Exogenous nitric oxide inhibits experimental autoimmune uveoretinitis development in Lewis rats by modulation of the Th1-dependent immune response

Experimental autoimmune uveoretinitis (EAU) is a T cell-mediated autoimmune disease of posterior uvea that closely resembles a human disease. The uvei togenic effector T cell has a Th1-like phenotype [high interferon-gamma (IF N-gamma), low interleukin-4 (IL-4)], and genetic susceptibility to EAU that is associated with an elevated Th1 response. Suppression of CD4(+) Th1 cel ls for the treatment of autoimmune disease is an attractive potential thera peutic approach. Nitric oxide (NO) has been implicated in the pathogenesis of several inflammatory and autoimmune diseases. In this study, we investig ated the potential role of NO as an immunoregulator to alter Th1/Th2 cytoki ne production, as well as to inhibit the interphotoreceptor retinoid bindin g protein (IRBP)-induced EAU, a CD4(+) Th1 cell-mediated autoimmune disease . Injection of IRBP (100 mug) into two footpads resulted in severe EAU. The beginning peak of the disease was days 12 to 15 after immunization. Oral t reatment with molsidomine (MSDM), a NO donor, began 24 h before IRBP immuni zation to the end of the experiments, which resulted in a significant inhib ition of the disease by clinical and histopathological criteria. When MSDM was administered until day 21, a complete reduction of incidence and severi ty of EAU was observed. To investigate the cytokine alterations from Th1 to Th2 cytokines by MSDM, the cytokines were assayed in a culture medium of I RBP-stimulated inguinal lymphocytes. IRBP-immunized rats secreted a high co ncentration of IFN-gamma and a low concentration of IL-10. In contrast, MSD M treatment enhanced IL-10 secretion and tended to decrease IFN-gamma secre tion. In conclusion, we show that the administration of NO suppresses EAU b y altering the Th1/Th2 balance of inflammatory immune responses. We suggest that NO may be useful in the therapeutic control of autoimmune uveitis.