Treatment of experimental leishmaniasis with the immunomodulators imiquimod and S-28463: Efficacy and mode of action

There is a need for new, effective, and less toxic treatments for leishmani asis, an infectious disease caused by Leishmania protozoa and is a major ca use of suffering and morbidity in much of the developing world. Imiquimod, an immune-response modifier, has recently been approved by the Food and Dru g Administration for the treatment of genital warts caused by human papillo maviruses. Imiquimod initiates a local immune reaction, including the stimu lation of macrophages, resulting in resolution of human papillomavirus infe ction and regression of the viral lesion. Since imiquimod activates a numbe r of immune cells, including macrophages, which are the only host cells of Leishmania species, an investigation was done to determine whether it induc es leishmanicidal properties in infected macrophages in vitro and in vivo i n a mouse model. Imiquimod and a related compound, S-28463, effectively sti mulated leishmanicidal activity in macrophages; moreover, imiquimod stimula ted signal transduction associated with inducing nitric oxide synthesis in macrophages.