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

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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.