BACTERIAL;EPITHELIAL; T-CELL INTERACTIONS IN GUT MUCOSA

细菌；上皮；

• 批准号: 7141821
• 负责人: Lloyd F Mayer
• 金额: $ 20.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141821
• 关键词: CD1 molecule; T lymphocyte; bacteria; biopsy; chemokine; chemokine receptor; cytokine; epithelium; gene expression; human subject; inflammatory bowel diseases; intermolecular interaction; intestinal mucosa; leukocyte activation /transformation; patient oriented research; receptor expression

In a germ free mouse there is minimal lymphoid infiltration in the gut. Upon colonization with normal flora there is significant influx and activation of lymphocytes into the gut mucosa and the phenomenon of controlled or physiologic inflammation is established. It is generally recognized that regulatory cells play a key role in the maintenance of this state. A trialogue between bacterial epithelial: T cell interactions has been demonstrated in a variety of different studies. We propose that bacterial:epithelial interactions promote an environment where specific Tregs can be generated. Commensal flora may upregulate/induce the expression of nonclassical class I molecules invovled in the activation of Tregs as well as promote selective chemokine production that recruits Tregs or Treg precursors into the mucosa and epithelium. Within the epithelium bacterial Ags presented by nonclassical class I molecules on lECs can activate Tregs to effect their function: the maintenance of the normal physiologic inflammatory state. In inflammatory bowel disease any number of defects in this process can lead to a failure in regulation. We have already shown that IBD lECs display defective expression of gplSO and CDld. The mechanism(s) underlying these defects have not been defined. Alteration in chemokine or cytokine production may account for these observations. This proposal will test distinct aspects of this model (in health and disease - all in human tissues). Specific Aim #1. Determine which Tregs are present (or absent) in the normal and IBD intestine and correlate these with defects in non-classical class I molecule expression in IBD (aim #2). Is the defect in TrE cells in IBD tissues reflective of a selective or global defect in Tregs? Specific Aim #2: Determine the expression and regulation of non-classical class I molecules on intestinal epithelial cells and define defects in expression on IBD lECs.

在无菌小鼠中，肠道中存在最小的淋巴浸润。殖民化后， 正常的植物群存在淋巴细胞显著流入和活化到肠粘膜中， 建立受控或生理性炎症的现象。一般 认识到调节细胞在维持这种状态中起着关键作用。三边对话 细菌上皮细胞与T细胞之间的相互作用已经在各种不同的 问题研究我们认为，细菌：上皮细胞的相互作用促进了一种环境， 可以产生特定的TdR。共生植物群可能上调/诱导 非经典的I类分子参与了T细胞的激活，并促进了选择性的 趋化因子的产生，其将T细胞或Treg前体募集到粘膜和上皮中。 在上皮内，由lEC上的非经典I类分子呈递的细菌Ag可以 激活甲状腺素以实现其功能：维持正常的生理功能， 炎症状态 在炎症性肠病中，该过程中的任何数量的缺陷都可能导致治疗失败。 调控我们已经表明IBD IEC显示gplSO和p53的表达缺陷， CDld.这些缺陷背后的机制尚未确定。的改变 趋化因子或细胞因子的产生可以解释这些观察结果。该提案将测试 这一模型的不同方面（在健康和疾病中--都在人体组织中）。 具体目标#1。确定正常和IBD中存在（或不存在）哪些TdR 并将这些与IBD中非经典I类分子表达缺陷相关 (aim#2）。IBD组织中TrE细胞的缺陷是否反映了IBD组织中的选择性或整体缺陷？ Tennis？ 具体目标#2：确定非经典I类分子的表达和调节 并定义了IBD IEC表达的缺陷。