METACYCLOGENESIS MODULATES THE ABILITY OF LEISHMANIA PROMASTIGOTES TOINDUCE IL-12 PRODUCTION IN HUMAN MONONUCLEAR-CELLS

Immunity against the intracellular protozoan Leishmania species is hig hly dependent on Th1 development. We have previously shown that IL-12 is a powerful and probably obligatory factor for Th? cell generation a nd proliferation. We also observed that the experimental infection of C3H and BALB/c mice with Leishmania major is associated with IL-12 pro duction in vivo. Now we demonstrate that metacyclic L. major promastig otes are poor inducers of IL-12 in vitro in fresh human PBMC and monoc ytes. In addition, we show that the ability of this pathogen to induce IL-12 and other cytokines is modulated by the metacyclogenic process, which had previously not been recognized. In contrast to the infectiv e parasites (metacyclic promastigotes), the procyclic promastigotes co llected at the logarithmic phase of the culture displayed a striking a bility to induce IL-12, IFN-gamma, TNF-alpha, and IL-10. Despite this differential effect of procyclic and metacyclic parasites in terms of IL-12 induction, both stages were inhibitory for IL-12 production indu ced by Staphylococcus aureus. The ability of procyclic promastigotes a nd, to a much lesser extent, that of metacyclic promastigotes to induc e IL-12 were enhanced by pretreatment of monocytes in a cytokine milie u containing lFN-gamma, IL-4, IL-13, or granulocyte-macrophage CSF or by neutralization of endogenous IL-10. Our results suggest the develop ment of an evasion mechanism as the Leishmania promastigotes mature to infectious forms and the possibility of using Ags derived from procyc lic promastigotes for immunization procedures.