Antigen presenting cells (APCs) play a critical role in the induction of graft-versus-host (GVHD)/ leukemia (GVL) responses after allogeneic bone marrow transplantation (BMT). Therefore agents that regulate the functions of dendritic cells (DCs), the most potent APCs, might have therapeutic potential in GVH processes. Protein lysine deacetylases, traditionally referred to as histone deacetylases (HDAC) play a pivotal role many biological processes. HDAC inhibitors (HDACi) have been developed as anti-tumor agents and they appear to be well tolerated in human clinical trials;but their immuno-modulatory effects have heretofore been largely unrecognized. Data generated by us demonstrate that HDACi regulate experimental acute GVHD partly through induction of the immuno-suppressive enzyme indoleamine 2, 3 dioxygenase (IDO) in host DCs. These exciting pre-clinical experimental data formed the rationale for the development of a proof of concept clinical trial at our institution ((IRB Approval # 2001.0234), which will test the effects of HDAC inhibition in prevention of acute GVHD. However, the precise molecular mechanisms remain unknown. Preliminary data demonstrate that acetylation of non-histone immuno-regulatory protein, STAT-3, in DCs is critical for the DC suppressive effects of HDACi. Data also show that HDAC-1 enzyme interacts with STAT-3 in DCs. In this proposal we will build on our exciting published and unpublished observations from both murine models and cells from healthy human donors. We will test the central hypothesis that acetylation of the non-histone protein, STAT-3, is critical for the negative regulation of DCs and experimental GVHD after treatment with HDACi.
The specific aims (SA) are as follows:
Specific Aim (SA) 1: To determine the specific HDAC enzyme critical for acetylation of STAT-3 and regulation of DC function by the HDACi. In this specific aim we will test the hypothesis that HDAC enzyme 1 is critical for STAT-3 acetylation and regulation of the innate and allo-stimulatory functions of DCs.
Specific Aim (SA) 2: To elucidate the critical role of STAT-3 in regulation of DCs and GVHD by HDACi. In this specific aim we will explore the hypothesis that acetylation of STAT-3 by HDACi is critical for suppression of DCs and experimental GVHD.

Public Health Relevance

Allogeneic hematopoietic stem cell transplantation is 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA143379-04
Application #
8462573
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2010-07-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$140,535
Indirect Cost
$45,935
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Choi, Sung Won; Braun, Thomas; Chang, Lawrence et al. (2014) Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol 15:87-95
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Toubai, Tomomi; Sun, Yaping; Luker, Gary et al. (2013) Host-derived CD8+ dendritic cells are required for induction of optimal graft-versus-tumor responses after experimental allogeneic bone marrow transplantation. Blood 121:4231-41
Mathewson, Nathan; Toubai, Tomomi; Kapeles, Steven et al. (2013) Neddylation plays an important role in the regulation of murine and human dendritic cell function. Blood 122:2062-73
MacDonald, Kelli P; Shlomchik, Warren D; Reddy, Pavan (2013) Biology of graft-versus-host responses: recent insights. Biol Blood Marrow Transplant 19:S10-4
Sun, Yaping; Sun, John; Tomomi, Toubai et al. (2013) PU.1-dependent transcriptional regulation of miR-142 contributes to its hematopoietic cell-specific expression and modulation of IL-6. J Immunol 190:4005-13
Tawara, Isao; Sun, Yaping; Lewis, Eli C et al. (2012) Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation. Proc Natl Acad Sci U S A 109:564-9
Reddy, Pavan (2012) Editorial: HDAC inhibition begets more MDSCs. J Leukoc Biol 91:679-81
Choi, Sung; Reddy, Pavan (2011) HDAC inhibition and graft versus host disease. Mol Med 17:404-16

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