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Blood First Edition Paper, prepublished online November 3, 2009; DOI 10.1182/blood-2009-03-210393. This Article Full Text (PDF) Supplemental Figures Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Sanchez-Abarca, L. I Articles by Perez-Simon, J. A PubMed PubMed Citation Articles by Sanchez-Abarca, L. I Articles by Perez-Simon, J. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 11, 2009; accepted September 28, 2009. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting Luis I Sanchez-Abarca1, Silvia Gutierrez-Cosio1, Carlos Santamaria1, Teresa Caballero-Velazquez2, Belen Blanco2, Carmen Herrero-Sanchez2, Juan L Garcia2, Soraya Carrancio2, Pilar Hernandez-Campo1, Francisco J Gonzalez3, Teresa Flores4, Laura Ciudad5, Esteban Ballestar5, Consuelo del Canizo2, Jesus F San Miguel2 and Jose A Perez-Simon2,5 1 Centro de Investigacion del Cancer (CIC/CSIC), Salamanca, Spain; 2 Servicio de Hematologia, Hospital Clinico Universitario de Salamanca, Salamanca, Spain; 3 OncoStem Pharma, Salamanca, Spain; 4 Servicio de Anatomia Patologica, Hospital Clinico Universitario de Salamanca, Salamanca, Spain; 5 Cromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL) * Corresponding author; email: pesimo{at}usal.es Abstract Cytokine genes are targets of multiple epigenetic mechanisms in T lymphocytes. 5-azacytidine (5-azaC) is a nucleoside-based DNA methyltransferases (DNMT) inhibitor which 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 G0-G1 phase and decreasing the production of proinflammatory cytokines such as TNF and IFN. This effect was not due to a pro-apoptotic 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 which induce cell growth arrest, such as DCUN1D2, U2AF2, GADD45B or p53. A longer exposure to the drug leads to demethylation of FOXP3 promoter, over-expression of FOXP3 and expansion of regulatory T cells. Finally, the administration of 5-azaC post-transplant prevented the development of GVHD leading to a significant increase in survival in a fully mismatched BMT 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 which must be explored in order to prevent graft-versus-host disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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