干扰素α-1b、白介素-2联合沙利度胺方案治疗急性髓系白血病免疫调节作用的协同机制研究

Synergistic Mechanism of Interferon alpha-1b,Interleukin-2 and Thalidomide for Immune Regulation in Patients with Acute Myeloid Leukemia

目的:探讨干扰素α-1b、白介素-2联合沙利度胺(简称"干白沙"方案)治疗急性髓系白血病(AML)的免疫调节的协同作用机制。方法:对2016年3月至2019年5月郑州大学附属肿瘤医院等11家医疗单位收治的初治或复发/难治性或行维持治疗的且自愿接受"干白沙"方案治疗的68例AML患者,采集患者用药前1天及规范用药3个月后的晨起空腹外周血标本,采用流式细胞术检测外周血淋巴细胞亚群及NK细胞颗粒酶B及穿孔素表达水平;微量样本多重定量技术(CBA)检测血浆中VEGF、IFN-γ、TNF-α、IL-6等4种细胞因子的表达水平。对照组为35例本院体检中心的健康体检者。结果:治疗前患者外周血CD4+/CD8+、NK细胞比例、NK细胞穿孔素及颗粒酶B的表达水平均较健康对照者低,外周血血浆中VEGF、IL-6及TNF-α水平较健康对照组高,差异有统计学意义;IFN-γ水平较健康对照组低,但差异无统计学意义。"干白沙"方案治疗3个月后,患者外周血CD4+/CD8+比例、NK细胞比例、NK细胞穿孔素及颗粒酶B的表达水平均较用药前升高,外周血血浆中IFN-γ水平较治疗前升高,VEGF水平较治疗前降低,差异均具有统计学意义;外周血CD3+CD4+及CD3+CD8+淋巴细胞比例及血浆中TNF-α水平较治疗前升高,IL-6水平较治疗前降低,差异无统计学意义。结论:"干白沙"方案可提高外周血CD4+/CD8+比例及NK细胞比例,增加NK细胞颗粒酶B及穿孔素的表达,促进IFN-γ的产生并减少VEGF的分泌,这可能增强AML患者机体抗肿瘤能力。

Objective:To explore the synergistic immunomodulatory mechanism of interferon alpha-1b,interleukin-2 and thalidomide(ITI)regimen on patients with acute myeloid leukemia(AML).Methods:Sixty eight untreated de novo or relapsed or refractory or maintenance therapy patients with AML admitted in the Affiliated Cancer Hospital of Zhengzhou University and the other 11 medical units from March 2016 to May 2019 were treated with ITI regimen.Peripheral blood specimen per patient was collected into EDTA-K3 anticoagulation vacuum tube before the administration of ITI and 3 months after the treatment;peripheral blood lymphocyte subsets and perforin and Granzyme B expression were analyzed by using flow cytometry;the levels of VEGF,IFN-γ,TNF-αand IL-6 in the plasma were detected by using a cytometric bead array.Thirty-five healthy subjects from the hospital physical examination centre were selected as normal controls.Results:The ratio of CD4^+/CD8^+T cells,the percentage of NK cells,the expression of perforin and Granzyme B of NK cells in the peripheral blood of patients with hematological malignancies were lower than those of healthy controls.The level of VEGF,IL-6 and TNF-αin the peripheral plasma were higher than those of the healthy control group,and the difference was statistically significant.The level of IFN-γwas lower,and the difference was not statistically significant.The ratio of CD4^+/CD8^+T cells,the percentage of NK cells,the expression of Granzyme B and Perforin of NK cells in peripheral blood were higher after the therapy of thalidomide combined with rhIFNα-1b for 3 months as compared with those before treatment of ITI,the level of the IFN-γin peripheral plasma was higher while that of VEGF was lower,the difference was statistically significant;after treatment,the ratio of CD3^+CD4^+and CD3^+CD8^+lymphocytes and the level of TNF-αin peripheral blood were higher those that before treatment,IL-6 was lower,while the difference was not statistically significant.Conclusion:The ITI regimen can raise the ratio of CD4^+/CD8^+T cells and the percentage of natural killer cells,also,can enhance the generation of perforin and granzyme B and the concentration of IFN-γas well as inhibit the generation of VEGF,suggesting that these activities may enhance the antitumour capacity of patients with AML.