title: Miltefosine efficiently eliminates Leishmania major amastigotes from infected murine dendritic cells without altering their immune functions.
abstract: As a treatment for leishmaniasis, miltefosine exerts direct toxic effects on the parasites. Miltefosine also modulates immune cells such as macrophages, leading to parasite elimination via oxidative radicals. Dendritic cells (DC) are critical for initiation of protective immunity against Leishmania through induction of Th1 immunity via interleukin 12 (IL-12). Here, we investigated the effects of miltefosine on DC in Leishmania major infections. When cocultured with miltefosine for 4 days, the majority of in vitro-infected DC were free of parasites. Miltefosine treatment did not influence DC maturation (upregulation of major histocompatibility complex II [MHC II] or costimulatory molecules, e.g., CD40, CD54, and CD86) or significantly alter cytokine release (IL-12, tumor necrosis factor alpha [TNF-alpha], or IL-10). Further, miltefosine DC treatment did not alter antigen presentation, since unrestricted antigen-specific proliferation of CD4+ and CD8+ T cells was observed upon stimulation with miltefosine-treated, infected DC. In addition, miltefosine application in vivo did not lead to maturation/emigration of skin DC. DC NO- production, a mechanism used by phagocytes to rid themselves of intracellular parasites, was also unaltered upon miltefosine treatment. Our data confirm prior studies indicating that in contrast to, e.g., pentavalent antimonials, miltefosine functions independently of the immune system, mostly through direct toxicity against the Leishmania parasite.
authors.affiliation: Department of Dermatology, Universitätsmedizin, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Griewank
authors.forename: Caroline
authors.initials: C
authors.lastname: Gazeau
authors.forename: Andreas
authors.initials: A
authors.lastname: Eichhorn
authors.forename: Esther
authors.initials: E
authors.lastname: von Stebut
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology*; D018320:Leishmania major / Q000187:drug effects* / Q000502:physiology; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000981:Antiprotozoal Agents; D010767:Phosphorylcholine; C039128:miltefosine