Interleukin-12 Regulates the Response to Chemotherapy in Experimental

In experimental visceral leishmaniasis, interleukin (IL)±12 initiates control over Leishmania donovani via Th1 cell activation, interferon (IFN)±g secretion, and granuloma formation. Because the leishmanicidal effect of conventional therapy, pentavalent antimony (Sb), also requires T cells and endogenous IFN-g, we tested IL-12 as a determinant of host respon-siveness to chemotherapy. L. donovani±challenged IL-12p35 gene knockout (KO) mice per-mitted uncontrolled hepatic infection and failed to respond to Sb. In contrast, 96 % of liver parasites in KO mice were killed by amphotericin B, which acts independently of immune responses. Exogenous IL-12 combined with Sb was tested in normal mice: low-dose Sb was converted from weakly to strongly leishmanicidal, and a no-effect Sb dose was converted to »100 % leishmanistatic. IL-12 plus Sb synergism in normal mice was IFN-g dependent; how-ever, IL-12 also increased responsiveness to Sb in IFN-g KO mice. Thus, IL-12 regulates host IFN-g±dependent and ±independent responses that permit and/or enhance the leishmanicidal activity of Sb. Successful host defense in experimental visceral leishmania-sis, a disseminated protozoal infection in which resident mac