KFO 257: Molecular Pathogenesis and Optimised Therapy of Inflammatory Bowel Diseases
Final Report Abstract
Inflammatory bowel diseases (IBD) include the two major forms Crohn’s disease (CD) and ulcerative colitis (UC). These disorders are characterized by episodes of inflammatory flares and periods of remission. IBD pose a substantial socio-economic burden to our healthcare systems: Patients typically suffer from abdominal pain, diarrhea, anemia, weight loss and fatigue, symptoms that may severely affect the quality of life and ability to hold down an employment. Moreover, IBD is a common inflammatory disease with an estimated 400.000 patients in Germany. Finally, IBD currently cannot be cured, as the pathophysiology of this disease is incompletely understood. The Clinical Research Unit (CRU) 257 entitled “CEDER” (Chronisch Entzündliche Darmerkrankungen ERlangen) started in February 2012 focusing on development and (pre-) clinical testing of novel diagnostic and therapeutic approaches for IBD and completed its program in July 2018. Indeed, numerous achievements have been made during the CRU funding with potential for future therapeutic improvements. Accordingly, one of the major problems during the therapeutic treatment of IBD patients is that subgroups of patients do not respond to a given therapy for unknown reasons. The project TP13 (Prof. R. Atreya) focused on the improvement of the predictability of therapy response of biological therapies. By using a fluorescently labeled antibody against TNFα, which was produced under GMP conditions, it was demonstrated that patients with high numbers of mTNF expressing cells, detected during confocal laser endomicroscopy, showed significantly higher response rates to subsequent anti-TNF therapy. This study therefore demonstrated that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in inflammatory bowel diseases. Project TP08 (Prof. Dr. M. F. Neurath/ Dr. C. Bosch-Voskens) successfully established a GMP conform method to greatly expand regulatory T cells isolated from the peripheral blood of UC patients. Based on this method, a protocol for Treg treatment of UC patients was developed and submitted to the Paul Ehrlich Institute for approval. A clinical phase I trial using such expanded Treg will start once the protocol is approved. The CRU was also successful on identifying novel molecular pathways involved in IBD pathogenesis. Accordingly, project TP12 (PD Dr. I. Atreya) demonstrated for the first time that the prenylationdependent activation of the GTPase Rho determines the maintenance of epithelial integrity and immune homeostasis in the gut. Project TP01 (Prof. Dr. C. Becker/ PD Dr. S. Wirtz) found an unexpected function of IL-33 as a regulator of epithelial barrier functions. In their study, they could demonstrate that gut pericryptal fibroblasts release IL-33 to translate bacterial challenge into an epithelial response to promote antimicrobial defense. As it has been reported in previous studies that IFN-γ acts anti-angiogenic in colorectal carcinoma, project TP05 (Prof. Dr. M. Stürzl/ Prof. Dr. M. Waldner) investigated the effects of IFN-γ on the vascular system in IBD. They demonstrated that genes associated with inflammatory cell activation, including IFN-γ were strongly upregulated in colitis tissues and that IFN-γ exerted direct effects on endothelial cells in IBD tissues. These findings provided new insights to the pathological functions of this cytokines and might contribute to the optimization of therapy approaches. Cyclosporine A (CsA) is a potential rescue treatment to avoid colectomy in severe steroid-refractory UC patients, however the underlying mechanism of CsA is not well understood. Project TP07 (PD Dr. B. Weigmann) focused on the underlying signaling axis of CsA. They could demonstrate that CsA treatment modulates the production of pro-inflammatory cytokines and T cell survival in UC via the induction of apoptosis and therefore might help to explain the clinical efficacy of CsA in patients that suffered from UC. In addition to the scientific achievements, the CRU has been able to recruit and train highly motivated national and international doctoral candidates. These doctoral candidates were integrated into a structured educational program provided by the CRU and the PhD program of the local IZKF (Interdisziplinäres Zentrum für Klinische Forschung) graduate school. Further on, the CRU 257 promoted the careers of female scientists. With the help of the central project Z, the CRU coordinated family compatibility and scientific training of doctoral students. The CRU 257 also promoted the careers of clinician scientists by enabling lab rotations for clinicians. 5 projects were led by young physicians setting up or consolidating their own research groups. Overall, the establishment of the CRU has created an outstanding scientific and clinical environment to study IBD. This has created the fundament for the establishment of the Collaborative Research Centre TRR241 which started in 2018.
