Scientific Abstract
Proposal No. IBD-0203
Principal Investigator: Fiona M. Powrie, DPhil
Applicant Organization: University of Oxford (United Kingdom)
Project Title: Role of TGF-β in the pathogenesis of IBD
Period of Award: August 1, 2007 – February 28, 2010
The immune regulatory cytokine TGF-β plays an important role in the control of IBD by regulatory T cells (TR). In mouse models of colitis we have found that TGF-β signaling into TR is indispensable for their function. 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 are refractory to TGF-β signaling suggesting this pathway is not active. In this program of work, we will test the hypothesis that in IBD there are deficiencies in TGF-β-TR interactions leading to impaired TR and sustained TE responses. Specifically, we will establish the role of TR in the induction and activation of TGF-β and determine how signaling of TGF-β into effector and TR cells effects TR activity in IBD patients relative to controls. In addition to its immune suppressive properties, TGF-β is also a key cytokine in the differentiation of Th17 T cell responses that may be involved in IBD pathogenesis. Recent studies suggest that DC play a key role in imprinting T cell function and that a specialist population of mucosal CD103+ DC promotes the accumulation of gut homing T cells with a TR phenotype. We will investigate the ability of human peripheral and intestinal DC to influence the balance between TE and TR cells through TGF-β dependent pathways and determine how this may change in IBD. Further understanding of how TGF-β modulates TR function in humans and how this may change in the inflamed intestine is crucial for the development of targeted anti-inflammatory strategies for IBD patients.