Department of Hematology, Division of Life Sciences and Medicine, the First Affiliated Hospital of USTC, University of Science and Technology of China, Lujiang Road No 17, Hefei, 230001, China.
Ann Hematol. 2024 Aug;103(8):2729-2741. doi: 10.1007/s00277-024-05846-1. Epub 2024 Jun 19.
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 CD8T 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.
TPO 受体激动剂（TPO-RAs）是治疗原发免疫性血小板减少症（ITP）的一类临床二线方案。它可以促进巨核细胞成熟并增加血小板生成，但它对 ITP 患者中免疫抑制细胞的作用尚未被探索。本研究纳入了 62 例 ITP 患者和 34 名健康对照者（HCs）。研究了 ITP 患者和 HCs 中髓系来源的免疫抑制细胞（MDSCs）的比例和功能。我们发现，接受 TPO-RAs 治疗的 ITP 患者的 MDSC 比例和功能明显高于接受糖皮质激素（GCs）治疗的患者，且这与临床疗效相关。接受 TPO-RAs 治疗的 ITP 患者中细胞毒性 Th1 细胞和 CD8+T 细胞的比例和功能降低，而 Treg 细胞的比例和免疫抑制功能增加。我们进一步通过 MDSC 耗竭试验证明，在 GCs 治疗的 ITP 患者原始免疫微环境中，MDSCs 对 Th1 细胞的抑制作用和对 Treg 细胞的促进作用受损；然而，在接受 TPO-RAs 治疗的患者中，这些 MDSCs 的功能得到了改善。最后，我们发现接受 TPO-RAs 治疗的 ITP 患者的 MDSC 细胞中的 KLF9 基因下调，导致 GADD34 基因的 mRNA 表达升高，MDSC 功能改善。这些结果通过评估 MDSCs 及其对 T 细胞的后续影响，为 TPO-RAs 治疗 ITP 的机制提供了新的证据，为 TPO-RAs 作为 ITP 一线治疗方法提供了新的依据。
