Department of Hematology.
Shangdong Key Laboratory of Immunochematology, and.
Blood. 2021 Aug 26;138(8):674-688. doi: 10.1182/blood.2020008477.
Our previous clinical study showed that low-dose decitabine exhibited sustained responses in nearly half of patients with refractory immune thrombocytopenia (ITP). The long-term efficacy of decitabine in ITP is not likely due to its simple role in increasing platelet production. Whether decitabine has the potential to restore immune tolerance in ITP is unknown. In this study, we analyzed the effect of decitabine on T-cell subpopulations in ITP in vitro and in vivo. We found that low-dose decitabine promoted the generation and differentiation of regulatory T (Treg) cells and augmented their immunosuppressive function. Splenocytes from CD61 knockout mice immunized with CD61+ platelets were transferred into severe combined immunodeficient mouse recipients to induce a murine model of ITP. Low-dose decitabine alleviated thrombocytopenia and restored the balance between Treg and helper T (Th) cells in active ITP mice. Treg deletion and depletion offset the effect of decitabine in restoring CD4+ T-cell subpopulations in ITP mice. For patients who received low-dose decitabine, the quantity and function of Treg cells were substantially improved, whereas Th1 and Th17 cells were suppressed compared with the pretreatment levels. Next-generation RNA-sequencing and cytokine analysis showed that low-dose decitabine rebalanced T-cell homeostasis, decreased proinflammatory cytokines, and downregulated phosphorylated STAT3 in patients with ITP. STAT3 inhibition analysis suggested that low-dose decitabine might restore Treg cells by inhibiting STAT3 activation. In conclusion, our data indicate that the immunomodulatory effect of decitabine provides one possible mechanistic explanation for the sustained response achieved by low-dose decitabine in ITP.
我们之前的临床研究表明，低剂量地西他滨在近一半的难治性免疫性血小板减少症（ITP）患者中表现出持续反应。地西他滨在 ITP 中的长期疗效不太可能仅仅是由于其增加血小板生成的简单作用。地西他滨是否有可能恢复 ITP 中的免疫耐受尚不清楚。在这项研究中，我们分析了地西他滨在体外和体内对 ITP 中 T 细胞亚群的影响。我们发现，低剂量地西他滨促进了调节性 T（Treg）细胞的生成和分化，并增强了其免疫抑制功能。用 CD61+血小板免疫的 CD61 敲除小鼠的脾细胞被转移到严重联合免疫缺陷小鼠受体中，以诱导 ITP 小鼠模型。低剂量地西他滨减轻了血小板减少症，并恢复了活动期 ITP 小鼠中 Treg 和辅助性 T（Th）细胞之间的平衡。Treg 缺失和耗竭抵消了地西他滨在恢复 ITP 小鼠 CD4+T 细胞亚群中的作用。对于接受低剂量地西他滨治疗的患者，与治疗前相比，Treg 细胞的数量和功能得到了显著改善，而 Th1 和 Th17 细胞则受到抑制。下一代 RNA 测序和细胞因子分析表明，低剂量地西他滨通过重新平衡 T 细胞稳态、减少促炎细胞因子和下调 ITP 患者中磷酸化 STAT3，来恢复 T 细胞的平衡。STAT3 抑制分析表明，低剂量地西他滨可能通过抑制 STAT3 激活来恢复 Treg 细胞。总之，我们的数据表明，地西他滨的免疫调节作用为低剂量地西他滨在 ITP 中实现持续反应提供了一种可能的机制解释。
