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The proliferation dynamics in vitro of the obligate intracellular protozoan parasite Leishmania donovani was studied for 14 days in resting monolayers of peritoneal macrophages of C57BL/6 $(Lsh sp{ rm s})$ mice inoculated with 5, 50, or 500 promastigotes/cell. Irrespective of the inoculum, only 50 to 65% of the cells became infected initially; only 3 to 6 amastigotes were present in each macrophage initially, suggesting a limited number of parasite ligands on the host cell. The amastigotes did not divide in the first 3 or 4 days after infection and then they actively proliferated from day 5 to day 8; the number of parasites was then reduced. Infection with L. donovani down-regulates immunity and parasite clearance by macrophages, but IL-2-stimulated splenocytes activate leishmanicidal action in vitro in infected peritoneal macrophages and in vivo in C57BL/6 (Lsh$ sp{ rm s})$ mice. IL-2-stimulated splenocytes were most effective when used in the non-proliferating phase of the infection, whereas the anti-leishmanial drug Pentostam was most effective when used during the proliferative phase. Immunochemotherapy was more effective than either treatment alone. Infection with L. donovani abolishes the ability of macrophages to produce the superoxide and INO microbicidal responses; curative treatment with IL-2-stimulated splenocytes restores the ability of infected macrophages to secrete inorganic nitrogen oxides, but not to produce a superoxide response. Pentostam had no effect to stimulate either microbicidal mechanism in infected cells; the drug is, therefore, probably directly toxic to the parasite. These studies have indicated, among other things, that IL-2-stimulated splenocytes rescue infected cells and infected animal from the immunological deficit which L. donovani induces, allowing the re-establishment of those mechanisms that make the macrophage an essential component of the host's protective immune system.

There are currently no ideal treatments or acceptable vaccines for cutaneous leishmaniasis, a worldwide health problem caused by infection with a number of species of the dimorphic protozoa Leishmania. Therefore, there is an urgent need to search for simple, safe, effective, and affordable treatments. Imiquimod is an immune-response modifying agent. Recently, 5% imiquimod cream (Aldara(TM)) received approval by the Food and Drug Administration in the United States and is currently available for the treatment of external genital and perianal warts caused by human papillomavirus infection. The antiviral activity of this drug is mediated through stimulation of cytokine release from many cell types including macrophages resulting in a local immune response at the site of application. Moreover, imiquimod has been shown to enhance cell-mediated immune responses (CMIR). Since imiquimod activates macrophages, the exclusive host cells of Leishmania, and stimulates CMIR which are required for host defence against Leishmania, we have investigated the potential of using imiquimod and its related compound, S-28463, as agents for treating leishmaniasis. It is demonstrated within that imiquimod and S-28463 effectively stimulated leishmanicidal activity both in vitro in macrophages and in vivo in a mouse model. These compounds also stimulated signal transduction associated with the induction of nitric oxide synthesis in macrophages. Imiquimod and S-28463 induced leishmanicidal activity in macrophages in the absence of any other cell types. We have demonstrated that S-28463 generated macrophage leishmanicidal activity by inducing genes involved in macrophage activation and inflammatory responses. Finally, we have also performed an analysis on the influence of L. donovani on macrophage gene expression using a cDNA array analysis, a similar methodology to study the effect of S-28463 on macrophage gene expression. Intramacrophage infection with L. donovani was shown to cause general

No description available.