The goal of this research proposal is to utilize the Interleukin-2-deficient (IL-2-/-) mouse as an animal model of ulcerative colitis (UC) to determine the role commensal gut bacteria play in the pathogenesis of inflammatory bowl disease (IBD). A perennial hypothesis for the initiation of IBD is that the host suffers a breakdown in the mechanisms that normally maintain """"""""oral tolerance"""""""" against environmental antigens in the gut such as commensal bacteria. The cause of this disregulation is obscure, as are most of the mechanisms that normally operate to maintain hyporesponsiveness to gut commensal bacteria. The IL-2/- mouse, however, seems to offer a promising model to probe the possible relationships between gut bacterial antigens and specific T cells that may initiate inflammatory bowl lesions. It is known that these mice develop pathogenic processes in many tissues, including IBD lesions that resemble those seen in UC patients, and that these are postponed or moderated by maintaining the mice under specific pathogen-free or germ-free conditions. Using these mice the PI proposes to determine if antigen recognition of endogenous microbial flora by mucosal T cells can initiate or maintain IBD. The guiding hypothesis for these studies is that the inflammatory immune response and colitis in IL-2- - mice is a consequence for the loss of regulation of T cell responses to normal intestinal bacterial flora. IL-2 may, therefore, be required for the generation and or function of a regulatory population(s) of mucosal T cells or, be directly involved in inhibiting the development of inflammatory responses to enteric antigens. The PI's proposed studies to experimentally test this hypothesis using the IL-2- - mice have two specific aims. The first is to identify members of commensal enteric bacteria that can activate mucosal T cells that initiate colitis.
The second aim i s to investigate the nature of the interaction between colonic epithelial cells and mucosal T cells and how T cells mediate the epithelial cell injury that is a hallmark feature of colitis. In particular, the possibility that epithelial cells can regulate mucosal T cell responses to enteric antigens by functioning as antigen presenting cells, and that through the production of soluble growth factors mucosal T cells can influence epithelial cell growth and function will be investigated. In addition, the ability of pathogenic T cells to cause or promote tissue injury through the production of toxic or inflammatory cytokines will also be investigated.
