Interleukin-12 regulates the response to chemotherapy in experimental visceral leishmaniasis.

In experimental visceral leishmaniasis, interleukin (IL)-12 initiates contr ol over Leishmania donovani via Th1 cell activation, interferon (IFN)-gamma secretion, and granuloma formation. Because the leishmanicidal effect of c onventional therapy, pentavalent antimony (Sb), also requires T cells and e ndogenous IFN-gamma, we tested IL-12 as a determinant of host responsivenes s to chemotherapy, L. donovani-challenged IL-12p35 gene knockout (KO) mice permitted uncontrolled hepatic infection and failed to respond to Sb. In co ntrast, 96% of liver parasites in KO mice were killed by amphotericin B, wh ich acts independently of immune responses. Exogenous IL-12 combined with S b was tested in normal mice: low-dose Sb was converted from weakly to stron gly leishmanicidal, and a no-effect Sb dose was converted to similar to 100 %. leishmanistatic. IL-12 plus Sb synergism in normal mice was IFN-gamma de pendent; however, IL-12 also increased responsiveness to Sb in IFN-gamma KO mice. Thus, IL-12 regulates host IFN-gamma -dependent and -independent res ponses that permit and/or enhance the leishmanicidal activity of Sb.