Azacytidine mitigates experimental sclerodermic chronic graft-versus-host diseaseReportar como inadecuado




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Journal of Hematology and Oncology

, 9:53

First Online: 04 July 2016Received: 01 April 2016Accepted: 21 June 2016DOI: 10.1186-s13045-016-0281-2

Cite this article as: Fransolet, G., Ehx, G., Somja, J. et al. J Hematol Oncol 2016 9: 53. doi:10.1186-s13045-016-0281-2

Abstract

BackgroundPrevious studies have demonstrated that regulatory T cells Tregs play a protective role in the pathogenesis of chronic graft-versus-host disease cGVHD. Tregs constitutively express the gene of the transcription factor Foxp3 whose CNS2 region is heavily methylated in conventional CD4 T cells CD4Tconvs but demethylated in Tregs.

MethodsHere, we assessed the impact of azacytidine AZA on cGVHD in a well-established murine model of sclerodermic cGVHD B10.D2 H-2d → BALB-cJ H-2d.

ResultsThe administration of AZA every 48 h from day +10 to day +30 at the dose of 0.5 mg-kg or 2 mg-kg mitigated chronic GVHD. Further, AZA-treated mice exhibited higher blood and thymic Treg frequencies on day +35, as well as higher demethylation levels of the Foxp3 enhancer and the IL-2 promoter in splenocytes at day +52. Interestingly, Tregs from AZA-treated mice expressed more frequently the activation marker CD103 on day +52. AZA-treated mice had also lower counts of CD4Tconvs and CD8 T cells from day +21 to day +35 after transplantation, as well as a lower proportion of CD4Tconvs expressing the Ki67 antigen on day +21 demonstrating an anti-proliferating effect of the drug on T cells.

ConclusionsOur results indicate that AZA prevented sclerodermic cGVHD in a well-established murine model of cGVHD. These data might serve as the basis for a pilot study of AZA administration for cGVHD prevention in patients at high risk for cGVHD.

KeywordsAZA Azacytidine Decitabine DAC Treg Regulatory T cells GVHD Graft-versus-host disease Chronic graft-versus-host disease Sclerodermic graft-versus-host disease GF and GE are co-first authors; GC and FB are co-senior authors.

Electronic supplementary materialThe online version of this article doi:10.1186-s13045-016-0281-2 contains supplementary material, which is available to authorized users.

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Autor: Gilles Fransolet - Grégory Ehx - Joan Somja - Loïc Delens - Muriel Hannon - Joséphine Muller - Sophie Dubois - Pierre D

Fuente: https://link.springer.com/







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