Visceral Leishmanicidal Activity of Hexadecylphosphocholine (Miltefosine) in Mice Deficient in T Cells and Activated Macrophage Microbicidal Mechanisms

Abstract

Hexadecylphosphocholine (miltefosine), a membrane-active alkylphospholipid, may be the first effective oral agent for visceral leishmaniasis, an intracellular protozoal infection of tissue macrophages. In vitro, miltefosine stimulates T cells and macrophages to respond to and secrete activating cytokines, 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 with Leishmania donovani. Intracellular visceral killing was retained in mice lacking or deficient in T cells, endogenous IFN-gamma, and macrophage generation of leishmanicidal RNIs and ROIs. Although mutant mice responded to miltefosine in the absence of tissue granulomas, treatment enhanced granuloma assembly in normal animals. These results suggest that miltefosine's visceral leishmanicidal effect does not require host T cell-dependent or activated macrophage-mediated mechanisms; thus, this agent may potentially be useful in treating T cell-deficient patients with kala-azar.

Mononuclear Cell Recruitment, Granuloma Assembly, and Response to Treatment in Experimental Visceral Leishmaniasis: Intracellular Adhesion Molecule 1-Dependent and -Independent Regulation

“…Intact efficacy of these two alternative antileishmanial agents in the absence of monocyte recruitment and granuloma formation is quite consistent with their apparently direct killing action. AmB and miltefosine, for example, retain full experimental leishmanicidal effects in the host devoid of mature T cells or lacking activating, pro-host defense cytokines including IFN-␥, IL-12, and TNF (18,23,24,26,27).…”

“…injections of amphotericin B deoxycholate (AmB), or five consecutive once-daily doses of oral miltefosine by gavage (23,24). Optimal doses of each drug were administered: Sb (sodium stibogluconate, Pentostam; Wellcome Foundation Ltd., London, United Kingdom), 500 mg/kg of body weight on day 0; AmB (Gensia Laboratories Ltd., Irvine, Calif.), 5 mg/kg on days 0, ϩ2, and ϩ4; and miltefosine (ASTA Medica AG, Frankfurt, Germany), 25 mg/kg on days 0 to ϩ4 (23,24). Seven days after treatment was started (day ϩ7), all mice were sacrificed and liver parasite burdens were measured.…”

“…To determine if monocyte influx and initial granuloma formation altered the response to chemotherapy, 2-week-infected mice were treated with AmB, miltefosine, or Sb using established protocols (23,24). ICAM-1-mutant mice responded to AmB with high-level leishmanicidal activity ( Table 2).…”

“…In contrast to two other agents now in clinical use, amphotericin B and miltefosine (18,23,24), the in vivo leishmanicidal efficacy of pentavalent antimony (Sb), the conventional treatment for visceral leishmaniasis (25), requires an intact host T-cell (Th1 cell)-dependent response. Thus far, characterization of this mechanism indicates obligatory roles for T cells and a cytokine network involving endogenous interleukin 12 (IL-12), IFN-␥, and tumor necrosis factor (TNF) (17,23,26,27).…”

Visceral Leishmaniosis and Canine Leishmaniosis in Greece and other mediterranean countries

“…Στις Ινδίες χρησιμοποιήθηκε επιτυχώς στο 97% των ασθενών με σπλαχνική λεϊσμανίωση (L.donovanï). Καταστρέφει το παράσιτο χωρίς τη βοήθεια των μηχανισμών άμυνας (Murray and Delph-Etienne 2000), αλλά δεν χορηγείται σε εγκύους επειδή εμφανίζει τερατογόνο δράση (Jha και συν. 1999, Davies και συν.…”