IFN-gamma increases the severity and accelerates the onset of experimentalautoimmune uveitis in transgenic rats

Experimental autoimmune uveitis (EAU) is a predominantly Th1-mediated intra ocular inflammatory disease that serves as a model for studying the immunop athogenic mechanisms of uveitis and organ-specific autoimmune diseases. Des pite the well-documented role of IFN-gamma in the activation of inflammator y cells that mediate autoimmune pathology, recent studies in IFN-gamma-defi cient mice paradoxically show that IFN-gamma confers protection from EAU. B ecause of the implications of these findings for therapeutic use of IFN-gam ma, we sought to reexamine these results in the rat, another species that s hares essential immunopathologic features with human uveitis and is the com monly used animal model of uveitis. We generated transgenic rats (TR) with targeted expression of IFN-gamma in the eye and examined whether constituti ve ocular expression of IFN-gamma would influence the course of EAU. We sho w here that the onset of rat EAU is markedly accelerated and is severely ex acerbated by IFN-gamma. In both wild-type and TR rats, we found that the di sease onset is preceded by induction of ICAM-1 gene expression and is chara cterized by selective recruitment of T cells expressing a restricted TCR re pertoire in the retina. In addition, these events occur 2 days earlier in T R rats. Thus, in contrast to the protective effects of IFN-gamma in mouse E AU, our data clearly show that intraocular secretion of IFN-gamma does not confer protection against EAU in the rat and suggest that IFN-gamma may act ivate distinct immunomodulatory pathways in mice and rats during uveitis.