Interleukin-12 regulates the response to chemotherapy in experimental visceral Leishmaniasis.
In experimental visceral leishmaniasis, interleukin (IL)-12 initiates control over Leishmania donovani via Th1 cell activation, interferon (IFN)-gamma secretion, and granuloma formation. Because the leishmanicidal effect of conventional therapy, pentavalent antimony (Sb), also requires T cells and endogenous IFN-gamma, we tested IL-12 as a determinant of host responsiveness to chemotherapy. L. donovani-challenged IL-12p35 gene knockout (KO) mice permitted 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 approximately 100% leishmanistatic. IL-12 plus Sb synergism in normal mice was IFN-gamma dependent; however, IL-12 also increased responsiveness to Sb in IFN-gamma KO mice. Thus, IL-12 regulates host IFN-gamma-dependent and -independent responses that permit and/or enhance the leishmanicidal activity of Sb.
Murray
H W
HW
Weill Medical College of Cornell University, New York, NY 10021, USA. hwmurray@med.cornell.edu
Montelibano
C
C
Peterson
R
R
Sypek
J P
JP
D000818:Animals; D000965:Antimony / Q000627:therapeutic use; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout
D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D000965:Antimony