Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase–dependent DC functions and regulates experimental graft-versus-host disease in mice
Pavan Reddy, … , Charles A. Dinarello, James L.M. Ferrara
Pavan Reddy, … , Charles A. Dinarello, James L.M. Ferrara
Published June 20, 2008
Citation Information: J Clin Invest. 2008;118(7):2562-2573. https://doi.org/10.1172/JCI34712.
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Research Article Immunology

Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase–dependent DC functions and regulates experimental graft-versus-host disease in mice

Abstract

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.

Authors

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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Figure 2

HDAC inhibition modulates allogeneic T cell proliferation and IL-2 production in vitro.

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HDAC inhibition modulates allogeneic T cell proliferation and IL-2 produ...
SAHA was added at the indicated concentrations to DCs isolated from C57BL/6 BM that were then immediately used as stimulators in an MLR with T cells from either BALB/c (allogeneic) or C57BL/6 (syngeneic) mice as described in Methods. (A) T cell proliferation was determined by 3H-thymidine incorporation at 72 h. Allogeneic T cell responses from control (0 μM SAHA) and SAHA-treated cultures and syngeneic T cell responses to control DCs (syn) are shown. Data are mean ± SEM of quadruplicate cultures. P = NS, control versus 0.5-μM SAHA. **P < 0.03 versus control. Results are from 1 of 3 similar experiments. (B) Supernatants of cultures with control (open symbols) or SAHA (filled symbols) were collected at 48 h, and IL-2 was measured by ELISA. Data are mean ± SEM of quadruplicate cultures. *P < 0.05 versus control. (C) B6BMDCs were pretreated with diluent or 500 nM SAHA for 16–18 h, washed, and used as stimulators with allogeneic BALB/c T cells at the indicated ratios. T cell proliferation was evaluated after 72 h of culture.