Lay Summary
Proposal No. IBD-0143
Principal Investigator: Rainer Duchmann, M.D.
Applicant Organization: Charité - Universitätsmedizin Berlin; Campus Benjamin Franklin (Germany)
Project Title: CD4+CD25+ T regulatory cells in inflammatory bowel disease
Period of Award: May 15, 2005 – August 14, 2007
The proposed project is based on the hypothesis that immune dysregulation in inflammatory bowel disease (IBD) encompasses both an excess of inflammatory stimuli and mediators and an inadequately low function or number of cellular components that downregulate mucosal immune responsiveness. Among the latter, CD4+CD25+ Treg is a new and very interesting T cell subset. Although there is a large literature on these cells in general, including detailed studies demonstrating that they can both prevent and treat chronic intestinal inflammation in animal models, their role in human IBD is still in a very early stage of exploration.
Using different techniques, we already showed that there is an increased and potentially protective level of functionally active CD4+CD25+Treg in peripheral blood of IBD patients in remission, but an insufficient level in peripheral blood and involved intestinal mucosa of patients with active disease.
Our submitted project builds on these results. It aims to further investigate the role of CD4+CD25+Treg in IBD pathogenesis and to determine whether measurement of their frequency provides a (sub)clinical marker of disease activity. In more detail, we want to perform a clinical long-term follow-up study in patients with Crohn’s disease to assess whether there is a correlation between the level of CD4+CD25+ Treg and clinical course. Thus, we hope to identify CD4+CD25+ Treg as a subclinical marker of disease activity that might predict relapse or identify patients with increased risk for relapse. This could improve patient care and outcome, e.g., by providing a rationale for starting preventive therapy.
The basic research suggested in this project aims to identify whether (and which)
antigen(s) activate and expand CD4+CD25+ Treg in IBD. In addition, we hypothesize that bacteria from the intestinal flora, which are the endogenous stimulus driving IBD, differentially activate CD4+CD25+ Treg function, so that some bacterial antigens (e.g., the most relevant in IBD) may not or only insufficiently activate suppressive CD4+CD25+ Treg function. To test this hypothesis, suppressive function of IBD Treg will be studied using bacterial antigens in an antigen specific system.
We expect that results from this work will further our understanding of the role of CD4+CD25+ Treg in IBD pathogenesis. In addition, information on the antigens driving CD4+CD25+ Treg in IBD and their functionality may be relevant to better assess the rational basis of potentially forthcoming therapies, which are likely to involve their in vitro propagation and reinfusion. The proposed studies on human CD4+CD25+ T reg are thus hoped to provide new information relating to IBD pathogenesis, clinical management and therapy.