Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting.
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.
Sánchez-Abarca
Luis I
LI
Hospital Clínico Universitario de Salamanca y Centro de Investigación del Cáncer (CIC/CSIC), Salamanca, Spain.
Gutierrez-Cosio
Silvia
S
Santamaría
Carlos
C
Caballero-Velazquez
Teresa
T
Blanco
Belen
B
Herrero-Sánchez
Carmen
C
García
Juan L
JL
Carrancio
Soraya
S
Hernández-Campo
Pilar
P
González
Francisco J
FJ
Flores
Teresa
T
Ciudad
Laura
L
Ballestar
Esteban
E
Del Cañizo
Consuelo
C
San Miguel
Jesus F
JF
Pérez-Simon
Jose A
JA
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
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007155:Immunologic Factors; D001374:Azacitidine