Abstract
Acute graft-versus-host disease (GVHD) is the leading cause of non-relapse mortality following allogeneic hematopoietic cell transplantation. The majority of patients non-responsive to front line treatment with steroids have an estimated overall 2-year survival rate of only 10%. Bromodomain and extra-terminal domain (BET) proteins influence inflammatory gene transcription, and therefore represent a potential target to mitigate inflammation central to acute GVHD pathogenesis. Using potent and selective BET inhibitors Plexxikon-51107 and -2853 (PLX51107 and PLX2853), we show that BET inhibition significantly improves survival and reduces disease progression in murine models of acute GVHD without sacrificing the beneficial graft-versus-leukemia response. BET inhibition reduces T cell alloreactive proliferation, decreases inflammatory cytokine production, and impairs dendritic cell maturation both in vitro and in vivo. RNA sequencing studies in human T cells revealed that BET inhibition impacts inflammatory IL-17 and IL-12 gene expression signatures, and Chromatin Immunoprecipitation (ChIP)-sequencing revealed that BRD4 binds directly to the IL-23R gene locus. BET inhibition results in decreased IL-23R expression and function as demonstrated by decreased phosphorylation of STAT3 in response to IL-23 stimulation in human T cells in vitro as well as in mouse donor T cells in vivo. Furthermore, PLX2853 significantly reduced IL-23R+ and pathogenic CD4+ IFNγ+ IL-17+ double positive T cell infiltration in gastrointestinal tissues in an acute GVHD murine model. Our findings identify a role for BET proteins in regulating the IL-23R/STAT3/IL-17 pathway. Based on our preclinical data presented here, PLX51107 will enter clinical trial for refractory acute GVHD in a Phase 1 safety, biological efficacy trial.
Highlights
Acute graft-versus-host disease (GVHD) is a T cell mediated disorder commonly associated with allogeneic hematopoietic cell transplantation (HCT) leading to transplant-related mortality
We asked whether administration of PLX51107 to mice after allogeneic bone marrow transplantation could improve overall survival and reduce clinical severity of acute GVHD
We investigated the effect of PLX51107 in a murine minor histocompatibility antigen mismatched acute GVHD model
Summary
Acute graft-versus-host disease (GVHD) is a T cell mediated disorder commonly associated with allogeneic hematopoietic cell transplantation (HCT) leading to transplant-related mortality. Tissue damage associated with pretransplant conditioning chemotherapy or radiation induces the secretion of a multitude of cytokines including tumor necrosis factor (TNF), interleukin 1 (IL-1), IL-12, IL-23 and IL-6 which leads to the activation of host antigen presenting cells (APC). APC subsequently activate donor T cells from the graft, further propagating the release of inflammatory cytokines such as IL-17, IFN-g, and TNF that results in target tissue destruction [4]. Th17-associated cytokines such as IL-17 and IL-23 are known to be increased in GVHD, highlighting the importance of this T cell subset in the pathogenesis of the disorder [7,8,9,10,11]. Loss of host gastrointestinal (GI) tissue integrity is of particular importance as GI damage permits the translocation of microbial products which trigger further host APC activation, resulting in a vicious cycle of rampant T cell activation and subsequent tissue destruction [2, 12,13,14,15]
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