gd IELs in chronic ileitis

慢性回肠炎的 gd IEL

• 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
• 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' 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

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。 维持完整的肠屏障对于防止微生物激活粘膜免疫至关重要。在 在炎症性肠病中，这种屏障受损，从而使粘膜免疫系统暴露于炎症性肠病。 肠腔内容物。上皮细胞脱落或挤出到 已经显示管腔是克罗恩病（CD）患者复发的预测因子。gd上皮内 淋巴细胞（IEL）在上皮细胞内广泛迁移，作为第一道防线 抵抗侵入性微生物并促进凋亡细胞脱落。虽然gd IEL在以下情况下具有保护性 在小鼠结肠炎模型中，这些前哨淋巴细胞参与慢性回肠炎的发病机制， 不太清楚。已发表的报告提供了相互矛盾的证据，说明gd IEL在 慢性回肠炎的发病机制;然而，我们现在表明，在疾病发生前， 引发会增加致命性。此外，在小鼠中IEL隔室的详细免疫分析显示， 自发性CD样回肠炎表明gd IEL的丢失与回肠炎的组织学发作一致， 炎症，这表明gd IEL的损失可能是一个起始事件。为了支持这一点，我们观察到 CD 39 + gd T细胞的频率降低，而较少活化的外周Vg 1 + T细胞浸润IEL 在疾病发展之前，因此，我们建议询问gd IELs在以下方面的贡献： 慢性回肠炎的发病机制，并阐明参与的细胞和分子机制， CD样回肠炎发展过程中Gd IEL隔室的失调。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确定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。通过 结合时间和细胞特异性基因靶向，尖端的实时成像技术和新模型， 通过离体分析gd IEL的功能，我们希望能够清楚地阐明gd IEL在肿瘤发生发展中的作用。 回肠疾病，并进一步定义在以下情况下gd IEL亚群内的功能失调： 慢性炎症更好地理解参与的细胞和分子机制， 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。