INTERFERON-GAMMA INDUCED LETHALITY IN THE LATE PHASE OF PLASMODIUM-VINCKEI MALARIA DESPITE EFFECTIVE PARASITE CLEARANCE BY CHLOROQUINE

A combination therapy was tested consisting of chloroquine and interferon-gamma (IFN-gamma) in the late phase of blood-stage Plasmodium vinckei malaria in BALB/c mice. When mice were treated with three times 300 mug chloroquine at 24-h intervals starting at a parasitemia of 30 %-50 %, only 5 of 14 mice (36 %) died 2-4 days after initiation of therapy. However, when infected mice received chloroquine plus 1 mug IFN-gamma at the same time, 14 of 18 mice (78 %) died 0.5-3 days after start of therapy (p < 0.05) despite clearance of parasitemia.The histopathology from mice dying after combination therapy revealed interstitial leukocyte infiltration of lung tissue, severe liver cell necrosis and kidney tubular necrosis. Pretreatment of P vinckei-infected mice with pentoxifylline, a phosphodiesterase inhibitor, led to a significant decrease of IFN-gamma-induced lethality (p < 0.05). In contrast, pretreatment with neutralizing antibodies to tumor necrosis factor or with L-N-monomethyl arginine, the latter an inhibitor of the nitric oxide synthase, significantly increased lethality (p < 0.05).