Histone deacetylase (HDAC) inhibitors are antitumor agents that also have antiinflammatory properties. However, the mechanisms of their immunomodulatory functions are not known. We investigated the mechanisms of action of 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and ITF 2357, on mouse DC responses. Pretreatment of DCs with HDAC inhibitors significantly reduced TLR-induced secretion of proinflammatory cytokines, suppressed the expression of CD40 and CD80, and reduced the in vitro and in vivo allostimulatory responses induced by the DCs. In addition, injection of DCs treated ex vivo with HDAC inhibitors reduced experimental graft-versus-host disease (GVHD) in a murine allogeneic BM transplantation model. Exposure of DCs to HDAC inhibitors increased expression of indoleamine 2,3-dioxygenase (IDO), a suppressor of DC function. Blockade of IDO in WT DCs with siRNA and with DCs from IDO-deficient animals caused substantial reversal of HDAC inhibition–induced in vitro suppression of DC-stimulated responses. Direct injection of HDAC inhibitors early after allogeneic BM transplantation to chimeric animals whose BM-derived cells lacked IDO failed to protect from GVHD, demonstrating an in vivo functional role for IDO. Together, these data show that HDAC inhibitors regulate multiple DC functions through the induction of IDO and suggest that they may represent a novel class of agents to treat immune-mediated diseases.
Pavan Reddy, Yaping Sun, Tomomi Toubai, Raimon Duran-Struuck, Shawn G. Clouthier, Elizabeth Weisiger, Yoshinobu Maeda, Isao Tawara, Oleg Krijanovski, Erin Gatza, Chen Liu, Chelsea Malter, Paolo Mascagni, Charles A. Dinarello, James L.M. Ferrara
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Modulation of antigen-presenting cells by HDAC inhibitors: implications in autoimmunity and cancer
KV Woan, E Sahakian, EM Sotomayor, E Seto, A Villagra |
Immunology and Cell Biology | 2011 |
IFN-γ and indoleamine 2,3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity
Y Lu, CR Giver, A Sharma, JM Li, KA Darlak, LM Owens, JD Roback, J Galipeau, EK Waller |
Blood | 2011 |
IDO in human gut graft-versus-host disease
P Ratajczak, A Janin, RP de Larour, L Koch, B Roche, D Munn, BR Blazar, G Socié |
Biology of Blood and Marrow Transplantation | 2011 |
The Histone Deacetylase Inhibitor ITF2357 Decreases Surface CXCR4 and CCR5 Expression on CD4+ T-Cells and Monocytes and is Superior to Valproic Acid for Latent HIV-1 Expression in Vitro
S Matalon, BE Palmer, MF Nold, A Furlan, A Kassu, G Fossati, P Mascagni, CA Dinarello |
Journal of acquired immune deficiency syndromes (1999) | 2010 |
Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect
M Dickinson, RW Johnstone, HM Prince |
Investigational New Drugs | 2010 |
Concise review: hitting the right spot with mesenchymal stromal cells
J Tolar, KL Blanc, A Keating, BR Blazar |
Stem Cells | 2010 |
A Crucial Role for Host APCs in the Induction of Donor CD4 + CD25 + Regulatory T Cell-Mediated Suppression of Experimental Graft-versus-Host Disease
I Tawara, WD Shlomchik, A Jones, W Zou, E Nieves, C Liu, T Toubai, R Duran-Struuck, Y Sun, SG Clouthier, R Evers, KP Lowler, RB Levy, P Reddy |
Journal of immunology (Baltimore, Md. : 1950) | 2010 |
Immunization with host-type CD8{alpha}+ dendritic cells reduces experimental acute GVHD in an IL-10-dependent manner
T Toubai, C Malter, I Tawara, C Liu, E Nieves, KP Lowler, Y Sun, P Reddy |
Blood | 2010 |
Dendritic Cells, Indoleamine 2,3 Dioxygenase and Acquired Immune Privilege
