IFN-GAMMA-DEFICIENT MICE DEVELOP EXPERIMENTAL AUTOIMMUNE UVEITIS IN THE CONTEXT OF A DEVIANT EFFECTOR RESPONSE

Experimental autoimmune uveitis (EAU) is a T cell-mediated disease tha t targets the neural retina and serves as a model of human uveitis, Uv eitogenic effector T cells have a Th1-like phenotype (high IFN-gamma, low IL-4), and genetic susceptibility to EAU is associated with an ele vated Th1 response, Here we investigate whether the ability to produce IFN-gamma is necessary for the development of EAU by immunizing IFN-g amma-deficient (GKO) mice with the uveitogenic protein interphotorecep tor retinoid binding protein (IRBP) and characterize the associated im munologic responses, GKO mice developed EAU comparable in severity and incidence to that of their wild-type littermates, However, the cytoki ne profile in their uveitic eyes as well as the cytokines produced by primed lymph node cells ire response to IRBP showed a distinct profile : undiminished TNF-alpha and elevated IL-5, IL-6 IL-10, and lymphotoxi n (but not IL-4) responses,The inflammatory infiltrate in GKO eyes con tained an excess of granulocytes and IL-5- and IL-6-producing cells, b ut uveitic GKO mice did not up-regulate inducible nitric oxide synthas e, GKOs had enhanced lymphocyte proliferation and delayed-type hyperse nsitivity responses to IRBP, Histology of the delayed-type hypersensit ivity lesion in GKO had superimposed elements of an allergic-like resp onse, Anti-IRBP Ab isotypes of GKO mice showed a reduction of IgG2a, b ut no enhancement of IgG1. Comparison of responses in +/+ and +/- wild -type mice revealed some limited evidence of a gene-dose effect, We co nclude that IFN-gamma is not required for priming of pathogenic T cell s or for effecting the retinal damage and photoreceptor loss typical o f EAU, However, what appears to be a grossly similar disease is caused in the GKO by a deviant type of effector response.