IFN-gamma increases the severity and accelerates the onset of experimental autoimmune uveitis in transgenic rats.
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-gamma in the activation of inflammatory cells that mediate autoimmune pathology, recent studies in IFN-gamma-deficient mice paradoxically show that IFN-gamma confers protection from EAU. Because of the implications of these findings for therapeutic use of IFN-gamma, 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-gamma in the eye and examined whether constitutive ocular expression of IFN-gamma would influence the course of EAU. We show here that the onset of rat EAU is markedly accelerated and is severely exacerbated by IFN-gamma. 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-gamma in mouse EAU, 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 activate distinct immunomodulatory pathways in mice and rats during uveitis.
Egwuagu
C E
CE
Laboratory of Immunology, National Eye Institute, Bethesda, MD 20892-1858, USA. emeka@helix.nih.gov
Sztein
J
J
Mahdi
R M
RM
Li
W
W
Chao-Chan
C
C
Smith
J A
JA
Charukamnoetkanok
P
P
Chepelinsky
A B
AB
D000818:Animals; D030801:Animals, Genetically Modified; D001327:Autoimmune Diseases / Q000209:etiology* / Q000473:pathology; D003459:Crystallins / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004198:Disease Susceptibility; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D015533:Transcriptional Activation; D014605:Uveitis / Q000209:etiology / Q000276:immunology* / Q000473:pathology
D003459:Crystallins; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma