INTRACELLULAR ANTIMICROBIAL ACTIVITY IN THE ABSENCE OF INTERFERON-GAMMA - EFFECT OF INTERLEUKIN-12 IN EXPERIMENTAL VISCERAL LEISHMANIASIS IN INTERFERON-GAMMA GENE-DISRUPTED MICE

Despite permitting uncontrolled intracellular visceral infection for 8 wk, interferon-gamma (IFN-gamma) gene knockout (GKO) mice infected wi th Leishmania donovani proceeded to reduce liver parasite burdens by 5 0% by week 12. This late-developing IFN-gamma-independent antileishman ial mechanism appeared to be dependent largely on endogenous tumor nec rosis factor-alpha (TNF-alpha): L. donovani infection induced TNF-alph a mRNA expression in parasitized GKO livers and neutralization of TNF- alpha reversed control at week 12. 7 d of treatment of infected GKO mi ce with interleukin-12 (IL-12) readily induced leishmanicidal activity and also partially restored the near-absent tissue granulomatous resp onse, observations that for the first time expand the antimicrobial re pertoire of IL-12 to include IFN-gamma-independent effects. The action of IL-12 against L. donovani was TNF-alpha dependent and required the activity of inducible nitric oxide synthase. These results point to t he presence of an IFN-gamma-independent antimicrobial mechanism, media ted by TNF-alpha, which remains quiescent until activated late in the course of experimental visceral leishmaniasis. However, as judged by t he effect of exogenous IL-12 this quiescent mechanism can readily be i nduced to rapidly yield enhanced intracellular antimicrobial activity.