Azacytidine mitigates experimental sclerodermic chronic graft-versus-host disease

作者：Fransolet Gilles; Ehx Gregory; Somja Joan; Delens Loic; Hannon Muriel; Muller Josephine; Dubois Sophie; Drion Pierre; Caers Jo; Humblet Baron Stephanie; Delvenne Philippe; Beguin Yves; Conteduca Giuseppina; Baron Frederic^*

来源：Journal of Hematology & Oncology, 2016, 9(1): 53.

DOI：10.1186/s13045-016-0281-2

• AZA
• Azacytidine
• Decitabine
• DAC
• Treg
• Regulatory T cells
• GVHD
• Graft-versus-host disease
• Chronic graft-versus-host disease
• Sclerodermic graft-versus-host disease

Background: Previous 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 (CD(4+)Tconvs) but demethylated in Tregs.
Methods: Here, 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)).
Results: The 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 CD4(+)Tconvs and CD8(+) T cells from day +21 to day +35 after transplantation, as well as a lower proportion of CD4(+)Tconvs expressing the Ki67 antigen on day +21 demonstrating an anti-proliferating effect of the drug on T cells.
Conclusions: Our 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.

• 出版日期2016-7-4
• 单位KU Leuven