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Abstract :
[en] The demethylating agent 5-azacytidine (AZA) has proven its efficiency in myeloid malignancies treatment. Recently, several studies have shown that AZA also presents an immunomodulatory activity, mainly through the induction of regulatory T cells (Treg) differentiation from conventional T cells. Treg promotion is a promising treatment option for graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. In this way, AZA has been shown to reduce GVHD in mouse-to-mouse transplantation models. However, the impact of AZA on human GVHD remains elusive as well as its effects on human Treg and on the other T cell subsets in vivo. Here we report AZA impact on GVHD in a xeno-transplantation model of the disease and describe the overall effects of the drug on human T cells in vivo. When administered to NSG mice receiving 2.107 human PBMC intravenously, AZA successfully ameliorated both survival (p < 0.001) and GVHD score. Flow cytometry analyses showed that this improvement may be mediated through an anti-proliferative effect of AZA on human T cells while these cells presented an increased activation state. We also observed a significant decrease of Th1 and 2 differentiation, assessed by RT-qPCR and cytokines secretion assays, and a reduced production of granzyme B and perforin 1 by cytotoxic T cells. As expected, AZA dramatically augmented Treg frequency while we could also observe a promotion of their IL-2 mediated proliferation over conventional T cells. Interestingly, Th17 frequency was not affected by AZA, therefore increasing the balance Treg/Th17. Finally our data suggest that AZA-induced Treg may have an improved suppressive activity and present long-term stability in vivo. Altogether our findings suggest that AZA may be a promising treatment option for GVHD in the clinical setting.