Antigen presenting cells (APCs) are critical for the induction of graft-versus-host / leukemia responses after allogeneic bone marrow transplantation (BMT). Therefore agents that target dendritic cells (DCs), the most potent APCs, might have therapeutic potential in graft-versus-host disease (GVHD). Histone deacetylase inhibitors (HDACi) are novel anti-tumor agents that appear to be well tolerated in human clinical trials. However their immuno-modulatory effects have heretofore been largely unrecognized. Preliminary data generated and published by us demonstrate that HDACi regulate experimental acute GVHD, in part, through induction of the immuno-regulatory enzyme indoleamine 2, 3 dioxygenase (IDO) in host DCs. These exciting pre-clinical data formed the rationale for the development of a proof in principle clinical trial that will test the effects of HDACi, vorinostat, in prevention of acute GVHD. Preliminary data also demonstrate that acetylation of non-histone protein, STAT-3, in DCs is critical for the induction of IDO by the HDACi. The specificity of the approach and the precise molecular mechanisms are not known. This proposal flows from our exciting published and unpublished observations generated from murine models and primary healthy human cells. We will test the central hypothesis that acetylation of non-histone protein, STAT-3, by HDACi is critical for suppression of DCs and the negative regulation of experimental GVHD.
The Specific Aims are: 1. To determine the specific HDAC enzyme critical for acetylation of STAT-3 and regulation of DC function by the HDACi 2. To elucidate the critical role of STAT-3 in regulation of DCs and GVHD by HDACi 3. To analyze the cellular markers of HDAC inhibition after vorinostat (an HDACi) administration following reduced intensity conditioning (RIC) allogeneic BMT
Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant diseases whose applicability has been impeded by the development of its most serious complication, GVHD. Strategies that mitigate GVHD will allow for better harnessing of this effective therapeutic modality to treat many patients with hematological cancers.
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