IL-12-induced protection against blood-stage Plasmodium chabaudi AS requires IFN-gamma and TNF-alpha and occurs via a nitric oxide-dependent mechanism

J Immunol. 1995 Sep 1;155(5):2545-56.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Female
  • Guanidines / pharmacology
  • Immunity, Innate / drug effects
  • Interferon-gamma / pharmacology*
  • Interleukin-12 / antagonists & inhibitors
  • Interleukin-12 / pharmacology*
  • Interleukin-12 / physiology
  • Malaria / blood
  • Malaria / immunology
  • Malaria / prevention & control*
  • Male
  • Mice
  • Mice, Inbred A
  • Mice, Inbred Strains
  • Nitric Oxide / pharmacology*
  • Plasmodium chabaudi / immunology*
  • Th1 Cells / immunology
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Guanidines
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Nitric Oxide
  • Interferon-gamma
  • pimagedine