Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide, and apoptosis.
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 gamma (IFN-gamma) were present in the serum during IL-12 treatment, but subsequent antigen-specific IFN-gamma 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-gamma-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-gamma, 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.
Tarrant
T K
TK
Laboratory of Immunology, National Institutes of Health, Bethesda, Maryland 20892, USA.
Silver
P B
PB
Wahlsten
J L
JL
Rizzo
L V
LV
Chan
C C
CC
Wiggert
B
B
Caspi
R R
RR
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D005136:Eye Proteins; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000172:deficiency*; D018664:Interleukin-12 / Q000494:pharmacology / Q000627:therapeutic use*; D015848:Interleukin-5 / Q000276:immunology; D008198:Lymph Nodes / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000276:immunology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology; D012177:Retinol-Binding Proteins / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014605:Uveitis / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
D005136:Eye Proteins; D007074:Immunoglobulin G; D007371:Interferon-gamma; D018664:Interleukin-12; D015848:Interleukin-5; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D019253:Proto-Oncogene Proteins c-bcl-2; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C496317:Nos2 protein, mouse