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 donor͞recipient 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.

HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen

“…1C). In addition, consistent with the previous reports (17,18), 0.5 M SAHA showed no inhibition of the donor T cells stimulated with allo-APCs, but 1 M SAHA markedly inhibited the T cell proliferation (Fig. 1D).…”

“…It was reported that an HDAC inhibitor (trichostatin A) represses IL-2 gene expression in anti-CD3 activated T cells (22). Low-dose SAHA treatment resulted in increased acetylation of histone H3 and decreased mRNA levels of IFN-␥ and TNF-␣ in activated spleen cells (17). SAHA treatment also inhibited phosphorylation of STAT1 and STAT3 in response to LPS and alloactivation in vitro (18), and STAT1 and STAT3 play a critical role in the production of proinflammtory cytokines such as IFN-␥ and IL-17 (23,24).…”

“…Although micromolar concentrations of SAHA are required for anti-tumor effects, nanomolar concentrations of SAHA can reduce the secretion of inflammatory cytokines such as TNF-␣, IFN-␥, IL-1␤, and IL-12 by nonmalignant cells (16). It was reported that administration of low-dose SAHA reduced serum levels of inflammatory cytokines and ameliorated GVHD without inhibiting donor T cell function and their GVL activity (17,18).…”

2-Methoxyestradiol-induced apoptosis in human leukemia cells proceeds through a reactive oxygen species and Akt-dependent process

“…For example, recent studies suggest that the antileukemic potential of several histone deacetylase (HDAC) inhibitors is dependent upon Akt activation status (Fuino et al, 2003). Thus, the possibility exists that 2ME might interact synergistically with these agents, a number of which are currently in clinical evaluation (Zhou et al, 2002;Reddy et al, 2004). Significantly, HDAC inhibitor lethality has, like 2ME, been attributed to generation of ROS (Rosato et al, 2003).…”

New perspectives on the biology of acute GVHD

“…Histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (SAHA) have been shown to reduce development of GVHD in murine models by STAT-3 acetylation, which controls indoleamine 2,3-dioxygenasedependent DC functions. [47][48][49] SAHA is currently in clinical trials for the prevention of GVHD. Another potential therapeutic approach to modulate DC tolerance is the development of an antibody to the DC surface maturation antigen CD83; this antibody has been shown to prevent acute GVHD in a humanized mouse model with severe congenital immunodeficiency disorder.…”