Interstitial cystitis (IC) or painful bladder syndrome is a complex disease entity with unknown etiology and pathogenesis. The disease effects predominantly women and encompasses a variety of symptoms including frequent urination and pelvic pain. IC is a chronic inflammatory disease of the bladder wall, and is characterized by edema, fibrosis and leukocyte infiltrates and mast cells. Although the presence of both lymphocytes as well as macrophages have been demonstrated in the bladders of IC patients, nothing is known about the nature or contribution of these cells nor their products (cytokine) to the pathogenesis of IC. Thus, we have hypothesized that IC represents a disease in which bladder- specific cell-mediated hypersensitivity participates directly in the pathogenesis of the disease by dysfunctional regulation of T cells; macrophages, and proinflammatory cytokines. To investigate this hypothesis, we propose to initially define the presence of both immunologic cells and cytokines within the blood, urine and tissue of IC patients, and correlate their presence with clinical history and disease. Additionally, we propose to characterize the immunologic status of mononuclear cells isolated from IC patients using non-specific mitogens, as well as bladder-specific antigens obtained from urine and bladder tissue. In addition to evaluating the immune status of primary leukocyte cultures isolated from IC patients, we also plan to isolate T cell clones from urinary bladder tissue of patients with IC. Also we will characterize them and evaluate their in vitro responsiveness to specific bladder antigens, as well as bladder cells. Finally, we propose to develop models of IC in the mouse. For these studies, we propose to induce both cell-mediated hypersensitivity and autoimmunity in both control and mutant mice (SCID, Steel and nude mice) using state-of-the-art immunologic techniques. Thus using both patient and animal models, we feel that these studies should provide important new insights into the role of immune cells and products in cystitis in general, and IC specifically.
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