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 critically dependent on cytokine-mediated macrophage activation to intracellular killing. We investigated the roles of IL-10, TNF, IFN-gamma, and IL-12 in the control of parasitism by innate and specific immunity. Mice with disrupted IL-10 genes (IL-10 KO) infected with Y strain T. cruzi 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 resulted in increased parasitemia. Mice with disrupted recombinase-activating genes (RAG/KO) that lack B and T cells provided a model for determining the importance of innate immunity to resistance. RAG/KO and WT mice had similar parasitemia levels until Day 13 of infection, suggestive of effective control of parasitism by the innate immune system during the early phase of infection; from them on parasitemia was higher in RAG/KO. Double RAG/IL-10 KO mice and RAG/KO mice had superimposable parasitemia curves, indicating that in the absence of T and B cells, endogenous IL-10 does not limit the efficacy of the innate immune system. Treatment of infected RAG/KO, IL-10/KO, and WT mice with anti-IFN-gamma, anti-TNF, or anti-IL-12 neutralizing mAbs increased parasitemia levels showing the importance of endogenous production of these cytokines in the control of parasitism by innate and specific immune responses. Spleen cells from anti-IL 12-treated WT mice had diminished production of IFN-gamma and NO, suggesting that early IFN-gamma synthesis is most dependent on IL-12 stimulation.
Abrahamsohn
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IA
Departamento de Imunologia, Universidade de Säo Paulo, Brasil.
Coffman
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002478:Cells, Cultured; D014355:Chagas Disease / Q000276:immunology* / Q000469:parasitology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D007110:Immunity, Active; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology*; D015603:Keratinocytes / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D009573:Nitrites / Q000378:metabolism; D018512:Parasitemia; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000254:growth & development / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
D000911:Antibodies, Monoclonal; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma