Reprogramming the immune system in IBD.

Immune function in the gut mucosa is tightly regulated to prevent deleterious tissue damaging responses to the indigenous microbiota. In animal models, negative regulatory molecules such as transforming growth factor β1 (TGFβ1) and interleukin (IL)-10 seem to be particularly important. Although IL-10 is made by macrophages, T cells and B cells, TGFβ1 is made by many non-lymphoid/myeloid cells, especially epithelial cells. We have been able to show that in the human gut, neutralization of TGFβ1 increases Th1 and Th17 responses. In IBD, however, especially Crohn's disease, exogenous TGFβ1 cannot inhibit inflammation because of a block in intracellular signalling mediated by Smad7. Knockdown of Smad7 allows endogenous TGFβ1 to dampen inflammation in mucosal tissues from Crohn's patients. We have also generated a mouse which over-expresses Smad7 in T cells. This animal develops more severe colitis in a number of different models, but the inflammation helps protect against colon cancer.