Synergistic effect of interferon-gamma and mannosylated liposome-incorporated doxorubicin in the therapy of experimental visceral leishmaniasis.
Active targeting of doxorubicin to macrophages was studied by incorporating it in mannose-coated liposomes by use of visceral leishmaniasis in BALB/c mice as the model macrophage disease. Mannosylated liposomal doxorubicin was more effective than liposomal doxorubicin or free doxorubicin. Because leishmaniasis is accompanied by immunosuppression, immunostimulation by interferon (IFN)-gamma was evaluated to act synergistically with mannosylated liposomal doxorubicin therapy. Combination chemotherapy with a suboptimal dose of IFN-gamma resulted in possibly complete elimination of spleen parasite burden. Analysis of mRNA levels of infected spleen cells suggested that targeted drug treatment together with IFN-gamma, in addition to greatly reducing parasite numbers, resulted in reduced levels of interleukin (IL)-4 but increased levels of IL-12 and inducible nitric oxide synthase. Such combination chemotherapy may provide a promising alternative for the cure of leishmaniasis, with a plausible conversion of antiparasitic T cell response from a Th2 to Th1 pattern indicative of long-term resistance.
Kole
L
L
Department of Molecular Cell Biology, Indian Institute of Chemical Biology, Calcutta, India.
Das
L
L
Das
P K
PK
D000818:Animals; D016207:Cytokines / Q000235:genetics*; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D004337:Drug Carriers; D004357:Drug Synergism; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007371:Interferon-gamma / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D007893:Leishmania donovani / Q000187:drug effects* / Q000302:isolation & purification; D007898:Leishmaniasis, Visceral / Q000628:therapy*; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects* / Q000469:parasitology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D011994:Recombinant Proteins; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D014158:Transcription, Genetic
D016207:Cytokines; D004337:Drug Carriers; D008081:Liposomes; D011994:Recombinant Proteins; D018664:Interleukin-12; D015847:Interleukin-4; D004317:Doxorubicin; D007371:Interferon-gamma; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D007041:Hypoxanthine Phosphoribosyltransferase