Analysis of the molecular mode of action of Cyclosporin A in inflammatory bowel disease

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While cyclosporine A therapy in Crohn's disease is of minor relevance. It has a long standing history in the treatment of ulcerative colitis especially in the setting of steroid-refractory associated with massive exacerbation as well as when there are contraindications for corticosteroids. Although the initial rate of treatment success in response to cyclosporine A is high, in long term a significant drop of the treatment response can be observed, resulting in the fact that a colectomy in about half the cases cannot be prevented. Therefore it is of critical relevance to find predictive markers for a positive treatment response to cyclosporine A, with the aim to protect IBD patients from unnecessary side effects and treatment hesitation. The aim of this project is therefore to characterize the cellular and molecular mechanisms involved in the action of cyclosporine in order to identify critical markers that are suited to predict a positive outcome upon cyclosporine application. In the present work, both Itk and NFATc1 were identified as predictive mariners of cyclosporine A therapy. In a next set of experiments, these factors will be evaluated with regard to new therapeutic strategies in human inflammatory bowel disease. Here, we propose to provide novel mechanistic insights into the mode of action of cyclosporine A by the use of well-established models of ulcerative colitis in the murine system and in correlation with inflammatory parameters. In addition, the project aims to fill a critical gap in the need to identify factors indicating a positive response upon cyclosporine A treatment in patients with inflammatory bowel disease with the overall mission to support the development of tailored personalized immune intervention strategies for the treatment of inflammatory bowel disease in the future.