The long-term aim of this research project is to gain a better understanding of the involvement of defined T- cell subpopulations in the establishment of protective and/or pathogenic immune responses in human Chagas' disease, a prevalent and endemic parasitic disease caused by the infection with Trypanosoma cruzi. Through a series of comprehensive mechanistic studies we will dissect the role of CD4+ and CD8+ T cells with differential expression of CD28 in the dynamics of the immune response in human Chagas' disease.
Specific aims are: 1.Determine the adhesion molecule expression by CD28+ and CD28- T cells from individuals with different clinical forms of Chagas' disease; 2. Determine the intensity and specificity of the cytotoxic function of CD28+ and CD28- T cells from individuals with different clinical forms of Chagas' disease; 3. Determine the regulatory function of CD28+ and CD28- T cells from individuals with different clinical forms of Chagas' disease. To perform these studies we will use peripheral blood mononuclear cells from a selected group of chagasic patients, carefully classified as belonging to the indeterminate or severe cardiac clinical forms. Cellular recruitment potential, cytotoxicity and regulatory functions will be evaluated ex vivo and after in vitro stimulation with parasite, as well as autologous antigens, through the analysis of expression of surface or intracellular molecules by FACS and by biological assays. These studies will greatly improve the knowledge on Chagas' disease immunopathology by clarifying how CD28+ and CD28- sub- populations relate to the differential clinical evolution of disease. We hope that the new concepts derived from our findings will allow for the identification of markers of disease evolution and/or morbidity, offering new possibilities of clinical intervention to benefit the 17 million infected people. Transcending the limits of Chagas' disease, our findings will add to our knowledge on the biology of human T cells with differential expression of CD28, opening new possibilities of studies in other human diseases. Finally, depending largely on a Brazilian scientific core of researchers and students, the implementation of these studies will also lead to increased research capacities in Brazil through intense collaborations with international and national specialists. ? ? ?
| Dutra, W O; Menezes, C A S; Magalhães, L M D et al. (2014) Immunoregulatory networks in human Chagas disease. Parasite Immunol 36:377-87 |
| Magalhaes, Luisa M D; Villani, Fernanda N A; Nunes, Maria do Carmo P et al. (2013) High interleukin 17 expression is correlated with better cardiac function in human Chagas disease. J Infect Dis 207:661-5 |
| Menezes, C A S; Sullivan, A K; Falta, M T et al. (2012) Highly conserved CDR3 region in circulating CD4(+)V?5(+) T cells may be associated with cytotoxic activity in Chagas disease. Clin Exp Immunol 169:109-18 |
| Menezes, Cristiane; Costa, Germano Carneiro; Gollob, Kenneth J et al. (2011) Clinical aspects of Chagas disease and implications for novel therapies. Drug Dev Res 72:471-479 |
| Coelho dos Santos, J S; Menezes, C A S; Villani, F N A et al. (2010) Captopril increases the intensity of monocyte infection by Trypanosoma cruzi and induces human T helper type 17 cells. Clin Exp Immunol 162:528-36 |
| Villani, Fernanda Nobre Amaral; Rocha, Manoel Otavio da Costa; Nunes, Maria do Carmo Pereira et al. (2010) Trypanosoma cruzi-induced activation of functionally distinct ýýýý and ýýýý CD4- CD8- T cells in individuals with polar forms of Chagas' disease. Infect Immun 78:4421-30 |
| Dutra, Walderez Ornelas; Menezes, Cristiane Alves Silva; Villani, Fernanda Nobre Amaral et al. (2009) Cellular and genetic mechanisms involved in the generation of protective and pathogenic immune responses in human Chagas disease. Mem Inst Oswaldo Cruz 104 Suppl 1:208-18 |
