Investigation into the functional role of ROR-gamma T in inflammatory bowel disease models. (360G-Wellcome-044651_Z_95_F)

Mucosal immune responses are actively regulated to prevent development of harmful cell mediated immune responses, yet little is known about the cell types and cytokines involved in this regulation. Two broad approaches will be used to identify the basic mechanisms of mucosal immune regulation. In the first, a recently described murine model of colitis with similarities to Crohn's disease in man, which develops spontaneously in SCID mice restored with CD45RBhigh CD4+ T cells from normal donors and is completely prevented by co-transfer of the reciprocal CD45RBlow population, will be used to investigate mechanisms of disease induction and prevention. The mechanism of action of the regulatory CD45RBlow population will be dissected in vivo, including identification of immunosuppressive cytokines and their cellular source, which are critical for suppression of disease and effects of the CD45RBlow population on the homing properties of CD45RBhigh population. Experiments using gnotobiotic mice suggest components of the normal flora are involved in disease induction and these experiments will be extended to identify the antigen specificity of cells which cause disease and those that prevent it. The second approach will involve study of T-helper cell subset differentiation in the gastrointestinal tract in both tolerance and non-responsiveness. A TCR transgenic mouse line will be used to determine which T helper cell subsets are induced by oral tolerance regimes compared with oral immunisation and which cytokines are involved in the differentiation and effector functions of these cells. Recent evidence suggests that induction of TGF-ß and IL-10 producing regulatory cells may be an important component of oral tolerance. A genetic approach will be taken to allow the detection of IL-10 producing cells in vivo, providing information on the anatomical location of regulatory cells within the gut associated lymphoid tissue. The results of these experiments should define the rules that govern T helper cell subset differentiation in the gut, providing a basis for manipulation of T helper cell responses to ingested antigen. This may be particularly useful in a number of autoimmune diseases where induction of cells that suppress cell mediated immune responses is desirable.