Sterile protection of monkeys against malaria after administration of interleukin-12.
An estimated 300-500 million new infections and 1.5-2.7 million deaths attributed to malaria occur annually in the developing world, and every year tens of millions of travelers from countries where malaria is not transmitted visit countries with malaria. Because the parasites that cause malaria have developed resistance to many antimalarial drugs, new methods for prevention are required. Intraperitoneal injection into mice of one dose of 150 ng (approximately 7.5 micrograms per kg body weight) recombinant mouse interleukin-12 (rmIL-12) 2 days before challenge with Plasmodium yoelii sporozoites protects 100% of mice against malaria. We report that one subcutaneous injection of 10 micrograms/kg recombinant human IL-12 (rhIL-12) 2 days before challenge with P. cynomolgi sporozoites protected seven of seven rhesus monkeys. Protection was associated with marked increases in plasma levels of interferon-gamma (IFN-gamma), and relative increases of lymphoid cell messenger RNA coding for IFN-gamma and several other cytokines. We speculate that rIL-12 protects monkeys through IFN-gamma-dependent elimination of P. cynomolgi-infected hepatocytes. This first report of rIL-12-induced protection of primates against an infectious agent supports assessment of rhIL-12 for immunoprophylaxis of human malaria.
Hoffman
S L
SL
Malaria Program, Naval Medical Research Institute, Rockville, Maryland 20852, USA.
Crutcher
J M
JM
Puri
S K
SK
Ansari
A A
AA
Villinger
F
F
Franke
E D
ED
Singh
P P
PP
Finkelman
F
F
Gately
M K
MK
Dutta
G P
GP
Sedegah
M
M
D000818:Animals; D004305:Dose-Response Relationship, Drug; D007371:Interferon-gamma / Q000097:blood / Q000187:drug effects / Q000235:genetics; D018664:Interleukin-12 / Q000097:blood / Q000494:pharmacology*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008253:Macaca mulatta / Q000276:immunology; D008288:Malaria / Q000517:prevention & control*; D016789:Plasmodium cynomolgi; D010967:Plasmodium yoelii; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D007378:Interleukins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma