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Increases the Severity and Accelerates the Onset of Experimental Autoimmune Uveitis in Transgenic Rats
Laboratories of
*
Immunology and
Molecular and Developmental Biology, and
Veterinary Research and Resources, National Eye Institute, National Institutes of Health, Bethesda, MD 20892
Experimental autoimmune uveitis (EAU) is a predominantly
Th1-mediated intraocular inflammatory disease that serves as a model
for studying the immunopathogenic mechanisms of uveitis and
organ-specific autoimmune diseases. Despite the well-documented role of
IFN-
in the activation of inflammatory cells that mediate autoimmune
pathology, recent studies in IFN--deficient mice paradoxically show
that IFN- confers protection from EAU. Because of the implications
of these findings for therapeutic use of IFN-, we sought to
reexamine these results in the rat, another species that shares
essential immunopathologic features with human uveitis and is the
commonly used animal model of uveitis. We generated transgenic rats
(TR) with targeted expression of IFN- in the eye and examined
whether constitutive ocular expression of IFN- would influence the
course of EAU. We show here that the onset of rat EAU is markedly
accelerated and is severely exacerbated by IFN-. In both wild-type
and TR rats, we found that the disease onset is preceded by induction
of ICAM-1 gene expression and is characterized by selective recruitment
of T cells expressing a restricted TCR repertoire in the retina. In
addition, these events occur 2 days earlier in TR rats. Thus, in
contrast to the protective effects of IFN- in mouse EAU, our data
clearly show that intraocular secretion of IFN- does not confer
protection against EAU in the rat and suggest that IFN- may activate
distinct immunomodulatory pathways in mice and rats during
uveitis.
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