High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia
High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia
复制标题
高剂量地塞米松通过 Ets1 纠正免疫性血小板减少症中受损的骨髓源性抑制细胞功能
DOI：
10.1182/blood-2015-10-674531
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发表时间：
2016-03-24
期刊：
影响因子：
20.3
通讯作者：
Peng, Jun
中科院分区：
文献类型：
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作者：
Hou, Yu;Feng, Qi;Peng, Jun
骨髓源性抑制细胞（MDSC）是异质性的未成熟细胞，是获得性免疫的天然抑制剂。在这项研究中，在原发性免疫性血小板减少症（ITP）成人患者中评价了MDSC人群，其中细胞介导的免疫机制参与血小板破坏。我们的数据表明，与健康对照患者相比，ITP患者外周血和脾脏中MDSC的数量和抑制功能均受损。高剂量地塞米松（HD-DXM）治疗挽救了ITP患者的MDSC数量。DXM调制可促进体外诱导的MDSCs的抑制功能。此外，白细胞介素10和转化生长因子β的表达显着上调DXM调制MDSC相比，未调制的文化。DXM调节的MDSC抑制自体CD 4（+）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溶解，进一步表明对T细胞反应的控制增强。在DXM调节的MDSC中鉴定了转录因子Ets 1的表达升高。转染Ets-1小干扰RNA可有效阻断MDSC的调节作用，这几乎抵消了DXM对MDSC功能的增强作用。同时，将CD 61（+）血小板免疫的CD 61基因敲除小鼠脾细胞输注给C57/B6背景的重症联合免疫缺陷（SCID）小鼠，建立重症ITP小鼠模型。我们被动地将从野生型C57/B6小鼠骨髓中诱导的DXM调节的MDSC转移到SCID小鼠受体中，与仅接受脾细胞移植的受体相比，其体内血小板计数显著增加。这些发现表明受损的MDSC参与ITP的发病机制，并且HD-DXM通过糖皮质激素作用和Ets 1的潜在机制纠正MDSC功能。
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 beta 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.