Expression of interferon-gamma in the lens exacerbates anterior uveitis and induces retinal degenerative changes in transgenic Lewis rats

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that has been implic ated in immunopathogenic mechanisms of a number of inflammatory diseases of autoimmune or infectious disease etiology. However, its exact role is stil l a matter of debate. In experimental mouse models, IFN-gamma has been show n to exacerbate autoimmune thyroiditis, insulin-dependent diabetes mellitus , and autoimmune neuritis while it confers protection against experimental allergic encephalomyelitis and experimental uveitis. In this study, we gene rated transgenic rats with constitutive expression of IFN-gamma in the eye to study its paracrine effects and to investigate whether local production of IFN-gamma also confers protection against uveitis in the rate species. W e show here that chronic exposure of ocular cells to IFN-gamma results in a poptotic death of retinal ganglion cells, development of chronic choroiditi s, formation of retinal in-foldings, and activation of proinflammatory gene s. In contrast to its protective systemic effect in the mouse, constitutive secretion of IFN-gamma in the rat eye was found to predispose the developm ent of severe anterior uveitis and induction of retinal degenerative proces ses that impair visual acuity. Our data underscore the danger in extrapolat ion of cytokine effects in the mouse to humans without corroborating eviden ce in other species.