Bioimmunotherapy of rodent malaria: co-treatment with recombinant mouse granulocyte-macrophage colony-stimulating factor and an enkephalin fragment peptide Tyr-Gly-Gly.
We have earlier shown that recombinant mouse granulocyte-macrophage colony-stimulating factor (rmGM-CSF) and methionine-enkephalin co-treatment can protect mice from malaria. We now report the bioimmunotherapeutic effect of rmGM-CSF and a synthetic enkephalin fragment peptide Tyr-Gly-Gly (TGG) co-treatment on blood-induced Plasmodium berghei infection in Swiss mice. Mice were completely aparasitimic following co-treatment with rmGM-CSF (10.0 microg/kg) and TGG (2.0 mg/kg x 3 per day, intraperitoneally (i.p.)) starting from day -1 to day +4; however, in monotherapy, neither of these agents showed any detectable bioimmunotherapeutic effect. Curiously, similar co-treatment with rmGM-CSF (10.0 microg/kg) and higher doses of TGG (10.0 mg/kg) did not protect the mice. The combined bioimmunotherapeutic effect of these agents was abrogated by the separate administration each of rabbit neutralizing anti-rmGM-CSF antibody, non-selective opioid receptor antagonist naltrexone (10.0 mg/kg x 6 per day, i.p.), and silica (3.0 mg per mouse, intravenously (i.v.)). The peritoneal and splenic macrophages from the protected mice showed a significant (P<0.05) increase in their pool-size and the phagocytic activity, ex vivo. Furthermore, the protected mice, as compared to the unprotected ones, showed a significant (P<0.05) maximum increase in their serum nitrate and nitrite, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) levels in their splenic homogenates, on the day before the beginning of the resolution of parasitaemia. Selective inhibitors of both inducible (aminoguanidine) and all forms (L-N(G)-monomethyl arginine) of nitric oxide (NO) synthase, significantly (P<0.05) augmented the mortality of co-treated mice, suggesting the role of NO in protection. These data show that, in P. berghei-infected mice, co-treatment with rmGM-CSF and conditional doses of TGG can impart protection, apparently through partly NO-dependent and macrophage-mediated mechanism(s).
Kaur
A
A
National Institute of Pharmaceutical Education and Research, S.A.S. Nagar 160062, India.
Kinhikar
A G
AG
Singh
Prati Pal
PP
D000818:Animals; D004338:Drug Combinations; D004745:Enkephalins / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology; D008288:Malaria / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D010587:Phagocytosis; D010962:Plasmodium berghei / Q000472:pathogenicity; D011994:Recombinant Proteins; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D004338:Drug Combinations; D004745:Enkephalins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor