散，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博士领导的项目2将使用mdrla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。项目3将由凯西韦弗博士领导，并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的作用，以及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。项目4由Stephan Targan博士领导，位于加利福尼亚州洛杉矶的Cedars-Sinai医疗中心。该项目将利用大量患者材料来定义对CBirl鞭毛蛋白有反应的克罗恩病患者的先天性和适应性免疫应答，以及他们的临床表型和基因型，以测试这些患者代表不同患者亚群的假设。这些项目得到了U.A.B.的管理核心和动物模型核心的支持。本补充申请是为了在第4年和第5年继续进行项目4中所代表的转化研究。在人类中继续进行这些研究对于提高我们对IBD基本机制的理解的长期目标至关重要，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) 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 of this Program Project. 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. The Program Project will be directed by Dr. Charles Elson and will consist of four projects and two cores. Project 1, headed by Dr. Charles Elson, 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. Project 2, headed by Dr. Robin Lorenz, will use the mdrla knockout model to define how the host epithelium and other innate immune cells detect and respond to the microbiota. Project 3 will be headed by Dr. Casey Weaver and 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 IFNy play in establishing the balance between pathogenic and regulatory T cell responses. Project 4, led by Dr. Stephan Targan, is located at Cedars-Sinai Medical Center in Los Angeles, CA. This project will utilize a large panel of patient materials to define the innate and adaptive immune response in patients with Crohn's disease who are reactive to CBirl flagellin, as well as their clinical phenotypes and genotypes, to test the hypothesis that these patients represent a distinct patient subset. These projects are supported by an Administrative Core and an Animal Model Core at U.A.B. This supplemental application is for funds to continue the translational studies represented in Project 4 in years 4 and 5. The continuation of these studies in humans is critical to the long-term goal of increasing our understanding of the fundamental mechanisms of IBD in order to develop better diagnostic and therapeutic strategies for patients.