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Interleukin 12 Protects from a T Helper Type 1–mediated Autoimmune Disease, Experimental Autoimmune Uveitis, through a Mechanism Involving Interferon , Nitric Oxide, and Apoptosis

Teresa K. Tarrant^*,, Phyllis B. Silver^*, Jennifer L. Wahlsten^*, Luiz V. Rizzo^*, Chi-Chao Chan^*, Barbara Wiggert, and Rachel R. Caspi^*

From the ^* Laboratory of Immunology and Laboratory of Retinal Cell and Molecular Biology of the National Eye Institute, and the Howard Hughes Medical Institute–NIH Research Scholars Program, National Institutes of Health, Bethesda, Maryland 20892

Pathogenic effector T cells in experimental autoimmune uveitis (EAU) are T helper type 1–like, and interleukin (IL)-12 is required for their generation and function. Therefore, we expected that IL-12 administration would have disease-enhancing effects. Mice were immunized with a uveitogenic regimen of the retinal antigen interphotoreceptor retinoid-binding protein, treated with IL-12 (100 ng/d for 5 d), and EAU was assessed by histopathology. Unexpectedly, IL-12 treatment failed to enhance EAU in resistant strains and downregulated disease in susceptible strains. Only treatment during the first, but not during the second, week after immunization was consistently protective. High levels of interferon (IFN-) were present in the serum during IL-12 treatment, but subsequent antigen-specific IFN- production in protected mice was diminished, as were IL-5 production, lymph node cell proliferation, and serum antibody levels. Treated mice had fewer cells and evidence of enhanced apoptosis in the draining lymph nodes. Unlike wild-type mice, IFN-–deficient, inducible nitric oxide synthase (iNOS)-deficient, and Bcl-2^lck transgenic mice were poorly protected by IL-12, whereas IL-10–deficient mice were protected. We conclude that administration of IL-12 aborts disease by curtailing development of uveitogenic effector T cells. The data are compatible with the interpretation that IL-12 induces systemic hyperinduction of IFN-, causing activation of iNOS and production of NO, which mediates protection at least in part by triggering Bcl-2 regulated apoptotic deletion of the antigen-specific T cells as they are being primed.

Key Words: interleukin 12 • apoptosis • autoimmune disease • uveitis • T helper type 1

Some of the material in this manuscript was presented at the AAAAI/ AAI/CIS joint meeting in San Francisco, February 1997. Portions of this work have appeared in abstract form (1997. J. Allergy Clin. Immunol. 99[No. 5, Pt. 2]).

¹ Abbreviations used in this paper: CIA, collagen-induced arthritis; DTH, delayed type hypersensitivity; EAE, experimental autoimmune encephalomyelitis; EAU, experimental autoimmune uveitis; GKO, IFN- knockout; iNOS, inducible nitric oxide synthase; IRBP, interphotoreceptor retinoid-binding protein; KO, knockout; NO, nitric oxide; NOD, nonobese diabetic; PTX, pertussis toxin.

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