L Huang, B Baban, BA Johnson, AL Mellor |
International Reviews of Immunology | 2010 |
B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase
BA 3rd, DJ Kahler, B Baban, PR Chandler, B Kang, M Shimoda, PA Koni, J Pihkala, B Vilagos, M Busslinger, DH Munn, AL Mellor |
Proceedings of the National Academy of Sciences | 2010 |
Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation
I Tawara, M Koyama, C Liu, T Toubai, D Thomas, R Evers, P Chockley, E Nieves, Y Sun, KP Lowler, C Malter, N Nishimoto, GR Hill, P Reddy |
Clinical cancer research | 2010 |
p21(Cip1) up-regulated during histone deacetylase inhibitor-induced CD4(+) T-cell anergy selectively associates with mitogen-activated protein kinases
AS Dagtas, KM Gilbert |
Immunology | 2010 |
Transcriptome analysis revealed unique genes as targets for the anti-inflammatory action of activated protein C in human macrophages
CP Pereira, EB Bachli, DJ Schaer, G Schoedon |
PloS one | 2010 |
HDAC inhibition by LBH589 affects the phenotype and function of human myeloid dendritic cells
W Song, YT Tai, Z Tian, T Hideshima, D Chauhan, P Nanjappa, MA Exley, KC Anderson, NC Munshi |
Leukemia | 2010 |
Pancreatic Islet Transplants and IDO: When Starving the Enemy Does You Good
L Crisa |
Diabetes | 2010 |
Indoleamine 2,3-dioxygenase in human hematopoietic stem cell transplantation.
Jürgens B, Raberger J, Fuchs D, Heitger A |
International journal of tryptophan research : IJTR | 2010 |
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd |
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2009 |
Acute graft-versus-host disease: from the bench to the bedside
G Socié, BR Blazar |
Blood | 2009 |
New perspectives on the biology of acute GVHD
S Paczesny, D Hanauer, Y Sun, P Reddy |
Bone Marrow Transplantation | 2009 |
The many roles of histone deacetylases in development and physiology: implications for disease and therapy
M Haberland, RL Montgomery, EN Olson |
Nature reviews. Genetics | 2009 |
Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells
L Wang, EF de Zoeten, MI Greene, WW Hancock |
Nature Reviews Drug Discovery | 2009 |
Cutting Edge: Negative Regulation of Dendritic Cells through Acetylation of the Nonhistone Protein STAT-3
Y Sun, YE Chin, E Weisiger, C Malter, I Tawara, T Toubai, E Gatza, P Mascagni, CA Dinarello, P Reddy |
Journal of immunology (Baltimore, Md. : 1950) | 2009 |
Targeting the immunoregulatory indoleamine 2,3 dioxygenase pathway in immunotherapy
BA rd, B Baban, AL Mellor |
Immunotherapy | 2009 |
Acute graft-versus-host disease: new treatment strategies:
S Paczesny, SW Choi, JL Ferrara |
Current Opinion in Hematology | 2009 |
Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality
LK Jasperson, C Bucher, A Panoskaltsis-Mortari, AL Mellor, DH Munn, BR Blazar |
Blood | 2009 |
Granulocyte colony-stimulating factor-induced immature myeloid cells inhibit acute graft-versus-host disease lethality through an indoleamine dioxygenase-independent mechanism
YD Joo, SM Lee, SW Lee, WS Lee, SM Lee, JK Park, IW Choi, SG Park, I Choi, SK Seo |
Immunology | 2009 |
The Importance of NAD in Multiple Sclerosis
Penberthy WT, Tsunoda I |
Current pharmaceutical design | 2009 |
IDO: a double-edged sword for T(H)1/T(H)2 regulation
H Xu, GX Zhang, B Ciric, A Rostami |
Immunology Letters | 2008 |
Gene microarray analysis of human renal cell carcinoma: The effects of HDAC inhibition and retinoid treatment
Tavares TS, Nanus D, Yang XJ, Gudas LJ |
Cancer biology & therapy | 2008 |