Experimental visceral leishmaniasis: Role of endogenous IFN-γ in host defense and tissue granulomatous response

The capacity of BALB/c mice to acquire resistance to and eliminate intracellular visceral Leishmania donovani is T cell dependent, associated with a granulomatous tissue reaction, and correlates with the ability to secrete the macrophage-activating lymphokine, IFN-γ. These responses appear by 4 wk after infection and are fully established by 8 wk. To examine the role of endogenous IFN-γ, BALB/c mice were injected with anti-IFN-γ mAb before and for 8 wk after infection. At 4 wk, mAb treatment inhibited the acquisition of resistance to L. donovani and abolished mature granuloma formation. Although liver parasite burdens in mAb-treated mice were fivefold higher than in controls at 8 wk, continually treated mice nevertheless began to form tissue granulomas and decreased their parasite loads by 50% from peak values. The levels of anti-IFN-γ antibody in the serum of mice injected for 8 wk were appreciably reduced, thus raising the possibilities of either insufficient neutralization of endogenous IFN-γ at this time point or a pathway independent of IFN-γ. Although the role of IFN-γ and the potential effect of an IFN-γ-independent mechanism in the resolution of visceral infection remain to be defined, these results indicate that IFN-γ plays a critical role in the early immune response that both optimally controls L. donovani infection and induces the tissue granuloma.