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Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting

2009; Elsevier BV; Volume: 115; Issue: 1 Linguagem: Inglês

10.1182/blood-2009-03-210393

1528-0020

Luís I. Sánchez-Abarca, Silvia Gutierrez-Cosío, Carlos Santamaría, Teresa Caballero‐Velázquez, Belén Blanco, Carmen Herrero-Sánchez, Juan Luis Garcı́a, Soraya Carrancio, Pilar Hernández-Campo, Xavier González-Argenté, Teresa Flores, Laura Ciudad, Esteban Ballestar, Consuelo del Cañizo, Jesús F. San Miguel, José Antonio Pérez‐Simón,

Cytomegalovirus and herpesvirus research

Abstract Cytokine genes are targets of multiple epigenetic mechanisms in T lymphocytes. 5-azacytidine (5-azaC) is a nucleoside-based DNA methyltransferase inhibitor that induces demethylation and gene reactivation. In the current study, we analyzed the effect of 5-azaC in T-cell function and observed that 5-azaC inhibits T-cell proliferation and activation, blocking cell cycle in the G0 to G1 phase and decreasing the production of proinflammatory cytokines such as tumor necrosis factor-α and interferon-γ. This effect was not attributable to a proapoptotic effect of the drug but to the down-regulation of genes involved in T-cell cycle progression and activation such as CCNG2, MTCP1, CD58, and ADK and up-regulation of genes that induce cell-growth arrest, such as DCUN1D2, U2AF2, GADD45B, or p53. A longer exposure to the drug leads to demethylation of FOXP3 promoter, overexpression of FOXP3, and expansion of regulatory T cells. Finally, the administration of 5-azaC after transplantation prevented the development of graft-versus-host disease, leading to a significant increase in survival in a fully mismatched bone marrow transplantation mouse model. In conclusion, the current study shows the effect of 5-azaC in T lymphocytes and illustrates its role in the allogeneic transplantation setting as an immunomodulatory drug, describing new pathways that must be explored to prevent graft-versus-host disease.