罗普司亭治疗原发免疫性血小板减少症相关免疫调节及临床疗效分析

Analysis of Immunomodulatory Effects and Clinical Efficacy of Romiplostim in the Treatment of Primary Immune Thrombocytopenia

摘要: 目的：旨在评估罗普司亭治疗成人慢性原发性免疫性血小板减少症(Primary Immune Thrombocytopenia, ITP)的临床疗效，并深入探究其潜在的免疫调节机制。方法：本研究募集30例对一线标准治疗(糖皮质激素及免疫球蛋白)应答不佳的慢性ITP患者，予以罗普司亭皮下注射(起始剂量1 μg/kg/周)治疗，疗程4周。分别于干预前、后采集患者外周血样本，系统评估血小板计数、淋巴细胞亚群、免疫球蛋白及补体水平以及血清细胞水平。同时，设立26名健康志愿者作为对照，以明确基线细胞因子状态。统计学分析采用配对t检验或Wilcoxon符号秩和检验。结果：罗普司亭干预后，患者血小板计数显著提升(由16.27 ± 11.06 × 10⁹/L升至171.50 ± 86.57 × 10⁹/L，P < 0.001)。免疫学检测结果显示，淋巴细胞亚群发生重塑：CD4⁺T细胞(503.13 ± 423.63 vs. 828.23 ± 426.66 cells/μL, P = 0.005)与自然杀伤(NK)细胞(104.80 ± 86.10 vs. 207.02 ± 132.89 cells/μL, P = 0.001)绝对计数显著上升，同时血清IgG水平降低(16.90 ± 7.35 vs. 13.22 ± 4.13 g/L, P = 0.019)。细胞因子失衡状态得到纠正：促炎因子IL-17A (10.12 ± 7.24 vs. 1.76 ± 1.48 pg/mL, P < 0.001)与IL-5 (7.71 ± 6.83 vs. 1.97 ± 2.38 pg/mL, P < 0.001)水平明显下降，而抗炎/调节性因子IL-10 (7.95 ± 5.70 vs. 13.08 ± 9.80 pg/mL, P = 0.016)及TGF-β (445.93 ± 160.86 vs. 1085.13 ± 425.30 pg/mL, P < 0.001)表达显著上调。患者肝肾功能及血脂均在治疗期间维持稳定。结论：本研究表明，罗普司亭除发挥强效促血小板生成作用外，尚具备免疫调节功能。其机制可能与上调TGF-β表达、抑制Th17/Th2极化、重塑淋巴细胞亚群及调节体液免疫应答相关，从而系统性地纠正ITP的免疫失衡状态，为阐释该药诱导免疫耐受的潜在机制提供了新的理论依据。

Abstract: Objective: This study aimed to evaluate the clinical efficacy of romiplostim in adult patients with chronic primary immune thrombocytopenia (ITP) and to further investigate its potential immunomodulatory mechanisms. Methods: We enrolled 30 patients with chronic ITP who had an inadequate response to first-line standard therapies (glucocorticoids and immunoglobulins). These patients received subcutaneous romiplostim (starting dose: 1 μg/kg/week) for 4 weeks. Peripheral blood samples were collected before and after the intervention to systematically assess platelet counts, lymphocyte subsets, immunoglobulin and complement levels, and serum cytokine profiles. A control group of 26 healthy volunteers was also included to define baseline cytokine levels. Statistical analyses were performed using paired t-tests or Wilcoxon signed-rank tests, as appropriate. Results: Following romiplostim treatment, patients exhibited a significant increase in platelet counts (from 16.27 ± 11.06 × 10⁹/L to 171.50 ± 86.57 × 10⁹/L, P < 0.001). Immunological assessments revealed a reconstitution of lymphocyte subsets: absolute counts of CD4⁺ T cells (503.13 ± 423.63 vs. 828.23 ± 426.66 cells/μL, P = 0.005) and natural killer (NK) cells (104.80 ± 86.10 vs. 207.02 ± 132.89 cells/μL, P = 0.001) were significantly elevated. Concurrently, serum IgG levels decreased (16.90 ± 7.35 vs. 13.22 ± 4.13 g/L, P = 0.019). The pre-existing imbalance in cytokines was notably corrected: levels of the pro-inflammatory cytokines IL-17A (10.12 ± 7.24 vs. 1.76 ± 1.48 pg/mL, P < 0.001) and IL-5 (7.71 ± 6.83 vs. 1.97 ± 2.38 pg/mL, P < 0.001) markedly decreased. In contrast, levels of the anti-inflammatory/regulatory cytokines IL-10 (7.95 ± 5.70 vs. 13.08 ± 9.80 pg/mL, P = 0.016) and TGF-β (445.93 ± 160.86 vs. 1085.13 ± 425.30 pg/mL, P < 0.001) were significantly upregulated. Liver and kidney function, as well as lipid profiles, remained stable throughout the treatment period. Conclusion: Our study demonstrates that romiplostim not only exerts a potent thrombopoietic effect but also possesses significant immunomodulatory functions in chronic ITP. The underlying mechanism may involve the upregulation of TGF-β, suppression of Th17 and Th2 polarization, reconstitution of lymphocyte subsets, and modulation of humoral immunity. These actions collectively contribute to a systemic correction of the immune imbalance characteristic of ITP. These findings provide novel insights into the potential mechanisms by which romiplostim may induce immune tolerance, extending its role beyond mere platelet production.