title: The effects of 5-azacytidine on the function and number of regulatory T cells and T-effectors in myelodysplastic syndrome.
abstract: Expansion of regulatory T cells occurs in high-risk myelodysplastic syndrome and correlates with a poor prognosis. DNA methyltransferase inhibitors, particularly 5-azacytidine, have been shown to increase the survival of patients with high-risk myelodysplastic syndrome. It is not entirely clear whether this improvement in patients' survival is related to the effects of DNA methyltransferase inhibitors on the immune system and/or the direct effect of these drugs on the dysplastic clone. In this study we investigated the effect of 5-azacytidine on the function and proliferation capability of regulatory T cells and T-helper cells. The number and function of CD4(+) T-cell subsets in 68 patients with intermediate-2/high-risk myelodysplastic syndrome were serially assessed at diagnosis and following treatment. The in-vitro effects of 5-azacytidine on CD4(+) T-cell subsets isolated from both healthy donors and patients with myelodysplastic syndrome were also investigated. The number of peripheral blood regulatory T cells was significantly higher in myelodysplastic syndrome patients than in healthy donors and responders to treatment (P=0.01). The absolute numbers of T-helper 1 and T-helper 2, but not T-helper 17, cells were significantly reduced following 12 months of treatment (P=0.03, P=0.03). The in vitro addition of 5-azacytidine to CD4(+) T cells reduced the proliferative capacity of regulatory T cells (P=0.03). In addition, the 5-azacytidine-treated regulatory T cells had reduced suppressive function and produced larger amounts of interleukin-17. The FOXP3 expression in 5-azacyti-dine-treated T-effectors was also increased. Interestingly, these FOXP3(+)/interleukin-17(+) cells originated mainly from effector T cells rather than regulatory T cells. Our data suggest that 5-azacytidine has profound effects on CD4(+) T cells, which correlate with disease status after treatment. Furthermore, despite the demethylation of the FOXP3 promoter and increased FOXP3 expression following 5-azacytidine treatment, these phenotypic regulatory T cell-like cells lack the regulatory function and cytokine profile of regulatory T cells. These findings are important in correlating the clinically relevant immunomodulatory effects of 5-azacytidine.
authors.affiliation: King’s College London, Department of Haematological Medicine, London, UK.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Costantini
authors.forename: Shahram Y
authors.initials: SY
authors.lastname: Kordasti
authors.forename: Austin G
authors.initials: AG
authors.lastname: Kulasekararaj
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.forename: Thomas
authors.initials: T
authors.lastname: Seidl
authors.forename: Pilar Perez
authors.initials: PP
authors.lastname: Abellan
authors.forename: Azim
authors.initials: A
authors.lastname: Mohamedali
authors.forename: Nicolas Shaun B
authors.initials: NS
authors.lastname: Thomas
authors.forename: Farzin
authors.initials: F
authors.lastname: Farzaneh
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018655:Lymphocyte Count / Q000379:methods; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D001374:Azacitidine