Department of Hematology and Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China;
Department of Hematology and.
Blood. 2016 Mar 24;127(12):1587-97. doi: 10.1182/blood-2015-10-674531. Epub 2016 Jan 7.
Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. In this study, the MDSC population was evaluated in adult patients with primary immune thrombocytopenia (ITP), where cell-mediated immune mechanisms are involved in platelet destruction. Our data demonstrated that both the numbers and suppressive functions of MDSCs were impaired in the peripheral blood and spleens of patients with ITP compared with healthy control patients. High-dose dexamethasone (HD-DXM) treatment rescued MDSC numbers in patients with ITP. And DXM modulation promoted the suppressive function of MDSCs induced in vitro. Moreover, the expression of interleukin 10 and transforming growth factor β was significantly upregulated in DXM-modulated MDSCs compared with the unmodulated cultures. DXM-modulated MDSCs inhibited autologous CD4(+)T-cell proliferation and significantly attenuated cytotoxic T lymphocyte-mediated platelet lysis, further indicating enhanced control over T-cell responses. Elevated expression of the transcription factor Ets1 was identified in DXM-modulated MDSCs. Transfection of Ets-1 small interfering RNA efficiently blocked regulatory effects of MDSCs, which almost offset the augmentation of MDSC function by DXM. Meanwhile, splenocytes from CD61 knockout mice immunized with CD61(+)platelets were transferred into severe combined immunodeficient (SCID) mouse recipients (C57/B6 background) to induce a murine model of severe ITP. We passively transferred the DXM-modulated MDSCs induced from bone marrow of wild-type C57/B6 mice into the SCID mouse recipients, which significantly increased platelet counts in vivo compared with those receiving splenocyte engraftment alone. These findings suggested that impaired MDSCs are involved in the pathogenesis of ITP, and that HD-DXM corrected MDSC functions via a mechanism underlying glucocorticoid action and Ets1.
髓系来源的抑制细胞（MDSCs）是异质性未成熟细胞，是适应性免疫的天然抑制剂。在这项研究中，评估了原发性免疫性血小板减少症（ITP）成年患者中的 MDSC 群体，其中细胞介导的免疫机制涉及血小板破坏。我们的数据表明，与健康对照患者相比，ITP 患者的外周血和脾脏中的 MDSC 数量和抑制功能均受损。大剂量地塞米松（HD-DXM）治疗可恢复 ITP 患者的 MDSC 数量。并且 DXM 调节可促进体外诱导的 MDSC 的抑制功能。此外，与未调节的培养物相比，DXM 调节的 MDSC 中白细胞介素 10 和转化生长因子 β 的表达显著上调。DXM 调节的 MDSC 抑制自身 CD4(+)T 细胞增殖，并显著减弱细胞毒性 T 淋巴细胞介导的血小板裂解，进一步表明对 T 细胞反应的控制增强。在 DXM 调节的 MDSC 中鉴定出转录因子 Ets1 的表达升高。转染 Ets-1 小干扰 RNA 可有效地阻断 MDSC 的调节作用，几乎抵消了 DXM 对 MDSC 功能的增强。同时，用 CD61(+)血小板免疫的 CD61 敲除小鼠的脾细胞转移到严重联合免疫缺陷（SCID）小鼠受体（C57/B6 背景）中，以诱导严重 ITP 的小鼠模型。我们将从野生型 C57/B6 小鼠骨髓中诱导的 DXM 调节的 MDSC 被动转移到 SCID 小鼠受体中，与单独接受脾细胞移植的受体相比，体内血小板计数显著增加。这些发现表明，受损的 MDSC 参与了 ITP 的发病机制，HD-DXM 通过糖皮质激素作用和 Ets1 机制纠正了 MDSC 功能。
