ACTIVITY OF PENTOSTAM (SODIUM-STIBOGLUCONATE) AGAINST CUTANEOUS LEISHMANIASIS IN MICE TREATED WITH NEUTRALIZING ANTI-INTERFERON-GAMMA ANTIBODY

Studies with Leishmania donovani in the mouse have demonstrated that a n intact T cell compartment is required for effective anti-leishmanial therapy using pentavalent antimony compounds such as Pentostam (sodiu m stibogluconate), suggesting that the in vivo efficacy of drug treatm ent is at least partially immune-based. Similarly, Leishmania-infected , immunodeficient human patients including those with acquired immunod eficiency syndrome (AIDS) generally relapse following therapy with ant imonials. However, sodium stibogluconate is directly parasiticidal in vitro, in the absence of T cells or T cell products. Using a model of a cutaneous form of leishmaniasis, in which susceptible BALB/c mice we re infected with Leishmania major, we investigated whether the antilei shmanial activity of the drug demonstrated a requirement for interfero n-gamma (IFN-gamma), a cytokine produced during a T helper cell type 1 (Th1) immune response and known to contribute to resistance to infect ion, and whether drug therapy affected the nature of the antileishmani al response. Lesion development was suppressed in mice treated from th e onset of infection with sodium stibogluconate alone, and in animals treated with sodium stibogluconate plus a neutralizing anti-IFN-gamma antibody, and tissue parasite burdens were approximately 10,000-fold l ess at the end of therapy in both groups compared with controls. Lesio n development was similarly suppressed in mice with established lesion s treated with either sodium stibogluconate alone, or sodium stibogluc onate plus anti-1FN-gamma antibody. The production of IFN-gamma by cel ls from infected animals was somewhat increased immediately following therapy with sodium stibogluconate, an effect that was not long-lastin g, while interleukin-4, (IL-4) production was not affected by treatmen t. Treatment with anti-IFN-gamma antibody alone significantly suppress ed IFN-gamma production, and led to very high levels of serum IgE, dem onstrating that the antibody was effective in vivo. We conclude that s odium stibogluconate activity can be readily demonstrated in IFN-gamma -depleted mice infected with L, major, and that a short course of sodi um stibogluconate treatment does not markedly affect IFN-gamma or IL-4 production.