Final Progress Report

Inflammatory bowel disease (IBD), encompassing Crohn’s Disease and Ulcerative Colitis is a chronic inflammatory disorder of the gastrointestinal tract. The cause of IBD is still unknown, but available evidence suggests that IBD involves an overactive inflammatory response to intestinal bacteria in genetically susceptible people. Several immune treatments have been developed to treat patients with IBD. However, a common problem of all these treatments is that they also switch off the immune response necessary for the body to eradicate infections. A specialized group of white blood cells called regulatory T cells (T_R) can not only suppress, but more importantly, cure IBD in mice. A subset of cells from the intestine called dendritic cells (DC) can be identified by the expression of the CD103 molecule. This subset of DC have the unique property of converting naïve T cells into T_R. This property is dependent of both, retinoic acid, a derivative of the nutrient vitamin A, and of transforming growth factor (TGF-β), a suppressory cytokine which is key in T_R control of intestinal inflammation. Studies in humans have shown that large amounts of TGF-β are present in the colon of IBD sufferers, however, there is evidence that activated cells from the intestine of IBD patients do not respond to the immunosupressory properties of TGF-β suggesting that TGF-β is not functioning. We characterized the phenotype of intestinal DC in normal and IBD patients in the contex of different subsets of DC and how these can produce and activate TGF-β and retinoic acid. To investigate how DC modulate TGF-β and how this leads to the conversion of T_R is of paramount importance for the development of therapeutics which could lead to the prevention of IBD.