Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.
Department of Hematology, Jinan Central Hospital affiliated to Shandong University, Jinan, China.
Blood. 2019 Feb 14;133(7):730-742. doi: 10.1182/blood-2018-05-847624. Epub 2018 Dec 14.
Increased macrophage phagocytosis of antibody-coated platelets, as well as decreased numbers and/or impaired function of CD4CD25Foxp3 regulatory T (Treg) cells, has been shown to participate in the pathogenesis of immune thrombocytopenia (ITP). Low-dose histone deacetylase inhibitors (HDACi's) are anti-inflammatory and immunomodulatory agents that can enhance immunosuppression in graft-versus-host disease by increasing the number and function of Foxp3 Treg cells, but it is unclear whether they have the potential to promote immune tolerance and platelet release in ITP. In this study, we performed in vitro and in vivo experiments and found that a low-dose HDACi (chidamide) alleviated thrombocytopenia in passive and active murine models of ITP. Further, low-dose HDACi's attenuated macrophage phagocytosis of antibody-coated platelets, stimulated the production of natural Foxp3 Treg cells, promoted the peripheral conversion of T cells into Treg cells, and restored Treg cell suppression in vivo and in vitro. Finally, we confirmed that low-dose HDACi's could regulate CTLA4 expression in peripheral blood mononuclear cells through modulation of histone H3K27 acetylation. Low-dose HDACi treatment in ITP could be offset by blocking the effect of CTLA4. Therefore, we propose that low-dose chidamide administration has potential as a novel treatment for ITP in the clinic.
已证实，巨核细胞吞噬抗体包被血小板的增加，以及 CD4+CD25+Foxp3+调节性 T（Treg）细胞数量减少和/或功能受损，参与了免疫性血小板减少症（ITP）的发病机制。低剂量组蛋白去乙酰化酶抑制剂（HDACi）是具有抗炎和免疫调节作用的药物，通过增加 Foxp3+Treg 细胞的数量和功能，可增强移植物抗宿主病中的免疫抑制作用，但尚不清楚其是否有潜力促进 ITP 中的免疫耐受和血小板释放。在这项研究中，我们进行了体外和体内实验，发现低剂量 HDACi（西达本胺）可缓解被动和主动 ITP 小鼠模型的血小板减少症。此外，低剂量 HDACi 可减轻巨核细胞对抗体包被血小板的吞噬作用，刺激天然 Foxp3+Treg 细胞的产生，促进 T 细胞在外周向 Treg 细胞的转化，并恢复体内和体外的 Treg 细胞抑制作用。最后，我们证实低剂量 HDACi 可通过调节组蛋白 H3K27 乙酰化来调节外周血单个核细胞中 CTLA4 的表达。在 ITP 中，低剂量 HDACi 治疗可通过阻断 CTLA4 的作用而抵消。因此，我们提出低剂量西达本胺给药具有作为 ITP 临床治疗的新方法的潜力。
