title: Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting.
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 G(0) to G(1) phase and decreasing the production of proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma. 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.
authors.affiliation: Hospital Clínico Universitario de Salamanca y Centro de Investigación del Cáncer (CIC/CSIC), Salamanca, Spain.
authors.forename: Luis I
authors.initials: LI
authors.lastname: Sánchez-Abarca
authors.forename: Silvia
authors.initials: S
authors.lastname: Gutierrez-Cosio
authors.forename: Carlos
authors.initials: C
authors.lastname: Santamaría
authors.forename: Teresa
authors.initials: T
authors.lastname: Caballero-Velazquez
authors.forename: Belen
authors.initials: B
authors.lastname: Blanco
authors.forename: Carmen
authors.initials: C
authors.lastname: Herrero-Sánchez
authors.forename: Juan L
authors.initials: JL
authors.lastname: García
authors.forename: Soraya
authors.initials: S
authors.lastname: Carrancio
authors.forename: Pilar
authors.initials: P
authors.lastname: Hernández-Campo
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: González
authors.forename: Teresa
authors.initials: T
authors.lastname: Flores
authors.forename: Laura
authors.initials: L
authors.lastname: Ciudad
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
authors.forename: Consuelo
authors.initials: C
authors.lastname: Del Cañizo
authors.forename: Jesus F
authors.initials: JF
authors.lastname: San Miguel
authors.forename: Jose A
authors.initials: JA
authors.lastname: Pérez-Simon
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000494:pharmacology*; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006086:Graft vs Host Disease / Q000276:immunology; D006801:Humans; D007109:Immunity / Q000187:drug effects / Q000235:genetics; D007155:Immunologic Factors / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects; D014184:Transplantation, Homologous
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007155:Immunologic Factors; D001374:Azacitidine