Visceral leishmanicidal activity of hexadecylphosphocholine (miltefosine) in mice deficient in T cells and activated macrophage microbicidal mechanisms

Hexadecylphosphocholine (miltefosine), a membrane-active alkylphospholipid, may be the first effective oral agent for visceral leishmaniasis, an intra cellular protozoal infection of tissue macrophages. In vitro, miltefosine s timulates T cells and macrophages to respond to and secrete activating cyto kines, including interferon (IFN)-gamma, and enhances macrophage production of microbicidal reactive nitrogen and oxygen intermediates (RNIs and ROIs, respectively). To determine whether these effects mediate miltefosine's in vivo leishmanicidal efficacy, genetically deficient mice were infected wit h Leishmania donovani. Intracellular visceral killing was retained in mice lacking or deficient in T cells, endogenous IFN-gamma, and macrophage gener ation of leishmanicidal RNIs and ROIs. Although mutant mice responded to mi ltefosine in the absence of tissue granulomas, treatment enhanced granuloma assembly in normal animals. These results suggest that miltefosine's visce ral leishmanicidal effect does not require host T cell-dependent or activat ed macrophage-mediated mechanisms; thus, this agent may potentially be usef ul in treating T cell-deficient patients with kala-azar.