Department of Cardiothoracic Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Sci Rep. 2017 Aug 17;7(1):8626. doi: 10.1038/s41598-017-09211-3.
Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-β. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases.
目前，人们对 Foxp3+ T 调节（Treg）细胞作为移植治疗靶点的兴趣主要集中在移植前的采集、移植后的扩增和输注上。另一种策略是使用组蛋白/蛋白去乙酰化酶抑制剂（HDACi）来调节 Treg 功能，这种策略可能具有更好的可调节性和更长期的给药效果。然而，广泛作用的 HDACi 的效果不同，因此可能需要针对特定的 HDAC 同工酶进行靶向治疗。我们报告了在 Foxp3+Treg 细胞中组成性或条件性缺失 HDAC11 的小鼠的数据，以及使用这些小鼠及其小分子 HDAC11 抑制剂在同种异体移植模型中的应用。全局 HDAC11 缺失对健康或发育没有影响，与 WT 对照组相比，缺乏 HDAC11 的 Foxp3+Treg 显示出增强的抑制功能，以及 Foxp3 和 TGF-β 的表达增加。同样，与 WT 受体相比，Treg 内 HDAC11 的条件性缺失导致完全 MHC 错配的心脏同种异体移植物的长期存活，并预防了 MHC 类 II 错配同种异体移植模型中移植性动脉硬化的发展。HDAC11 靶向的转化意义在于，HDAC11i 能够促进完全 MHC 不同的品系中同种异体移植物的长期存活。这些数据为进一步开发和测试 HDAC11 选择性药理抑制剂提供了有力的动力，并可能最终为移植和自身免疫性疾病提供新的治疗方法。
