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

• Published in: Blood Vol. 115; no. 1; pp. 107 - 121
• Main Authors: Sánchez-Abarca, Luis I., Gutierrez-Cosio, Silvia, Santamaría, Carlos, Caballero-Velazquez, Teresa, Blanco, Belen, Herrero-Sánchez, Carmen, García, Juan L., Carrancio, Soraya, Hernández-Campo, Pilar, González, Francisco J., Flores, Teresa, Ciudad, Laura, Ballestar, Esteban, del Cañizo, Consuelo, San Miguel, Jesus F., Pérez-Simon, Jose A.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 07.01.2010; Americain Society of Hematology
• Subjects: Animals; Azacitidine - pharmacology; Biological and medical sciences; Bone Marrow Transplantation; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Proliferation - drug effects; Cell Survival - drug effects; DNA Methylation - drug effects; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Expression Profiling; Gene Expression Regulation - drug effects; Graft vs Host Disease - immunology; Hematologic and hematopoietic diseases; Humans; Immunity - drug effects; Immunity - genetics; Immunologic Factors - pharmacology; Lymphocyte Activation - drug effects; Lymphocyte Count; Male; Medical sciences; Mice; Promoter Regions, Genetic - genetics; Spleen - cytology; Spleen - drug effects; Survival Analysis; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - drug effects; Transplantation, Homologous; Antineoplastic agent; Immunomodulator; Azanucleoside; Treatment; Antimetabolic; Hematology; Azacitidine; Immunomodulation; Surgery; Triazine derivatives; Graft; Transplantation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-03-210393

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.