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Regulation Of Immune Responses In Humans and in Experimental Animals

人类和实验动物免疫反应的调节

基本信息

批准号：
7732455
负责人：
WARREN STROBER
金额：
$ 79.49万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7732455
关键词：
Animals Apoptosis Appearance CD4 Positive T Lymphocytes Cells Chronic Colitis Collagen Crohn&apos s disease Defect Dendritic Cells Development Disruption Down-Regulation Epithelial Epithelium Ethanol Event Evolution Fibroblasts Fibrosis Gastrointestinal tract structure Human ITGAX gene Immune Immune response Inbred BALB C Mice Indium Inflammation Inflammatory Inflammatory Bowel Diseases Insulin-Like Growth Factor I Interleukin-13 Interleukin-17 Lamina Propria Lesion Link Mediating Minor Modeling Modification Motion Mus Myofibroblast Organism Pathway interactions Peptides Permeability Physiological Process Production Reaction Rectal Administration Regulation Reporting Resistance Severities Signal Transduction Small Interfering RNA Sulfonic Acids T-Lymphocyte TLR2 gene Thinking Tight Junctions Time Transcription Factor AP-1 Trinitrobenzenes Vibrio cholerae Week Zot protein attenuation cytokine human TGFB1 protein in vivo interleukin-13 receptor prevent programs receptor response

项目摘要

Project 1: The studies reported in this interval and previously establish the unexpected finding that the development of fibrosis in a chronic inflammation of the gastrointestinal tract is an outgrowth of the inflammation itself, namely the production of Th17 cytokines and the induction of IL-13 synthesis. In addition, they show that fibrosis was ultimately dependent on IL-13 signaling via IL-13Ralpha2 that results in the production of TGF-beta1. The particular focus of the study reported here is the downstream events of the fibrotic program set in motion by the production of TGF-beta1. Evidence is presented that the latter cytokine results in the production of IGF-1 and Egr-1, two factors that mediate old myofibroblast apoptosis and new myofibroblast collagen formation. Project 2: As pointed out above, "conventional wisdom" holds that breaches of the epithelial barrier by commensal organisms in the mucosal lumen leads to colitis. In fact, it is widely believed that defects in epithelal barrier function is a cause of Crohn's disease. These studies will require a modification in this view. They provide strong evidence that minor and/or transient breaches of barrier function have, in fact, the opposite effect: the induction of regulatory T cells that prevent colitis. This, in a sense, is not unexpected when it is pointed out that cross-talk between the commensal flora and immune elements in the lamina propria is known to occur even in the absence of disruptions in barrier function. These findings will have important impact on the interpretation of the significance of changes in epithelial barrier function in inflammatory bowel disease.

项目1：在此期间和之前报道的研究证实了一个意想不到的发现，胃肠道慢性炎症中纤维化的发展是炎症本身的产物，即Th17细胞因子的产生和IL-13合成的诱导。此外，他们还表明，纤维化最终依赖于通过IL-13Ralpha2传递的IL-13信号，从而导致转化生长因子β1的产生。这里报道的研究重点是由转化生长因子-β1的产生启动的纤维化程序的下游事件。有证据表明，后者的细胞因子导致IGF-1和Egr-1的产生，这两个因素介导了旧的肌成纤维细胞的凋亡和新的肌成纤维细胞胶原的形成。项目2：如上所述，“传统观点”认为，粘膜管腔中的共生生物破坏上皮屏障会导致结肠炎。事实上，人们普遍认为上皮屏障功能缺陷是克罗恩病的原因之一。这些研究需要对这一观点进行修改。它们提供了强有力的证据，表明轻微和/或短暂的屏障功能破坏实际上具有相反的效果：诱导调节性T细胞预防结肠炎。在某种意义上，这并不出人意料，因为有人指出，即使在屏障功能没有中断的情况下，固有层中的共生菌群和免疫元件之间的串扰也会发生。这些发现将对解释炎症性肠病上皮屏障功能改变的意义有重要影响。