When administered at or near the initiation of experimental intracellular infection caused by Leishmania major, Toxoplasma gondii, or Cryptococcus neoformans, treatment with the immuno-regulatory cytokine interleukin 12 (IL-12), induces protective antimicrobial activity. In contrast, once infections are established, IL-12 exerts considerably less or no effect in the face of a suppressive Th2 cell-associated response (L. major) or rapidly progressive fatal infection (T. gondii). To test the efficacy of IL-12 in an established intracellular protozoal infection but under quite different immunologic conditions (Th1 cell response, acquired resistance), L. donovani-infected BALB/c mice were treated starting 2 wk after challenge coincident with the onset of the Th1 cell response. In this environment, 7 d of IL-12 treatment reduced liver parasite burdens by 47%, an effect comparable to that induced by exogenous interferon (IFN) gamma. The in vivo mechanism responsive to IL-12 was complex, and required both CD4+ and CD8+ T cells as well as natural killer cells and the action of multiple endogenous antileishmanial cytokines (IFN-gamma, IL-2, tumor necrosis factor alpha). Early treatment with IL-12 before the expression of the Th1 cell response was also effective and induced an accelerated, near-cure response via an IFN-gamma-dependent mechanism. These results extend the antimicrobial-inducing capacity of IL-12 beyond prophylaxis by indicating that IL-12 can exert clear-cut therapeutic activity in an established intracellular infection.

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