Abstract

In established Leishmania donovani visceral infection in normal mice, anti-interleukin (IL)-10 receptor (IL-10R) monoclonal antibody (MAb) treatment induced intracellular parasite killing within liver macrophages. IL-10R blockade maintained IL-12 protein 40, markedly increased interferon (IFN)-γ serum levels, and enhanced tissue inducible nitric oxide synthase (iNOS) expression and granuloma assembly. Optimal MAb-induced killing, including synergism with antimony chemotherapy, required endogenous IL-12 and/or IFN-γ and at least one IFN-γ-regulated macrophage mechanism—iNOS or phagocyte oxidase. However, in IFN-γ knockout mice, anti-IL-10R also induced both granuloma formation and leishmanistatic activity. As judged by IL-10R blockade, endogenous IL-10 primarily regulates killing in L. donovani infection by suppressing production of and responses to the Th1 cell-type cytokines, IL-12, and IFN-γ. However, because anti-IL-10R also released IFN-γ-independent effects, IL-10 appears to act more broadly and suppresses multiple antileishmanial mechanisms.

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