Subproject A4

For the pathogenesis of inflammation in Crohn's disease a role for inflammatory effector cells have been postulated which are specific for gut bacteria. Especially an immune response to bacteria form the normal gut flora such as E.coli seems to be relevant. In the first grant period we synthesized recombinantly more than 200 E.coli -derived proteins which are evolutionary conserved and which can be found in all three biological realms. Until now we have analysed Th cell specific response directed against these proteins quantitatively and qualitatively in 33 patients with Crohn's disease, in 11 patients with ankylosing spondylitis, and in 14 healthy controls. We could show for the first time that a higher frequency of E.coli -specific T cells could be found in healthy controls in comparison to patients with Crohn's disease. First results also indicate that this might be the consequence of a systemic immunosuppression. In the follow-up project we will investigate the antigen-specific T cells derived from the gut focussing on E.coli -specific T reg. For this we will apply newly developed techniques for analysis and direct isolation of in-vivo-activated Tregs. Finally, by using human Tregs in in vitro experiments and Tregs in animal models we will address the question whether such cells can be used for therapeutic interventions. Furthermore, we will also investigate how these bacteria-specific T cells are involved in the pathogenesis of extraintestinal manifestations such as Crohn's disease.