ROLE OF INFILTRATING IEL IN INTESTINAL GVHD

浸润性 IEL 在肠道 GVHD 中的作用

• 批准号: 6024283
• 负责人: TESU T LIN
• 金额: $ 7.35万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6024283
• 关键词: apoptosis; cell cell interaction; cellular pathology; cytokine; cytotoxic T lymphocyte; enzyme activity; gastrointestinal absorption /transport; gastrointestinal epithelium; glycosidases; graft versus host disease; integrins; laboratory mouse; pore forming protein; tumor necrosis factor alpha

DESCRIPTION (adapted from the application) The intestinal epithelium is a major target of graft-versus-host disease (GVHD). Because the intestinal epithelium serves both as an absorptive organ for numerous nutrients and a barrier toward harmful pathogens in the intestinal lumen, injury to the intestinal epithelium alone in GVHD can result in severe morbidity and mortality. GVHD is mediated primarily by donor T cells, which recognize and destroy host cells. Our present understanding of GVHD, however, has been based on studies on donor T cells found in the periphery. Whether these findings are relevant to the mechanism of intestinal epithelial injury in GVHD is not known. Thus, to further understand the mechanism of intestinal epithelial injury in GVHD, we propose to study the donor T cells, which specifically infiltrate the intestinal epithelium during GVHD (Infiltrating Intestinal Intraepithelial Lymphocytes or Infiltrating IEL). Our proposal is based on the hypothesis that intestinal epithelial injury in GVHD is primarily mediated by these Infiltrating IEL which infiltrate the host intestinal epithelium and subsequently induce the apoptotic death of host intestinal epithelial cells (IEC). The questions that emerge from our hypothesis form the basis of our specific aims. Aim 1) What are the mechanisms by which Infiltrating IEL induce intestinal epithelial injury in GVHD? Previous studies have demonstrated that Infiltrating IEL can induce IEC apoptosis through Fas-mediated cytotoxicity. Here we will address whether other mechanisms are also involved. Aim 2) Are Infiltrating IEL necessary for intestinal epithelial apoptosis seen in GVHD? Here, we will address whether the infiltration of donor T cells into the intestinal epithelium is required for the IEC apoptosis seen in GVHD. Aim 3) What is the significance of IEC apoptosis induced by Infiltrating IEL? Here, we will address whether infiltrating IEL can impair well-described IEC function such as disaccharidase activity and intestinal permeability.

描述（改编自应用程序） 肠上皮是移植物抗宿主病的主要靶点 （移植物抗宿主病）。因为肠上皮既是吸收器官 提供多种营养素和肠道中有害病原体的屏障 在GVHD中，仅对肠上皮细胞的损伤可导致严重的 发病率和死亡率。 GVHD主要由供体T细胞介导，其识别并破坏宿主 细胞然而，我们目前对GVHD的理解是基于以下研究： 外周血中的T细胞这些发现是否与 GVHD中肠上皮损伤的机制尚不清楚。从而 为进一步了解GVHD中肠上皮损伤的机制， 我建议研究供体T细胞，它们特异性地浸润 GVHD期间的肠上皮（浸润性肠上皮内 淋巴细胞或浸润性IEL）。我们的建议是基于这样的假设， GVHD中的肠上皮损伤主要由这些细胞介导， 浸润性IEL，浸润宿主肠上皮， 随后诱导宿主肠上皮细胞凋亡 （IEC）。从我们的假设中出现的问题构成了我们的基础。 具体目标。 目的1）浸润性IEL诱导肠上皮细胞凋亡的机制 GVHD中的上皮损伤？以前的研究表明，渗透 IEL可通过Fas介导的细胞毒作用诱导IEC凋亡。这里我们将 是否还涉及其他机制。 目的2）浸润性IEL是否为肠上皮细胞凋亡所必需 在GVHD？ 在这里，我们将讨论是否供体T细胞浸润到 肠上皮细胞是GVHD中所见的IEC凋亡所必需的。 目的3）浸润性IEL诱导IEC凋亡的意义？ 在这里，我们将讨论渗透IEL是否会损害描述良好的IEC 功能，如二磷酸脱氢酶活性和肠通透性。