Valproic Acid Ameliorates Graft-versus-Host Disease by Downregulating Th1 and Th17 Cells

J Immunol. 2015 Aug 15;195(4):1849-57. doi: 10.4049/jimmunol.1500578. Epub 2015 Jul 15.

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.

MeSH terms

  • Animals
  • Bone Marrow Transplantation / adverse effects
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Disease Models, Animal
  • Female
  • Graft vs Host Disease / drug therapy
  • Graft vs Host Disease / etiology*
  • Graft vs Host Disease / metabolism
  • Graft vs Host Disease / pathology
  • Immunity, Cellular / drug effects
  • Immunity, Cellular / immunology
  • Mice
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Severity of Illness Index
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Th1 Cells / cytology
  • Th1 Cells / drug effects*
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Th17 Cells / cytology
  • Th17 Cells / drug effects*
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism
  • Transplantation, Homologous
  • Valproic Acid / administration & dosage
  • Valproic Acid / pharmacology*

Substances

  • Valproic Acid
  • Proto-Oncogene Proteins c-akt