Azacytidine prevents experimental xenogeneic graft-versus-host disease without abrogating graft-versus-leukemia effects.

Détails

ID Serval
serval:BIB_82EA43119A1E
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Azacytidine prevents experimental xenogeneic graft-versus-host disease without abrogating graft-versus-leukemia effects.
Périodique
Oncoimmunology
Auteur(s)
Ehx G., Fransolet G., de Leval L., D'Hondt S., Lucas S., Hannon M., Delens L., Dubois S., Drion P., Beguin Y., Humblet-Baron S., Baron F.
ISSN
2162-4011 (Print)
ISSN-L
2162-4011
Statut éditorial
Publié
Date de publication
2017
Peer-reviewed
Oui
Volume
6
Numéro
5
Pages
e1314425
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
The demethylating agent 5-azacytidine (AZA) has proven its efficacy in the treatment of myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 (FOXP3i1) leading to the generation of regulatory T cells (Treg). Here, we investigated the impact of AZA on xenogeneic graft-vs.-host disease (xGVHD) and graft-vs.-leukemia effects in a humanized murine model of transplantation (human PBMCs-infused NSG mice), and described the impact of the drug on human T cells in vivo. We observed that AZA improved both survival and xGVHD scores. Further, AZA significantly decreased human T-cell proliferation as well as IFNγ and TNF-α serum levels, and reduced the expression of GRANZYME B and PERFORIN 1 by cytotoxic T cells. In addition, AZA significantly increased Treg frequency through hypomethylation of FOXP3i1 as well as increased Treg proliferation. The latter was subsequent to higher STAT5 signaling in Treg from AZA-treated mice, which resulted from higher IL-2 secretion by conventional T cells from AZA-treated mice itself secondary to demethylation of the IL-2 gene promoter by AZA. Importantly, Tregs harvested from AZA-treated mice were suppressive and stable over time since they persisted at high frequency in secondary transplant experiments. Finally, graft-vs.-leukemia effects (assessed by growth inhibition of THP-1 cells, transfected to express the luciferase gene) were not abrogated by AZA. In summary, our data demonstrate that AZA prevents xGVHD without abrogating graft-vs.-leukemia effects. These findings could serve as basis for further studies of GVHD prevention by AZA in acute myeloid leukemia patients offered an allogeneic transplantation.

Mots-clé
Azacytidine, NOD-scid IL-2Rγnull, graft-vs.-host disease, graft-vs.-leukemia effect, regulatory T cells
Pubmed
Web of science
Création de la notice
26/06/2017 18:23
Dernière modification de la notice
03/03/2018 18:51
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