TRYPANOSOMA-CRUZI - IL-10, TNF, IFN-GAMMA, AND IL-12 REGULATE INNATE AND ACQUIRED-IMMUNITY TO INFECTION

Control of the acute phase of Trypanosoma cruzi infections is critical ly dependent on cytokine- mediated macrophage activation to intracellu lar killing. We investigated the roles of IL-IO, TNF, IFN-gamma, and I L-12 in the control of parasitism by innate and specific immunity. Mic e with disrupted IL-10 genes (IL-10 KO) infected with Y strain T. cruz i have lower parasite numbers in the blood and tissues and higher IFN- gamma and nitric oxide (NO) production by spleen cells than wild type (WT) mice. Treatment of IL-10 KO and WT mice with recombinant IL-10 re sulted in increased parasitemia. Mice with disrupted recombinase-activ ating genes (RAG/KO) that lack B and T cells provided a model for dete rmining the importance of innate immunity to resistance. RAG/KO and WT mice had similar parasitemia levels until Day 13 of infection, sugges tive of effective control of parasitism by the innate immune system du ring the early phase of infection; from then on parasitemia was higher in RAG/KO. Double RAG/IL-10 KO mice and RAG/KO mice had superimposabl e parasitemia curves, indicating that in the absence of T and B cells, endogenous IL-10 does not Limit the efficacy of the innate immune sys tem. Treatment of infected RAG/KO, IL-10/KO, and WT mice with anti-IFN -gamma, anti-TNF, or anti-IL-12 neutralizing mAbs increased parasitemi a levels showing the importance of endogenous production of these cyto kines in the control of parasitism by innate and specific immune respo nses. Spleen cells from anti-IL12-treated WT mice had diminished produ ction of IFN-gamma and NO, suggesting that early IFN-gamma synthesis i s most dependent on IL-12 stimulation. (C) 1996 Academic Press, Inc.