Study of influence of the Leishmania Chagasi infection and the therapeutical specific efficient of the impact in the cell immune reponse in carriers patients Leishmaniose visceral
We evaluated the cellular immunity profile associated with the infection for Leishmania chagasi and with the cure of Visceral Leishmaniasis (VL) after specific chemotherapy, by studying the plasmatic cytokine profile, nitric oxide (NO) levels and intracellular cytokine expression in the absence of stimuli as well as after short-term in vitro stimulation with soluble-Leishmania-antigen (SLA). Our results suggest that a strong and dysfunctional activation of the immune system occurs in patients with classic VL, characterized by the presence of high levels of inflammatory cytokines such as IL-8, IFN., TNF-a and IL-6 that is also associated with IL-10 expression. The increase on the inflammatory cytokine levels could be associated with the pathophysiologic changes observed in the active VL. On the other hand, IL-10 could be important for parasite survival and maintenance in the macrophages. This hypothesis is supported by the finding that in these patients there was a lower frequency of monocytes expressing TNF-a and basal levels of plasmatic NO. In contrast, asymptomatic VL individuals and non-infected individuals had similar profile, presenting basal levels of cytokine expression and plasmatic NO. Our analyses also demonstrated that cured individuals presented an increase on intracellular cytokine expression in innate as well as adaptive immunity, when compared with non-infected individuals. Interestingly, a higher frequency of TNF-a+ NK cells, IFN-.+ T and B lymphocytes were observed in the cured individuals and seemed to be related to the activation of leishmanicidal mechanisms. Further, a higher number of IL-4+ neutrophils and IL-4+ and IL-5+ T lymphocytes could be contributing for the establishment of Leishmania control mechanisms during VL infection. The current trend on the analysis of the role of these cytokines, especially IL-4, and their participation in the inhibition of the leishmanicidal response has been associated with the presence of higher levels of IL-10. After in vitro specific stimulation, we observed distinct immunity profile among asymptomatic individuals and classic VL patients. Our data demonstrated that, the cells of both, innate and adaptive immunity, from patients with classic VL showed an increase on IL-4 and IL10 expression and a decrease on the TNF-a, IFN-., IL-12 and IL-5 expression. Taken together, these data suggest that the antigenic-stimulation favors a type 2 immune response, facilitating parasite survival and disease development. In asymptomatic individuals, the LSA stimulation induced an increase on the both, type 1 cytokine expression, IFN-. and IL-12, as well as type 2 cytokines as IL-4 and IL-10. This profile, of a mixed cytokines milieu, would produce the establishment of balanced immune response, predominantly type 0. This immune response profile could be essential for the development of asymptomatic infection and disease control. The individuals could develop a modulated immune response favoring parasite destruction, therefore preventing inherent pathological alterations to the classic VL. On the other hand, in cured individuals, we observed that the LSA stimulation induced an important increase on the IFN-. expression regarding cells of the innate immunity, including neutrophils, eosinophils and NK cells, as well as an increase on the IL-12 monocyte expression. The increase on the IL-4 and IL-5 expression regarding cells of the adaptive immunity also suggests the participation of these cytokines in the establishment of anti-Leishmania protection mechanisms, since we observed in these individuals, basal IL-10 levels associated with higher IFN-. levels. In this context, we propose that, after the cure of the VL, the individuals are capable of developing a type 1 immune response, responsible for both the disease control and establishment of protective mechanisms mediated by the innate and adaptive immune responses.
Advisor:Olindo Assis Martins Filho; Rodrigo Corrêa de Oliveira
School:Faculdades Oswaldo Cruz
Source Type:Master's Thesis
Keywords:Leishmania infantum Leishmaniasis Visceral
Date of Publication:08/04/2006