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Specific depletion of myeloid-derived suppressor cells by the chemotherapeutic agent 5-Fluorouracil enhances protective immune response in Paracoccidioidomycosis.
Preite, Nycolas Willian; Kaminski, Valéria de Lima; Borges, Bruno Montanari; Dos Santos, Bianca Vieira; Calich, Vera Lúcia Garcia; Loures, Flávio Vieira.
Afiliação
  • Preite NW; Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, São Paulo, Brazil.
  • Kaminski VL; Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, São Paulo, Brazil.
  • Borges BM; Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, São Paulo, Brazil.
  • Dos Santos BV; Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, São Paulo, Brazil.
  • Calich VLG; Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
  • Loures FV; Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, São Paulo, Brazil.
J Infect Dis ; 2024 Jul 11.
Article em En | MEDLINE | ID: mdl-38990787
ABSTRACT

BACKGROUND:

Paracoccidioidomycosis (PCM), a systemic mycosis in Latin America, is regulated by suppressive mechanisms mediated by tolerogenic plasmacytoid-dendritic-cells and regulatory T-cells. Our recent studies revealed that myeloid-derived suppressor cells (MDSCs), are important mediators in PCM. Their suppressive activity on Th1/Th17 immunity was shown to be mediated by inhibitory effect of IL-10, IDO-1 and PD-L1. Studies revealed the chemotherapeutic drug 5-Fluorouracil (5-FU) as a selective MDSC apoptosis-inducing agent, but its in vivo effect on infectious processes remains poorly investigated.

METHODS:

MDSCs and other leukocytes were evaluated in the lungs of 5-FU-treated mice after four, six, and eight weeks of P. brasiliensis infection. Disease severity and immunological response were evaluated in MDSCs-depleted.

RESULTS:

5-FU treatment caused a significant reduction of pulmonary MDSCs and fungal loads. The specific depletion of MDSCs by 5-FU reduced all pulmonary CD4+ T-cell populations (Th1, Th2, Th17, and Treg) resulting in improved tissue pathology and increased survival rates. Importantly, this reduction was concomitant with increased frequencies of Th1/Th17 cells and the increased levels of Th1/Th2/Th17 cytokines in the lungs and liver of treated mice suggesting an early and efficient protective effect of these cells. Furthermore, the immuneprotection conferred by the specific depletion of MDSCs by 5FU treatment could be reversed by the adoptive transfer of MDSCs.

CONCLUSIONS:

5-FU treatment depletes lung-MDSCs of P. brasiliensis-infected mice resulting in enhanced immunity. The protective effect of 5-FU treatment in pulmonary PCM suggests that the specific depletion of MDSCs can be viewed as a potential immunotherapeutic tool for PCM.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: J Infect Dis Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: J Infect Dis Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos