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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Programmed Cell Death Protein 1-PDL1 Interaction Prevents Heart Damage in Chronic Trypanosoma cruzi Infection

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Autor(es):
Fonseca, Raissa [1] ; Salgado, Rafael Moyses [1] ; da Silva, Henrique Borges [2] ; do Nascimento, Rogerio Silva [1] ; D'Imperio-Lima, Maria Regina [1] ; Alvarez, Jose Maria [1]
Número total de Autores: 6
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Lab Immunol Infect Dis, Sao Paulo - Brazil
[2] Univ Minnesota, Dept Lab Med & Pathol, Ctr Immunol, Minneapolis, MN 55455 - USA
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: FRONTIERS IN IMMUNOLOGY; v. 9, MAY 7 2018.
Citações Web of Science: 3
Resumo

Chagas disease is a neglected parasitic infection that affects around six to seven million people, mainly in Latin America. About 30-35% of infected people present chronic Chagas cardiomyopathy (CCC), which eventually leads to death. This condition is characterized by local parasite persistence and leukocyte infiltration. In a murine model of CCC, we observed that among infiltrating leukocytes, CD4(+) and CD8(+) T cells were in higher frequency in the heart of chronically infected mice, although elevated expression of the regulatory molecules programmed cell death protein 1 (PD1) and PDL1 suggested these cells could be inhibited. To investigate if PD1-PDL1 interaction in the heart of chronically infected mice negatively impacts on the local immune response, facilitating parasite persistence, and progression to CCC, we attempted to recover the local immune response by treating chronically infected mice with anti-PD1 and anti-PDL1-blocking antibodies together with irradiated Trypanosoma cruzi, which provides immune response boosting. Irradiated parasites promote expression of costimulatory molecules in dendritic cells and provide specific parasite antigen, which should aid T cell reactivation upon checkpoint blockade. Following treatment, there was an increased frequency of heart-infiltrating CD4(+) and CD8(+) T cells with an effector memory phenotype, an increased histopathology score and decreased heart rate, supporting our previous hypothesis of local immunosuppression induced by this pathway during CCC. In addition, blood parasitemia was reduced, which was associated with increased T. cruzi-specific immunoglobulin G 1 antibodies. However, no difference was observed in cytokine production or T. cruzi burden in the hearts of treated mice. Taken together, our results suggest PD1-PDL1 interaction protects the heart from excessive immune response. (AU)

Processo FAPESP: 15/20432-8 - Intervenção em vias de sinalização associadas ao reconhecimento de dano celular visando reduzir a patologia das formas graves de malária e tuberculose
Beneficiário:Maria Regina D'Império Lima
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 14/03802-3 - Análise do papel modulador da interação PD-1/PD-L1 na fase crônica da infecção murina pelo Trypanosoma cruzi
Beneficiário:Raíssa Fonseca
Linha de fomento: Bolsas no Brasil - Doutorado Direto
Processo FAPESP: 13/08199-0 - Estudo da infecção murina pelo clone de Trypanosoma cruzi Sylvio X10/4, um parasita de baixa virulência
Beneficiário:José Maria Álvarez Mosig
Linha de fomento: Auxílio à Pesquisa - Regular