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

作     者：Xin Zhang Shu Hann Yindong Kang Meng Guo Shanjuan Hong Fang Liu Shangxi Fu Liming Wang Quan-Xing Wang 

作者机构：Institute of Organ TransplantationChangzheng HospitalShanghaiChina National Key Laboratory of Medical ImmunologySecond Military Medical UniversityShanghaiChina These authors contributed equally to this work. 

出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)

年 卷 期：2012年第9卷第5期

页      面：390-398页

核心收录：

学科分类：0710[理学-生物学] 090603[农学-临床兽医学] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 07[理学] 09[农学] 0906[农学-兽医学] 071002[理学-动物学] 

基　　金：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) 

主　　题：allograft rejection HDAC inhibitor Th17 Treg 

摘      要：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）-y but increased IL-IO 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 RORyt 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.