Determinants of Response to Interleukin-10 Receptor Blockade Immunotherapy in Experimental Visceral

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)–g serum levels, and en-hanced 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-g and at least one IFN-g–regulated macrophage mechanism—iNOS or phagocyte oxidase. However, in IFN-g 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-g. However, because anti–IL-10R also released IFN-g–independent effects, IL-10 appears to act more broadly and suppresses multiple anti-leishmanial mechanisms. Visceral leishmaniasis is a disseminated intracellular protozoal infection that targets resident macrophages in the liver, spleen, and bone marrow. In experimental Leishmania donovani infection, initially susceptibl