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Low-dose chidamide restores immune tolerance in ITP patients and mice by modulating nTreg cells and CTLA4 expression

Hong-yu Zhao, Ya-hui Ma, Da-qi Li, Tao Sun, Li-zhen Li, Ping Li, Xin-guang Liu, Hai Zhou, Yu Hou, Yang Liu, Pan-pan Han, Ya-jing Zhao, Fang-miao Jing, Jun Peng and Ming Hou

Key points

  • Decreased number and/or impaired function of nTreg cells participates in the pathogenesis of immune thrombocytopenia.

  • Low-dose chidamide restored immune tolerance in ITP via modulation of nTreg cells and CTLA4 gene expression.

Abstract

Increased macrophage phagocytosis of antibody-coated platelet as well as decreased number and/or impaired function of CD4+CD25+Foxp3+ regulatory T (Treg) cells have been shown to participate in the pathogenesis of immune thrombocytopenia (ITP). Low-dose histone deacetylase inhibitors (HDACi) are anti-inflammatory and immunomodulatory agents that can enhance immunosuppression in graft-versus-host disease by increasing the number and function of Foxp3+ T-regulatory cells. Whether low-dose HDACi has potential in promoting immune tolerance and platelet release in ITP is unclear. In this study, we performed in vitro and in vivo experiments and found that low-dose HDACi (chidamide) alleviated thrombocytopenia in passive and active murine models of ITP. Further, low-dose HDACi attenuated macrophage phagocytosis of antibody-coated platelets, stimulated production of natural Foxp3+ Tregs, promoted peripheral conversion of T cells into Tregs, and restored Treg suppression in vivo and in vitro. Finally, we confirmed that low-dose HDACi 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 of ITP in the clinic.

  • Submitted May 2, 2018.
  • Accepted December 6, 2018.