IMMUNOLOGIC MECHANISMS OF OCULAR DISEASE

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The goal of this project is 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 in the development of uveitis and ocular allergy. Over the past year, we showed that lymphocyte activation is critical for the adoptive transfer of cellular immunity and inflammatory eye disease in a transgenic animal model of autoimmune uveitis. Importantly, fluorescein activated cell sorter (FACS) analysis showed that this activation appeared to involve the upregulated expression of cell adhesion molecules, including very late antigen-4 (VLA-4), intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function-associated molecule-1 (LFA-1). Furthermore, administration of monoclonal antibodies against these adhesion molecules significantly inhibited the transfer of disease, suggesting that blocking these cell adhesion molecules may be an effective therapeutic approach for patients with autoimmune uveitis. Over the past year, we have investigated the effect of two drugs, ammonium trichloro (dioxyethelene-0-0') tellurate (AS101) and gallium nitrate (GN) in animal models of uveitis. AS101 is a potent immunomodulator that augments cytokine production, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-12 (IL-12). We showed that AS101 significantly inhibits the development of endotoxin-induced uveitis (EIU) in Lewis rats, decreasing both the number of inflammatory cells infiltrating the eye and the concentration of protein in the aqueous humor. These results are consistent with our previous findings that intracameral IL-12 inhibits endotoxin-induced ocular inflammation. We also tested the effect of GN on both experimental autoimmune uveitis (EAU) and EIU. GN significantly inhibited the development of EAU, a T-cell mediated animal model of uveitis. In contrast, GN exacerbated ocular inflammatory disease elicited by endotoxin. Because increased expression of ICAM-1 has been shown to be important in the pathogenesis of EIU, we examined the effect of GN on ICAM-1 expression on spleen cells. GN treatment was associated with a small but reproducible increase in the expression of ICAM-1 on spleen cells when compared with saline-treated animals. Therefore, although GN suppresses T-cell mediated inflammatory diseases, this compound has the potential to exacerbate T-cell independent inflammatory processes, possibly by upregulated expression of cell adhesion molecules. Finally, our lab is interested in the role of T-cells, cytokines, and cell adhesion molecules in the pathogenesis of allergic ocular disease, which affects millions of people in the United States each year. We have developed a new experimental model to study this disorder. Animals immunized with ragweed are challenged with topical ragweed. Clinical signs of conjunctivitis occur within 20 minutes of topical ragweed administration, and inflammatory cells, including lymphocytes and eosinophils, start infiltrating the eye within 6 hours. We now plan to use this new model to test novel therapeutic approaches such as blocking cell adhesion molecules and oral tolerance.