A função da IL-10 na paracoccidioidomise pulmonar murina. / The role of IL-10 in murine pulmonary paracoccidioidomycosis.

Tânia Alves da Costa

Cellular immunity is the main defense mechanism of hosts infected by the Paracoccidioide brasiliensis (Pb), a dimorphic fungus that causes the most important systemic mycosis in Latin America. IFN-g activated macrophages participate in this activity that is antagonized by IL-10 an anti-inflammatory cytokine. Both, in the human pathology and in experimental models, there are a number of evidences indicating that IL-10 acts as a suppressor of cellular immunity leading to deleterious effects to the hosts. However, direct studies aimed at investigating the function of IL-10 in the immunity to paracoccidioidomycosis (PCM) have not been performed. Thus, the fundamental objective of this work was to study the function of IL-10 in the mechanisms of innate and adaptive immunity against Pb using as experimental model IL-10 deficient mice (IL-10 Knockout, IL-10 KO) compared to their respective wild type (WT) controls. We demonstrated in vitro that normal peritoneal macrophages of IL-10 KO mice presented increased phagocytic and microbicidal activities than macrophages of WT mice and this was associated witch an elevated production of IFN-g, TNF-α, nitric oxide (NO) and the chemokine MCP-1. However, the production of IFN-g seen to be performed by NTK cells contaminating adherent macrophages, suggesting a possible participation of these cells in the activation of macrophages and T cells of IL-10 KO mice. In vivo studies revealed that at the second week of infection IL-10 KO mice presented an earlier immune response when compared to wild-type mice, since their lungs exhibited a significantly reduced fungal burden and an increased production of almost all antibodies isotypes (IgM, IgG1, IgGM, IgG2b). This effect was accompanied by a total absence of IL-4 and IL-5, showing a regulatory action of IL-10 in the synthesis of Th2 cytokines. Four weeks post-infection, the fungal load was still lower in the IL-10 KO mice but no differences in antibody synthesis was observed. However, the analysis of lung infiltrating leukocytes revealed an increased frequency of TCD4+ and TCD4+CD44 high lymphocytes in IL-10 KO mice, again demonstrating an early activation of cellular immunity in IL-10 KO mice. When compared with WT mice, the pulmonary fungal loads of IL-10 KO mice at week 8 of infection were drastically reduced and no dissemination to other organs were observed. The histopathological analysis revealed an absence of granulomas and fungi in the lungs of IL-10 KO in comparison with WT mice. The analysis of lung infiltrating leukocytes showed that IL-10 KO mice had a reduction in the frequency of B cells, in agreement with the reduced synthesis of immunoglobulins. An increased frequency of activated T CD4+ and a drastic increase of TCD4+ and T CD8+ effector/memory cells charactering once again an efficient immune response associated with IL-10 deficiency. In later stages, sixteen weeks after infection, a regressive infection of IL-10 KO mice was further characterized by low numbers of fungi in the lung, reduced synthesis of cytokines (IL-4 and IL-5) and anti- P. brasiliensis antibodies. By week 23 after infection, in addition to the characteristic reduction of fungal loads and reduced frequency of immune cells, we observed a decrease in the frequency of Treg cells, demonstrating the implication of IL-10 in the control of this T cell population. The elevated survival (90%) of IL-10 KO mice was in total agreement with the low fungal burdens and efficient immune response observed during infection. In conclusion, our work demonstrates for the first time that IL-10 plays a major role in the control of innate and adaptive immunity to Pb infection.

A função da IL-10 na paracoccidioidomise pulmonar murina. / The role of IL-10 in murine pulmonary paracoccidioidomycosis.

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