title: Impact of the hypomethylating agent 5-azacytidine on dendritic cells function.
abstract: Recent evidence suggested that 5-azacytidine (5-aza) can impact important immune functions via epigenetic modifications, making it an attractive candidate for pharmacologic manipulation of the immune system. The aim of this work was to study the effects of 5-aza on human dendritic cells (DC) generated from peripheral blood monocytes, and to test the type of immune response induced in patients treated with 5-aza. On the phenotypic level, CD40 and CD86 expression was significantly increased on mature DC exposed to 5-aza (5-aza-DC), compared with control untreated DC. Mature control DC and mature 5-aza-DC secreted comparable amounts of interleukin (IL)-6, IL-12p70, IL-23, and tumor necrosis factor-α. However, mature 5-aza-DC secreted significantly lower levels of IL-10 and IL-27 compared to mature control DC (p = 0.04 and p = 0.005, respectively). In the peripheral blood of 14 patients (7 males and 7 females; age range, 53-81 years) with advanced myeloid malignancies (8 acute myeloid leukemia and 6 myelodysplastic syndrome) treated with 5-aza, there was a significant decrease of IL-4-secreting CD4(+) T cells (p = 0.001), and a significant increase of IL-17A- and IL-21-secreting CD4(+) T cells (p = 0.003 and p = 0.01, respectively, compared to 5 healthy donors) suggesting a Th17 response pattern in the blood of patients receiving 5-aza. In all, these data suggest potentially novel mechanisms of action of epigenetic therapies, such as 5-aza, which may have broader implications for immunotherapeutic strategies.
authors.affiliation: Nantes, France.
authors.forename: Jihane
authors.initials: J
authors.lastname: Frikeche
authors.forename: Aline
authors.initials: A
authors.lastname: Clavert
authors.forename: Jacques
authors.initials: J
authors.lastname: Delaunay
authors.forename: Eolia
authors.initials: E
authors.lastname: Brissot
authors.forename: Marc
authors.initials: M
authors.lastname: Grégoire
authors.forename: Béatrice
authors.initials: B
authors.lastname: Gaugler
authors.forename: Mohamad
authors.initials: M
authors.lastname: Mohty
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D057890:Epigenomics; D005260:Female; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D007167:Immunotherapy / Q000379:methods; D007378:Interleukins / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D007378:Interleukins; D001374:Azacitidine