The bladder, as a mucosal immune organ often exposed to foreign antigens, is linked to the expression of immunity. Examples of bladder-associated immune responsiveness include bacterial infection, response to therapeutic antigens such as BCG (used in treatment of interstitial cystitis and bladder cancer), and although controversial, some have suggested a role for immunity in interstitial cystitis. Considerable data has been published on the histopathology of bladder inflammation. Reports have shown the predominant infiltrating T cell to be CD4+ helper T cells and also have demonstrated the presence of HLA DR expression on transitional epithelial cells. While the expression of immunity in the bladder has important disease-related consequences, the mechanisms by which intravesical antigens initiate immunity and the role of MHC Class II expressing epithelial cells in the expression of immunity have not been established. The objective of the studies outlined herein is to characterize the initiation, expression and regulation of antigen specific CD4+ T cell immunity in the bladder. The working hypothesis is that the activation and expression of CD4+ T cell immunity in the bladder is regulated by bladder-associated cytokines and the antigen presenting function of bladder epithelial cells. The hypothesis will be tested through the in vitro characterization of the immunomodulatory potential of bladder epithelial cells and in vivo using the ovalbumin (OVA)-specific CD4+ DO11.10 T cell receptor transgenic mouse model. The studies outlined with DO11.10 T cells, which can be identified with a unique clonotypic antibody, will provide a basis for the critical evaluation of the hypothesis in an in vivo model. Preliminary data show that bladder epithelial cells function as antigen presenting cells for CD4+ T cells, appear to provide sub-optional activation of CD4+ helper T cell responses, and function as target cells for CD4+ T cell-mediated killing through Fas-induced apoptosis. These observations form the basis for experiments aimed at characterizing T cell-induced bladder inflammation, defining regulatory mechanisms of the inflammatory response, and developing approaches for modifying the inflammatory response through re-directing and/or abrogating CD4+ T cell responses. To accomplish these objectives, the following specific aims will be pursued: (1) characterize the effects of antigen presentation by bladder epithelial cells on CD4+ T cell responses in vitro, (2) characterize the effects of bladder epithelial cell antigen presentation on CD4+ T cell activation in vivo using the ovalbumen-specific CD4+ DO11.10 T cell receptor transgenic model, and (3) determine the effects of CD4+ T cell-directed chronic bladder inflammation on bladder function and evaluate strategies for modifying the response.
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