title: Valproic Acid Ameliorates Graft-versus-Host Disease by Downregulating Th1 and Th17 Cells.
abstract: Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow transplantation. Valproic acid (VPA) was described as a histone deacetylase inhibitor that had anti-inflammatory effects and reduced the production of proinflammatory cytokines in experimental autoimmune disease models. Using well-characterized mouse models of MHC-mismatched transplantation, we studied the effects of VPA on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of VPA significantly attenuated the clinical severity of GVHD, the histopathology of GVHD-involved organs, and the overall mortality from GVHD. VPA downregulated Th1 and Th17 cell responses and cytokine production in vitro and in vivo, whereas its effect on GVHD was regulatory T cell independent. The effect of VPA was related to its ability to directly reduce the activity of Akt, an important regulator of T cell immune responses. Importantly, when mice received lethal doses of host-type acute leukemia cells, administration of VPA did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a unique role for VPA as a histone deacetylase inhibitor in reducing the donor CD4(+) T cells that contribute to GVHD, which may provide a strategy to reduce GVHD while preserving the GVL effect.
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Jun
authors.initials: J
authors.lastname: Long
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Li
authors.initials: L
authors.lastname: Chang
authors.affiliation: Research Center for Experimental Medicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Gao
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Yue-Nv
authors.initials: YN
authors.lastname: Wu
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Han-Bo
authors.initials: HB
authors.lastname: Dou
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Meng-Meng
authors.initials: MM
authors.lastname: Huang
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Wei-Yue
authors.initials: WY
authors.lastname: Fang
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Jie-Hui
authors.initials: JH
authors.lastname: Shan
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Yue-Ying
authors.initials: YY
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and hujiong@medmail.com.cn.
authors.forename: Jiong
authors.initials: J
authors.lastname: Hu
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D051379:Mice; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D014635:Valproic Acid; D051057:Proto-Oncogene Proteins c-akt