Low-dose decitabine modulates T-cell homeostasis and restores immune tolerance in immune thrombocytopenia.
Low-dose decitabine modulates T-cell homeostasis and restores immune tolerance in immune thrombocytopenia.
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低剂量地西他滨可调节 T 细胞稳态并恢复免疫性血小板减少症的免疫耐受。
DOI：
10.1182/blood.2020008477
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发表时间：
2021-08-26
期刊：
影响因子：
20.3
通讯作者：
Hou M
中科院分区：
文献类型：
--
作者：
Han P;Hou Y;Zhao Y;Liu Y;Yu T;Sun Y;Wang H;Xu P;Li G;Sun T;Hu X;Liu X;Li L;Peng J;Zhou H;Hou M
难治性免疫性血小板减少症(ITP)患者需要新的治疗方案，这种疾病由于调节性T细胞(Treg)活性降低而失去免疫耐受性。Han等人证明，去甲基化药物地西他滨通过调节Tregs来恢复T细胞的稳态，增加T细胞的数量并增强其免疫抑制功能，从而增加ITP患者的血小板数量。低剂量地西他滨可增强Treg细胞的抑制作用，并重新平衡ITP中的CD4+T细胞亚群。地西他滨通过调节Treg细胞和抑制STAT3的激活来恢复ITP的免疫耐受。我们先前的临床研究表明，小剂量地西他滨对近一半的难治性免疫性血小板减少症(ITP)患者表现出持续的反应。地西他滨治疗ITP的长期疗效不太可能，因为它只起到增加血小板生成的作用。地西他滨是否有可能恢复ITP的免疫耐受尚不清楚。在本研究中，我们分析了地西他滨在体内外对ITP患者T细胞亚群的影响。我们发现低剂量地西他滨促进调节性T(Treg)细胞的生成和分化，并增强其免疫抑制功能。将CD61+血小板免疫的CD61基因敲除小鼠的脾细胞移植到重度联合免疫缺陷小鼠体内，建立ITP小鼠模型。小剂量地西他滨可减轻活动期ITP小鼠的血小板减少症，恢复Treg和辅助性T(Th)细胞之间的平衡。Treg缺失和耗尽抵消了地西他滨恢复ITP小鼠CD4+T细胞亚群的效果。与治疗前相比，接受小剂量地他滨治疗的患者Treg细胞数量和功能显著改善，而Th1和Th17细胞受到抑制。下一代RNA测序和细胞因子分析显示，小剂量地西他滨重新平衡了ITP患者的T细胞稳态，减少了促炎细胞因子，并下调了磷酸化的STAT3。STAT3抑制分析提示小剂量地西他滨可能通过抑制STAT3的激活来恢复Treg细胞。总之，我们的数据表明，地西他滨的免疫调节作用为小剂量地西他滨在ITP中实现持续反应提供了一种可能的机制解释。
New treatment options are required for patients with refractory immune thrombocytopenia (ITP), a disease in which immune tolerance has been lost due to reduced regulatory T-cell (Treg) activity. Han et al demonstrate that the hypomethylating agent decitabine increases platelet counts in ITP by restoring T-cell homeostasis through modulation of Tregs, increasing their numbers and enhancing their immunosuppressive function. Low-dose decitabine augments the inhibitory effect of Treg cells and rebalances CD4+ T-cell subsets in ITP. Decitabine restores immune tolerance in ITP by modulating Treg cells and inhibiting STAT3 activation. 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.
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影响因子：
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