IMMUNOLOGIC MECHANISMS OF OCULAR DISEASE

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The goals of this project are to study the immunologic mechanisms involved in the pathogenesis of ocular inflammation and ocular malignancy and to develop and test therapies based on these data. Recently, we have concentrated on the role of cell adhesion molecules (CAMs) and cytokines in the development of ocular inflammatory disease. CAMs are surface proteins important for antigen sensitization and the migration of leukocytes to sites of inflammation. We are currently investigating compounds that block CAMs as a treatment for uveitis and other ocular inflammatory diseases. We previously showed that monoclonal antibodies against lymphocyte function-associated antigen-1 (LFA-1), intercellular adhesion molecule (ICAM-1), and Mac-1 could effectively inhibit ocular inflammation in two animal models of uveitis: endotoxin-induced uveitis and experimental autoimmune uveitis. During the past year, we showed that the combination of monoclonal antibodies against E-selectin and P-selectin significantly reduced ocular inflammation in endotoxin-induced uveitis. Again, a monoclonal antibody against LFA-1 had a similar inhibitory effect. We are also studying the use of CAMs in the serum as a marker for disease activity. In clinical studies, we demonstrated elevated levels of soluble-ICAM-1 in the serum of patients with uveitis when compared with age- and sex-matched controls without uveitis. Furthermore, the highest soluble-ICAM-1 levels were found in patients with uveitis associated with an underlying systemic disease. These data suggest that serum soluble-ICAM-1 levels may be used to determine which uveitis patients would be evaluated for underlying systemic disease. We are also interested in studying the role of cytokines in ocular inflammatory disease. Iridectomy specimens were examined from 10 uveitis patients. A lack of transforming growth factor-beta (TGF-beta) in the specimens was associated with increased inflammation, suggesting that this cytokine may have an inhibitory effect on uveitis. This project also involves the development and testing of new immunosuppressive therapies for ocular inflammation. Cyclosporine A (CsA) is an effective immunosuppressive agent, but systemic administration is associated with significant toxicity. We examined the safety and efficacy of a topical preparation of CsA for the treatment of ocular inflammation. Topical CsA significantly inhibited mast-cell-mediated conjunctivitis in a murine model. In contrast, topical CsA had limited effect on the ocular inflammation in endotoxin-induced uveitis. These data suggest that topical CsA may be useful for treating allergic conjunctivitis in humans; however, its utility for the treatment of anterior uveitis is unclear. Gallium nitrate was shown to inhibit the development of experimental autoimmune uveitis and may be useful for treating patients with uveitis. Finally, previous studies from our laboratory showed that MDL 28,842, a potent irreversible inhibitor of S-adenosyl-L-homocysteine hydrolase, inhibited experimental autoimmune uveitis in mice. Over the past year, we showed that lower doses of the drug could be used effectively in combination with corticosteroids for the treatment of experimental uveitis.