title: Azacytidine mitigates experimental sclerodermic chronic graft-versus-host disease.
abstract: 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 (CD4(+)Tconvs) but demethylated in Tregs.
  
  
  
  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)).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I3, Laboratory of Hematology, University of Liège, Liège, Belgium.
authors.forename: Gilles
authors.initials: G
authors.lastname: Fransolet
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I3, Laboratory of Hematology, University of Liège, Liège, Belgium.
authors.forename: Grégory
authors.initials: G
authors.lastname: Ehx
authors.affiliation: GIGA-R, Department of Pathology, University of Liège, Liège, Belgium.
authors.forename: Joan
authors.initials: J
authors.lastname: Somja
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I3, Laboratory of Hematology, University of Liège, Liège, Belgium.
authors.forename: Loïc
authors.initials: L
authors.lastname: Delens
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I3, Laboratory of Hematology, University of Liège, Liège, Belgium.
authors.forename: Muriel
authors.initials: M
authors.lastname: Hannon
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I3, Laboratory of Hematology, University of Liège, Liège, Belgium.
authors.forename: Joséphine
authors.initials: J
authors.lastname: Muller
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I3, Laboratory of Hematology, University of Liège, Liège, Belgium.|Department of Medicine, Division of Hematology, CHU of Liège, Liège, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dubois
authors.affiliation: GIGA-R, Animal care unit, University of Liège, Liège, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Drion
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I3, Laboratory of Hematology, University of Liège, Liège, Belgium.|Department of Medicine, Division of Hematology, CHU of Liège, Liège, Belgium.|Department of Hematology, University of Liège, CHU Sart-Tilman, 4000, Liège, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Caers
authors.affiliation: Translational Immunology Laboratory, VIB, Leuven, Belgium.|Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Humblet-Baron
authors.affiliation: GIGA-R, Department of Pathology, University of Liège, Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I3, Laboratory of Hematology, University of Liège, Liège, Belgium.|Department of Medicine, Division of Hematology, CHU of Liège, Liège, Belgium.|Department of Hematology, University of Liège, CHU Sart-Tilman, 4000, Liège, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Beguin
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I3, Laboratory of Hematology, University of Liège, Liège, Belgium.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Conteduca
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I3, Laboratory of Hematology, University of Liège, Liège, Belgium. f.baron@ulg.ac.be.|Department of Medicine, Division of Hematology, CHU of Liège, Liège, Belgium. f.baron@ulg.ac.be.|Department of Hematology, University of Liège, CHU Sart-Tilman, 4000, Liège, Belgium. f.baron@ulg.ac.be.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baron
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D001374:Azacitidine / Q000008:administration & dosage*; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D004334:Drug Administration Schedule; D051858:Forkhead Transcription Factors / Q000235:genetics; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D012595:Scleroderma, Systemic / Q000517:prevention & control*; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000964:Antimetabolites, Antineoplastic; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D001374:Azacitidine
keywords: AZA; Azacytidine; Chronic graft-versus-host disease; DAC; Decitabine; GVHD; Graft-versus-host disease; Regulatory T cells; Sclerodermic graft-versus-host disease; Treg