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SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection

Cellular & Molecular Immunology volume 9, pages 390–398 (2012)Cite this article

Abstract

Suberoylanilide hydroxamic acid (SAHA), as a histone deacetylase (HDAC) inhibitor (HDACi), was recently found to exhibit an immunosuppressive effect. However, whether SAHA can synergize with calcineurin inhibitors (CNIs) to inhibit allograft rejection and its underlying mechanism remain elusive. In this study, we demonstrated the synergistic effects of SAHA and non-therapeutic dose of tacrolimus (FK506) in prolonging the allograft survival in a murine cardiac transplant model. Concomitant intragraft examination revealed that allografts from SAHA-treated recipients showed significantly lower levels of IL-17 expression, and no discernable difference for IL-17 expressions was detected between SAHA- and SAHA/FK506-treated allograft as compared with allografts from FK506-treated animals. In contrast, administration of FK506 significantly suppressed interferon (IFN)-γ but increased IL-10 expression as compared with that of SAHA-treated animals, and this effect was independent of SAHA. Interestingly, SAHA synergizes with FK506 to promote Foxp3 and CTLA4 expression. In vitro, SAHA reduced the proportion of Th17 cells in isolated CD4+ T-cell population and decreased expressions of IL-17A, IL-17F, STAT3 and RORγt in these cells. Moreover, SAHA enhances suppressive function of regulatory T (Treg) cells by upregulating the expression of CTLA-4 without affecting T effector cell proliferation, and increased the proportion of Treg by selectively promoting apoptosis of T effector cells. Therefore, SAHA, a HDACi, may be a promising immunosuppressive agent with potential benefit in conjunction with CNI drugs.

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Acknowledgements

This work was supported by grants from the National Key Basic Research Program of China (2009CB522402) and the National Natural Science Foundation of China (31170856, U0832009 and 30772046).

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Author notes

  1. Xin Zhang and Shu Han: These authors contributed equally to this work.

  2. Dr QX Wang, National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, China. E-mail: wangqx64@yahoo.com.cn

  3. Dr LM Wang, Institute of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China. E-mail: wt2530@yahoo.com.cn

Authors and Affiliations

  1. Institute of Organ Transplantation, Changzheng Hospital, Shanghai, China

    Xin Zhang, Shu Han, Yindong Kang, Fang Liu, Shangxi Fu & Liming Wang

  2. National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China

    Meng Guo, Shanjuan Hong & Quan-Xing Wang

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Zhang, X., Han, S., Kang, Y. et al. SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection. Cell Mol Immunol 9, 390–398 (2012). https://doi.org/10.1038/cmi.2012.28

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