INNATE AND ADAPTIVE MICROBIAL IMMUNITY IN IBD

IBD 的先天性和适应性微生物免疫

• 批准号: 6913933
• 负责人: CHARLES O ELSON
• 金额: $ 118.77万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-10 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6913933
• 关键词: cellular immunity; clinical research; disease /disorder model; enteric bacteria; genetically modified animals; host organism interaction; immunopathology; inflammatory bowel diseases; laboratory mouse

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.

总体描述 炎症性肠病 (IBD) 仍然是复杂的疾病，但在过去十年中，IBD 的实验模型增进了我们对其发病机制中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，CD4 T 细胞是介导疾病的效应细胞，肠道菌群驱动这种致病反应，而先天免疫系统（上皮、树突状细胞、巨噬细胞）是这两个要素之间的关键联系。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主要焦点。我们从微生物、小鼠和人类来源组装了新颖的工具、技术和试剂，使有待解决的实质性问题和有待回答的有趣假设成为可能。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，它已被证明可以刺激多种小鼠模型和部分克罗恩病患者的免疫反应。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以及与其进展相关，并将确定结肠炎小鼠中致病性 T 细胞在何处以及如何致敏。 在 Robin Lorenz 博士的带领下，我们将使用 mdr1alpha 敲除模型来定义宿主上皮和其他先天免疫细胞如何检测微生物群并对其做出反应。在 Casey Weaver 博士的带领下，我们将使用新型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 以及 IL-17 与 IFNgamma 在建立致病性 T 细胞反应和调节性 T 细胞反应之间的平衡方面所发挥的作用。由博士领导。 加利福尼亚州洛杉矶 Cedars-Sinai 医疗中心的 Stephan Targan 将领导利用大量患者材料来定义对 CB​​iM 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一个独特的患者子集的假设。这项研究将为 U.A.B. 提供行政支持和协调以及动物模型。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，并产生可供使用的转基因小鼠库存。其目的是加速从基础实验室到诊所发现的信息的传输，反之亦然。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。