Impact of immune cell trafficking for mucosal wound healing and intestinal inflammation in inflammatory bowel diseases

免疫细胞运输对炎症性肠病粘膜伤口愈合和肠道炎症的影响

• 批准号: 429884888
• 负责人: Professor Dr. Sebastian Zundler
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/429884888?language=en
• 关键词: Impact; immune; cell; trafficking; mucosal

Inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis are remitting diseases of the gastrointestinal tract, which are characterized by chronic inflammation. The complex pathogenesis of these diseases results from a complex interplay of multiple factors. In particular, the local immune system of the gut is centrally implicated. To reach the gut, immune cells need to extravasate from the blood (“gut homing”). Further on, re-exit from the tissue or the opposite process of retention in the tissue is possible. All these trafficking processes are potential targets for the therapy of inflammatory bowel diseases, which is documented by the successful use of the drug vedolizumab, which inhibits gut homing.Monocytes and descending macrophages as well as T cells are central components of the intestinal immune systems and crucially implicated in the development of inflammation in inflammatory bowel diseases. The mechanisms, however, controlling gut homing of monocytes and the functional consequences of the inhibition of such events for processes like inflammation and wound healing, which are controlled by macrophages, are unclear. Moreover, a special T cell population, so called tissue resident memory T cells (TRM cells) could recently be identified as a central mediator of inflammation and flares in inflammatory bowel diseases and, thus, as potential candidate for future therapeutic approaches, but practically usable translational insights are so far missing.The central hypothesis of this project is that the trafficking and function of these immune cells is clinically relevant for the development of inflammatory bowel diseases and associated conditions. Thus, detailed investigation of these aspects will open innovative avenues towards the implementation of new therapeutic approaches and/or the optimization of existing ones.To this end, two main goals shall be pursued in this project: 1. Functional characterization of monocyte homing to the gut and assessment of the consequences of inhibition of specific homing pathways for intestinal wound healing and inflammation. 2. Elucidation of the functional role of TRM cells in IBD and translation of the concept to arthritis as well as development of pharmacological strategies for TRM targeting.Answering these questions using a variety of innovative techniques shall finally lead to substantial improvements in the therapy of affected patients.

炎症性肠病如克罗恩病和溃疡性结肠炎是胃肠道的缓解性疾病，其特征在于慢性炎症。这些疾病的复杂发病机制是多种因素复杂相互作用的结果。特别是，肠道的局部免疫系统与中枢有关。为了到达肠道，免疫细胞需要从血液中渗出（“肠道归巢”）。此外，从组织中重新退出或相反的保留在组织中的过程是可能的。所有这些运输过程都是炎症性肠病治疗的潜在靶点，这一点通过成功使用抑制肠道归巢的药物Vedolizumab得到了证明。单核细胞和下行巨噬细胞以及T细胞是肠道免疫系统的核心组成部分，并与炎症性肠病的炎症发展密切相关。然而，控制单核细胞肠道归巢的机制以及抑制这些事件对炎症和伤口愈合等过程（由巨噬细胞控制）的功能后果尚不清楚。此外，一种特殊的T细胞群，所谓的组织驻留记忆T细胞，TRM细胞（TRM细胞）最近被鉴定为炎症性肠病中炎症和发作的中心介质，因此，作为未来治疗方法的潜在候选者，但实际上可用的翻译见解目前尚不清楚。该项目的中心假设是，这些免疫细胞的运输和功能与临床相关炎症性肠病和相关病症的发展。因此，这些方面的详细调查将打开新的治疗方法的实施和/或优化现有的创新途径。为此，两个主要目标应在这个项目中追求：1。单核细胞归巢至肠道的功能表征和肠道伤口愈合和炎症特异性归巢途径抑制的后果评估。2.阐明TRM细胞在IBD中的功能作用，将这一概念转化为关节炎，以及开发TRM靶向的药理学策略。使用各种创新技术解决这些问题，最终将导致受影响患者的治疗得到实质性改善。