A characteristic feature of ulcerative colitis (UC) and Crohn's disease which is an alteration in the isotypes expressed by mucosal B cells. In mild inflammation, the numbers of IgA and IgM-producing B cells increases and as the process becomes more severe and chronic, the numbers of IgG- producing cells is strikingly increased, with a disproportionate increase in the IgG1 sub-class in UC and of IgG2 in Crohn's disease. The mechanisms underlying these characteristic changes in mucosal B cells are unknown. The mucosal immune system functions in an integrated manner, with cells induced in one area of the mucosa trafficking to and populating other, remote mucosal sites. Another major feature of this system is that antigen exposure in the mucosa may result in a state of unresponsiveness to that antigen, i.e. """"""""oral tolerance"""""""". The function of the mucosal immune system in the setting of chronic inflammation of the gut has never been systematically explored and is the overall goal of this project. These studies will utilize two newly developed models of experimental colitis in the mouse, which is particularly appropriate because much of our understanding of the mucosal immune system is derived from studies in mice. Colitis is induced in one model by administration of the contact allergen TNBS in 50% ethanol into the colon and the other by cyclosporine A interference with negative selection in the thymus after irradiation and bone marrow reconstitution. Using these models, we will determine how the isotype distribution in the mucosal B cell system is perturbed both in the lesions and in remote mucosal sites. The isotype pattern of B cells specific for the hapten TNP will also be measured in the lesions and remote mucosal tissues during TNBS-induced colitis. The ratio of Th1 to Th2 helper T cells subsets will be determined in mucosal tissues to test the hypothesis that changes in B cell isotypes are the result of an alteration in local T helper cell subsets. Abnormalities of IgG+ B cell trafficking to colitic mucosa will also be examined. The lymphoid follicles that develop in the lesions will be studied to determine whether they are Peyers patch equivalents or instead are typical of systemic follicles. We will determine how intestinal inflammation affects well defined oral immunogens at both local and remote mucosal sites. Lastly, we will determine whether a state of intestinal inflammation affects the development of tolerance to antigens delivered into either the upper gut or locally into the colon, and whether oral tolerance to TNBS affects the B cell anti-TNP response during TNBS-induced colitis. These studies should yield new insights into the mechanisms involved in the perturbation of the mucosal B cell system during inflammatory bowel disease.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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