IL-12-induced protection against blood-stage Plasmodium chabaudi AS requires IFN-gamma and TNF-alpha and occurs via a nitric oxide-dependent mechanism.
The effects of IL-12 administration on the development of protective immunity to blood-stage Plasmodium chabaudi AS were analyzed. Treatment of susceptible A/J mice on the day of infection and for 5 days postinfection with various doses 0.025-0.3 microgram) of rIL-12 significantly decreased the peak parasitemia level, but only treatment with 0.1 microgram resulted in increased survival. Treatment of resistant B6 mice with 0.1 microgram of rIL-12 using the same regimen also significantly decreased the peak parasitemia level, but 40% of the animals died. Treatment of these mice with anti-IL-12 mAb resulted in a more severe course of infection, but survival was not significantly altered. The mechanism of IL-12-induced resistance was examined in A/J mice during infection. Compared with spleen cells from untreated mice, cells from IL-12-treated mice produced significantly higher levels of IFN-gamma spontaneously as well as in response to Con A or Ag stimulation on day 7 postinfection. Significantly higher levels of INF-gamma and TNF-alpha were found in the sera of IL-12-treated mice, which correlated with high levels of the nitric oxide (NO) metabolite, NO3-. Furthermore, CD4+T cell depletion was found to abrogate IL-12-induced resistance. Administration of neutralizing mAb against IFN-gamma or TNF-alpha to IL-12-treated mice showed that simultaneous depletion of both cytokines resulted in 100% mortality. The role of NO was investigated by administration of aminoguanidine, a selective inhibitor of cytokine-inducible nitric oxide synthase, to IL-12-treated mice. Significantly increased mortality was observed following treatment twice daily with 9 mg of aminoguanidine, but there was no effect on parasitemia. In conclusion, these results demonstrate that IL-12 regulates the development of resistance to P. chabaudi AS via a CD4+ Th1 response, which involves the cytokines IFN-gamma and TNF-alpha, and is in part NO dependent. Therefore, IL-12, given in the appropriate dose, may be useful in the induction of protective immunity to blood-state malaria.
Stevenson
M M
MM
Center for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada.
Tam
M F
MF
Wolf
S F
SF
Sher
A
A
D000818:Animals; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D007113:Immunity, Innate / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D008288:Malaria / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000494:pharmacology*; D016788:Plasmodium chabaudi / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D006146:Guanidines; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; C004479:pimagedine