gd IELs in chronic ileitis

慢性回肠炎的 gd IEL

基本信息

批准号：
10607078
负责人：
Karen Leigh Edelblum
金额：
$ 48.7万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607078
关键词：
Activities of Daily Living Acute Address Affect American Anti-Inflammatory Agents Apoptotic Behavior Biological Process Biology Cells Chronic Crohn&apos s disease Data Development Disease Enterocytes Epithelial Cells Epithelium Event Frequencies Future Gene Targeting Goals Granzyme Health Heterogeneity Histologic Homeostasis Host Defense Human Ileal Diseases Ileitis Imaging Techniques Immune system Immunologic Surveillance Infection Inflammation Inflammatory Inflammatory Bowel Diseases Intestinal Content Intestinal permeability Knowledge Lymphocyte Lymphocyte Subset Maintenance Mission Modeling Molecular Mucosal Immune System Mucosal Immunity Mucous Membrane Mus National Institute of Diabetes and Digestive and Kidney Diseases Onset of illness Pathogenesis Patients Peripheral Population Process Public Health Publishing Recurrent disease Regulation Regulatory T-Lymphocyte Relapse Reporter Reporting Research Role Sentinel T cell infiltration T-Cell Receptor T-Lymphocyte TNF gene United States National Institutes of Health Villous Work cell motility defined contribution diphtheria toxin receptor human disease immunoregulation improved insight intestinal barrier intestinal epithelium intestinal homeostasis intraepithelial intravital microscopy microbial microorganism migration mouse model murine colitis new therapeutic target novel prevent receptor function recruit relapse prediction response response to injury therapy design transcriptomics

项目摘要

PROJECT SUMMARY. Maintenance of an intact intestinal barrier is critical to prevent microbial activation of mucosal immunity. In inflammatory bowel disease, this barrier is compromised, thus exposing the mucosal immune system to the contents of the intestinal lumen. A substantial increase in the shedding or extrusion of epithelial cells into the lumen has been shown to be a predictor of relapse in Crohn’s disease (CD) patients. gd intraepithelial lymphocytes (IEL) migrate extensively within the epithelial compartment to serve as a first line of defense against invasive microorganisms and facilitate apoptotic cell shedding. Although gd IELs are protective in mouse models of colitis, the involvement of these sentinel lymphocytes in the pathogenesis of chronic ileitis is less clear. Published reports provide conflicting evidence regarding the contribution of gd IELs in the pathogenesis of chronic ileitis; however, we now show that inducible depletion of gd T cells prior to disease initiation increases lethality. Further, detailed immunoprofiling of the IEL compartment in mice that develop spontaneous CD-like ileitis indicates that the loss of gd IELs coincides with the histological onset of ileal inflammation, suggesting that loss of gd IELs may be an initiating event. In support of this, we observe a reduction in the frequency of CD39+ gd Tregs, while less activated, peripheral Vg1+ T cells infiltrate the IEL compartment prior to disease development. Therefore, we propose to interrogate the contribution of gd IELs in the pathogenesis of chronic ileitis and elucidate the cellular and molecular mechanisms involved in the dysregulation of the gd IEL compartment during the development of CD-like ileitis. To address these questions, we will take advantage of unique gd T-cell-specific mouse models and intravital microscopy to define how gd IEL motility and effector function are regulated in the events leading up to the onset of chronic ileitis. By combining temporal and cell-specific gene targeting, cutting-edge live imaging techniques, and novel models to analyze gd IEL function ex vivo, we expect to clearly elucidate the contribution of gd IELs to the development of ileal disease and further define the functional dysregulation within gd IEL subpopulations in the context of chronic inflammation. Developing a better understanding of the cellular and molecular mechanisms involved in gd IEL immunosurveillance and immunoregulation may elucidate additional targets for future therapies designed to reinforce the epithelial barrier and prevent disease relapse.

项目摘要。维持完整的肠道屏障对于防止微生物激活粘膜免疫至关重要。炎症性肠病时，该屏障受到损害，从而使粘膜免疫系统暴露于肠腔内的上皮细胞脱落或挤出大量增加。管腔已被证明是克罗恩病 (CD) 上皮内复发的预测因子。淋巴细胞 (IEL) 主要在上皮区室中迁移，作为第一道防线尽管 gd IEL 具有保护作用，但它可以抵抗侵入性微生物并促进凋亡细胞脱落。在结肠炎小鼠模型中，这些前哨淋巴细胞参与慢性回肠炎的发病机制是已发表的报告提供了关于 gd IEL 在全球经济中的贡献的相互矛盾的证据。慢性回肠炎的发病机制；然而，我们现在表明，在疾病之前诱导性消耗 gd T 细胞此外，对发育的小鼠的 IEL 区室进行详细的免疫分析。自发性 CD 样回肠炎表明 gd IEL 的丧失与回肠的组织学发病一致炎症，表明 gd IEL 的丢失可能是一个始发事件，我们观察到了这一点。 CD39+ gd Tregs 频率减少，同时活化程度较低，外周 Vg1+ T 细胞浸润 IEL 因此，我们建议询问 gd IEL 在疾病发展之前的贡献。慢性回肠炎的发病机制并阐明参与慢性回肠炎的细胞和分子机制 CD 样回肠炎发展过程中 gd IEL 室的失调为了解决这些问题，我们将利用独特的 gd T 细胞特异性小鼠模型和活体显微镜来定义 gd IEL 运动和效应器功能在导致慢性回肠炎发作的事件中受到调节。结合时间和细胞特异性基因靶向、尖端实时成像技术和新颖模型离体分析 gd IEL 功能，我们期望清楚地阐明 gd IEL 对发展的贡献回肠疾病并进一步定义 gd IEL 亚群内的功能失调更好地了解慢性炎症所涉及的细胞和分子机制。 gd IEL 免疫监视和免疫调节可能阐明未来治疗的其他靶点旨在加强上皮屏障并防止疾病复发。