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 This proposal flows from our exciting published and unpublished observations generated from murine models and primary healthy human cells.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

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
New York
United States
Zip Code
Curry Jr, William T; Gorrepati, Ramana; Piesche, Matthias et al. (2016) Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Stimulates Antitumor Immunity and T Lymphocyte Activation in Patients with Recurrent Malignant Glioma. Clin Cancer Res 22:2885-96
Kitko, Carrie L; Braun, Thomas; Couriel, Daniel R et al. (2016) Combination Therapy for Graft-versus-Host Disease Prophylaxis with Etanercept and Extracorporeal Photopheresis: Results of a Phase II Clinical Trial. Biol Blood Marrow Transplant 22:862-8
Harris, Andrew C; Young, Rachel; Devine, Steven et al. (2016) International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant 22:4-10
Renteria, Anne S; Levine, John E; Ferrara, James L (2016) Development of a biomarker scoring system for use in graft-versus-host disease. Biomark Med 10:793-5
Abedin, Sameem; Yanik, Gregory A; Braun, Thomas et al. (2015) Predictive value of bronchiolitis obliterans syndrome stage 0p in chronic graft-versus-host disease of the lung. Biol Blood Marrow Transplant 21:1127-31
Chiaranunt, Pailin; Ferrara, James L M; Byersdorfer, Craig A (2015) Rethinking the paradigm: How comparative studies on fatty acid oxidation inform our understanding of T cell metabolism. Mol Immunol 68:564-74
Levine, John E; Braun, Thomas M; Harris, Andrew C et al. (2015) A PROGNOSTIC SCORE FOR ACUTE GRAFT-VERSUS-HOST DISEASE BASED ON BIOMARKERS: A MULTICENTER STUDY. Lancet Haematol 2:e21-e29
Levine, John E; Braun, Thomas M; Harris, Andrew C et al. (2015) A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol 2:e21-9
Tkachev, Victor; Goodell, Stefanie; Opipari, Anthony W et al. (2015) Programmed death-1 controls T cell survival by regulating oxidative metabolism. J Immunol 194:5789-800
Levine, John E; Hogan, William J; Harris, Andrew C et al. (2014) Improved accuracy of acute graft-versus-host disease staging among multiple centers. Best Pract Res Clin Haematol 27:283-7

Showing the most recent 10 out of 219 publications