Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect
ABSTRACT Acute graft-versus-host disease (GVHD) and leukemic relapse are the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies have demonstrated that the dysregulation of proinflammatory cytokines and the loss of gastrointestinal tract integrity contribute to GVHD, whereas the donor cytotoxic responses are critical for graft-versus-leukemia (GVL) preservation. Suberoylanilide hydroxamic acid (SAHA) is currently in clinical trials as an antitumor agent; it inhibits the activity of histone deacetylases and at low doses exhibits antiinflammatory effects by reducing the production of proinflammatory cytokines. Using two well characterized mouse models of BMT, we have studied the effects of SAHA on GVHD severity and GVL activity. Administration of SAHA from day +3 to day +7 after BMT reduced serum levels of the proinflammatory cytokines and decreased intestinal histopathology, clinical severity, and mortality from acute GVHD compared with vehicle-treated animals. However, SAHA had no effect on donor T cell proliferative and cytotoxic responses to host antigens in vivo or in vitro. When mice received lethal doses of tumor cells at the time of BMT, administration of SAHA did not impair GVL activity and resulted in significantly improved leukemia-free survival by using two different tumor and donor/recipient combinations. These findings reveal a critical role for histone deacetylase inhibition in the proinflammatory events contributing to GVHD and suggest that this class of pharmacologic agents may provide a strategy to reduce GVHD while preserving cytotoxic T cell responses to host antigens and maintaining beneficial GVL effects.
- SourceAvailable from: Rolf Marschalek
- "However, in two mouse models, administration of vorinostat after allogenic bone marrow transplantation led to a reduced acute mortality due to graft-versus-host disease (GvHD). By contrast, a stable graft-versus-leukaemia (GvL) activity was observed in addition to a reduction of proinflammatory cytokines (Reddy et al, 2004). Based on these findings, clinical trials to assess the potential of HDACi as supportive treatment after haematopoietic stem cell transplantation have already been initiated (NCT01451268, NCT00810602). "
Article: Epigenetics and blood disorders.[Show abstract] [Hide abstract]
ABSTRACT: The last three decades of cancer research were guided by the hypothesis that cancer cells evolve due to the accumulation of many genetic aberrations over time. While this is still true for most solid cancers, it might be different in haemato-malignant diseases, which are mostly characterized by chromosomal translocations that exhibit only few additional mutations. Some of the resulting fusion gene products functionally interfer with epigenetic mechanisms. Recent findings of mutated IDH1, IDH2, DNMT3A or TET2 in myelodysplastic syndrome/acute myeloid leukaemia patients underscore this notion, and point to the importance of epigenetic changes for developing tumour cells. This review aims (i) to give an overview about the different components of the epigenetic system, (ii) to describe the functions of different proteins or complexes that are involved in setting-up the epigenetic layer, (iii) to highlight some recent findings, and (iv) to describe the failures and successes when using drugs that are targeting epigenetic components.British Journal of Haematology 06/2012; 158(3):307-22. DOI:10.1111/j.1365-2141.2012.09193.x · 4.96 Impact Factor
Clinical Epigenetics 08/2011; 2(2):411-6. DOI:10.1007/s13148-011-0048-0 · 6.22 Impact Factor
- "In bone marrow transplantation mouse model, addition of SAHA day +3 to +7 after transplantation prevents gastrointestinal tract damage by reducing cytokine release of TNF-α, IFN-γ and IL-1 in a dose-dependent manner. When compared with allogeneic controls, mortality and grade of acute GvHD were reduced corresponding to significantly improved survival (Reddy et al. 2004). Surprisingly, prophylactic treatment with SAHA did not alter cytotoxic T cell reaction against host antigens and thereby preserved GvL effect. "
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- "For instance, TSA was shown to reverse the aberrant expression of cytokines in T cells from patients with systemic lupus erythematosus (SLE) . TSA and SAHA have been shown to be effective in immune disease rodent models, including SLE  , graft-versushost-disease , rheumatoid arthritis , and experimental autoimmune encephalomyelitis . In addition, there is a report of therapeutic usage of TSA on allergic mouse model . "
ABSTRACT: Mast cells (MCs) are activated upon stimulation via TLRs or FcepsilonRI, contributing to immune protection and/or leading to allergic diseases. In the present study, the effects of Trichostatin A (TSA) on the activation of MCs were analyzed with bone marrow-derived (BM) MCs. TSA increased the transcription and protein secretion of IL-6 in case of LPS-stimulation, in contrast to the suppressive effect on IgE-mediated activation of BMMCs. Chromatin immunoprecipitation assay showed IgE-mediated signaling-specific suppression of transcription factors recruitment to the IL-6 promoter. TSA-treatment inhibited nuclear translocation of NF-kappaB following IgE-mediated, but not LPS-induced activation in MCs.FEBS letters 04/2010; 584(11):2315-20. DOI:10.1016/j.febslet.2010.03.047 · 3.34 Impact Factor