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.
Subject(s)
Graft vs Host Disease/etiology , Th1 Cells/drug effects , Th1 Cells/immunology , Th17 Cells/drug effects , Th17 Cells/immunology , Valproic Acid/pharmacology , 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/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/metabolism , Th17 Cells/cytology , Th17 Cells/metabolism , Transplantation, Homologous , Valproic Acid/administration & dosageABSTRACT
For adult patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation(allo-HSCT) from HLA-matched related donors(MSD) is recommended for standard and high-risk patients. The role of unrelated donor transplantation (URD) in first remission has not been fully determined. We sought to compare directly the outcome of URD allo-HSCT and chemotherapy in patients with high-risk ALL. In this single center retrospective analysis, we included 74 consecutive adult patients with high-risk ALL in first complete remission(CR) and without a sibling donor, in which 32 patients received URD allo-HSCT in CR1 with busulfan-cyclophosphamide preparation regimen and in vivo T-cell depletion with anti-T-lymphoglobulin (ATG). The remaining 42 patients received chemotherapy consolidation and maintenance only in first remission. With median follow-up of 18 months, in the URD allo-HSCT group, the relapse rate(RR) was 30.6 ± 11.4 % which was significantly lower than that of the chemotherapy group (80.5 ± 10.1 %,p < 0.001), while non-relapse mortality (NRM) was higher(16.4 ± 6.7 % vs. 0, p = 0.028). Overall, 3-year leukemia free survival (LFS) was superior in the URD allo-HSCT group compared to chemotherapy group (57.8 ± 10.6 vs.19.5 ± 10.5 %, p = 0.002), as was 3-year overall survival(OS, 63.5 ± 13.3 vs. 31.6 ± 10.6 %, p = 0.016). URDHSCT was the only factor associated with improved OS, LFS and reduced RR in multivariate analysis. Based on our data, URD allo-HSCT significantly reduced the relapse in high-risk ALL and the benefit translated into improvement in both LFS and OS. Prospective studies based on availability of HLA-matched URD are warranted to evaluate the precise role of URD transplantation in adult ALL.
