Scientific Abstract
Proposal No. IBD-0067R
Principal Investigator: Daniel C. Baumgart, M.D., Ph.D.
Applicant Organization: Charité Medical Center - Medical School of the Humboldt - University of Berlin (Germany)
Project Title: Dendritic cells in inflammatory bowel disease
Period of Award: September 1, 2003 - March 31, 2006
Patients with inflammatory bowel disease (IBD) have an inappropriate T cell response (TH1 in Crohn’s disease and TH2 in ulcerative colitis) to antigenic components of their indigenous gut flora and/or food antigens. This breakdown in “oral tolerance” is poorly understood. However, this phenomenon likely relates to how antigen presenting cells process and present antigen(s) to T cells.
Dendritic cells are the longest known professional antigen presenting cells first described by Langerhans in 1868. They are located at mucosal interfaces with the outside world and patrol the organism ubiquitously via the blood stream. Their large surface allows them to sample and process antigens before they migrate to lymphatic organs, such as mesenteric lymph nodes (MLN) to encounter T cells with specific T cell receptors (TCR) they activate or deactivate. This dual role, tolerogenic vs. activating, goes along with a change in their maturational status.
Immature dendritic cells delete reactive T cell clones, promote differentiation of naïve T cells into regulatory TR cells, which in turn secrete anti-inflammatory cytokines such as TGF beta and IL-10 and thereby silence antigen-specific T cells. In contrast, maturation of dendritic cells through contact with microbes or pro-inflammatory cytokines, such as TNF alpha and IFN gamma, results in an activated phenotype with increased co-stimulatory molecules promoting proliferation of antigen-specific T cells.
Dendritic cells therefore may induce the differentiation of distinct T cell subsets in IBD patients compared to healthy individuals. In other words it is conceivable that they normally maintain oral tolerance by inducing TH3 and TR cells and promote inflammation by activating TH1 cells in IBD patients. This may be caused by a lack of tolerogenic dendritic cells, a failure in maturation and/or false recognition of the indigenous flora.
Studying dendritic cells in IBD patients may not only provide a greater insight into mucosal immunology, but also carries the potential for future biological therapies, i.e., in vitro or in vivo induction of regulatory T cells (TR).