Interleukin 12 induction of interferon gamma-dependent protection against malaria.
Intraperitoneal injection of recombinant Interleukin 12 (rIL-12) at 30 ng/day for 5 days beginning 1 to 2 days before sporozoite challenge or administration of a single dose of 150 ng of rIL-122 days before challenge protected 100% of BALB/c mice against challenge with 10(2) Plasmodium yoelii sporozoites. rIL-12-induced protection was eliminated in all mice by administration of a monoclonal antibody against interferon gamma and in 50% of mice by administration of NG-monomethyl-L-arginine, a competitive inhibitor of nitric oxide synthase. rIL-12 protected BALB/c mice treated with cytotoxic anti-CD4 and anti-CD8 monoclonal antibodies, as well as T-cell- and B-cell-deficient severe combined immunodeficiency mice. These data suggest that rIL-12 stimulates non-B, non-T cells to produce interferon gamma that kills intrahepatic parasites by stimulating nitric oxide production. If rIL-12 proves to be well tolerated by humans, our findings support consideration of rIL-12 as an immunoprophylactic against malaria.
Sedegah
M
M
Malaria Program, Naval Medical Research Institute, Bethesda, MD 20889-5607.
Finkelman
F
F
Hoffman
S L
SL
D000818:Animals; D000911:Antibodies, Monoclonal; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000276:immunology / Q000502:physiology*; D018664:Interleukin-12 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D008288:Malaria / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010967:Plasmodium yoelii; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D019323:omega-N-Methylarginine
D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D018664:Interleukin-12; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine