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 3

HDAC inhibitors regulate in vitro and in vivo functions of DCs.

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HDAC inhibitors regulate in vitro and in vivo functions of DCs. B6BMDCs ...
B6BMDCs were pretreated with diluent or SAHA and used as stimulators in MLR cultures as described in Methods. (A) BALB/c T cell proliferation after 72 h of culture. (B) IL-2 levels in supernatants at 48 h of culture. P = NS, control versus 0.1 μM SAHA. *P < 0.02, **P < 0.01 versus control. (C and D) Addition of (C) anti–TGF-β or (D) anti–IL-10 to SAHA-treated DC cultures did not reverse SAHA-treated DC–mediated suppression. P = NS, SAHA-treated versus control DCs. *P < 0.05 versus control. (E) Naive BALB/c T cells, or those obtained after 48 h of culture with C57BL/6 (B6) DCs pretreated with 0.5 μM SAHA, were restimulated in secondary cultures with control C57BL/6 DCs either separately or together at a 1:1 ratio. T cells cultured from primary SAHA-treated DCs were restimulated with third-party C3H/HeJ BMDCs. P = NS for all between-group comparisons. Data are mean ± SEM of quadruplicate cultures. (F and G) Cd74–/– and HLA-G–/– animals were irradiated and transplanted as described in Methods. Syngeneic (n = 3–4) and some allogeneic animals (n = 4–5) received 4 × 106 to 5 × 106 control B6BMDCs, while some allogeneic recipients (n = 5) received similar numbers of SAHA-treated B6BMDCs, on days –1, 0, and 2 relative to BMT. (F) Donor CD4+ cell number was evaluated in recipients’ spleens on day 7. **P < 0.001 versus allogeneic. Data (mean ± SEM) are from 1 of 3 similar experiments. (G) Donor CD8+ cell number was evaluated in recipients’ spleens on day 21. *P < 0.05 versus allogeneic. Data (mean ± SEM) are from 1 of 2 similar experiments.