Benznidazole Treatment during Early‐indeterminate Chagas’ Disease Shifted the Cytokine Expression by Innate and Adaptive Immunity Cells toward a Type 1‐modulated Immune Profile

Trypanosoma cruzi‐infected children was treated with benznidazole (Bz) during the early‐indeterminate disease (E‐IND) and the cytokine pattern of innate and adaptive immune compartments were evaluated prior to the treatment and 1 year after it. At first, we observed that the ex vivo cytokine profile of circulating leukocytes from E‐IND (n = 6) resembled the one observed for healthy schoolchildren (n = 7). Additionally, in vitro stimulation with T. cruzi antigens drove the E‐IND cytokine pattern toward a mixed immune profile with higher levels of IFN‐γ+, TNF‐α+ and IL‐4+ NK cells, increased numbers of IFN‐γ+, TNF‐α+ and IL‐10+ CD4+ T cells in addition to enhanced frequency of TNF‐α+/IL‐4+ CD19+ lymphocytes. Interestingly, upon T. cruzi antigen in vitro stimulation, E‐IND CD8+ lymphocytes displayed a selective enhancement of IFN‐γ expression, accounting for a global type 1‐modulated cytokine microenvironment. A shift toward a type 1‐modulated profile was also the hallmark of Bz‐treated children (E‐INDT). In this context, despite the mixed overall ex vivo cytokine profile observed for NK and CD8+ T cells, increased ability of these leukocytes to produce IFN‐γ in response to T. cruzi antigens was reported. Most noteworthy was the IL‐10 production evidenced at T lymphocytes, mainly CD4+ cells, as well as B lymphocytes, both ex vivo and upon antigen stimulation. Together, these findings gave evidence that NK cells and CD8+ T lymphocytes are the major sources of IFN‐γ, a pivotal cytokine for successful therapeutic response in human Chagas’ disease. Moreover, our data have also brought additional information, pointing out IL‐10 production by CD4+ cells and B lymphocytes, as the putative key element for parasite clearance in the absence of deleterious tissue damage.