Abstract：
TPO receptor agonists (TPO-RAs) are a class of clinical second-line regimens for the treatment of primary immune thrombocytopenia (ITP). It can promote megakaryocyte maturation and increase platelet production, but its effect on immunosuppressive cells in patients with ITP has not been explored. Sixty-two ITP patients and 34 healthy controls (HCs) were included in this study. The proportion and functions of myeloid-derived immunosuppressive cells (MDSCs) in ITP patients and HCs were investigated. We found that the proportion and function of MDSCs in ITP patients treated with TPO-RAs were significantly higher than those treated with glucocorticoids (GCs), which was correlated with the clinical efficacy. The proportion and function of cytotoxic Th1 cells and CD8+T cells decreased, while the proportion and immunosuppressive function of Treg cells increased in ITP patients treated with TPO-RAs. We further proved, through MDSC depletion tests, that the inhibitory effect of MDSCs on Th1 cells and the promotion of Treg cells in the original immune micro-environment of GCs-treated ITP patients were impaired; however, these MDSCs\' functions were improved in TPO-RAs-treated patients. Finally, we found that the KLF9 gene in MDSCs cells of ITP patients treated with TPO-RAs was down-regulated, which contribute to the higher mRNA expression of GADD34 gene and improved function of MDSCs. These results demonstrate a novel mechanism of TPO-RAs for the treatment of ITP through the assessment of MDSCs and their subsequent impact on T cells, which provides a new basis for TPO-RAs as first-line treatment approach to the treatment of ITP.
摘要：
TPO受体激动剂（TPO-RA）是一类用于治疗原发性免疫性血小板减少症（ITP）的临床二线方案。它可以促进巨核细胞成熟，增加血小板生成，但其对ITP患者免疫抑制细胞的影响尚未被研究。本研究包括62例ITP患者和34例健康对照（HCs）。研究了骨髓来源的免疫抑制细胞（MDSC）在ITP患者和HCs中的比例和功能。我们发现TPO-RA治疗的ITP患者中MDSCs的比例和功能明显高于糖皮质激素（GC）治疗的患者。与临床疗效相关。细胞毒性Th1细胞和CD8+T细胞的比例和功效下降，而TPO-RAs治疗的ITP患者中Treg细胞的比例和免疫抑制功能增加。我们进一步证明,通过MDSC耗竭测试，MDSCs对GCs治疗的ITP患者原有免疫微环境中Th1细胞的抑制作用和Treg细胞的促进作用受损;在接受TPO-RA治疗的患者中,这些MDSCs的功能得到改善.最后,我们发现TPO-RAs治疗的ITP患者MDSCs细胞中KLF9基因下调,GADD34基因mRNA表达较高,改善了MDSCs的功能。这些结果通过评估MDSCs及其随后对T细胞的影响，证明了TPO-RA治疗ITP的新机制。为TPO-RAs作为ITP的一线治疗方法提供了新的依据。
