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.

描述，总体 炎症性肠道疾病（IBD）仍然是复杂的疾病，但是在过去的十年中，IBD的实验模型已经提出了我们对某些细胞和分子机制在其发病机理中重要的理解。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，即肠细菌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品的相互作用是主要重点。我们从微生物，老鼠和人类来源组装了新的工具，技术和试剂，这些工具和人类来源使可能要解决的实质性问题以及要回答的有趣的假设。这些资源中有一组免疫主体微生物抗原， 特别是细菌鞭毛蛋白，已显示出在多种小鼠模型中刺激免疫反应和克罗恩病患者的一部分。 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. 由Robin Lorenz博士领导，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并响应微生物群。由凯西·韦弗（Casey Weaver）博士领导，我们将使用新型的转基因细胞因子记者小鼠系列来研究对微生物群的自适应T细胞反应，尤其是IL-23与IL-12相比IL-12的作用，而IL-17与IFNGAMMA相对于IFNGAMMA在确定致病性和调节性T细胞反应之间的平衡。由博士领导 斯蒂芬·塔根（Stephan Targan）位于加利福尼亚州洛杉矶的Cedars-Sinai医疗中心，将领导使用大量患者材料来定义Crohn病患者的先天和适应性免疫反应，这些患者对CBIM Flagellin有效的患者，以测试这些假设的患者，这些患者对CBIM Flagellin有效，以测试其临床表型和基因型。这项研究将提供行政支持和协调，并在美国B.这将通过实验性结肠炎将小鼠的产生集中，提供中心的病理分析，并产生转基因小鼠的库存。这是为了加速从基本实验室发现的信息传递到诊所，反之亦然。长期的目标是提高我们对IBD基本机制的理解，以便为患者提供更好的射射和治疗性地层。