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目的探讨EB病毒(EBV)特异性细胞毒性T细胞(CTL)免疫治疗对EBV相关非霍奇金淋巴瘤(NHL)化疗效果的影响及机制。方法通过细胞学实验成功诱导并扩增出大量的EBV特异性CTL;建立人EBV相关NHL的Balb/c裸雌鼠动物模型,设单纯免疫(EBV-CTL)治疗组、单纯化疗(CHOP)组、免疫治疗联合化疗疫(EBV-CTL+CHOP)治疗组以及空白对照组,5只/组,观察各组动物肿瘤生长情况;治疗结束后剥离肿瘤组织检测瘤内免疫细胞变化情况。结果体外杀伤实验显示伴随效靶比的增加,EBV-CTL杀伤能力逐渐增大:效靶比例分别在2.5∶1、5.0∶1与、10∶1及20∶1时,杀伤效率(%)分别为9.41±1.23、19.45±3.54、50.34±6.77和55.26±7.21(P<0.01);动物实验显示自免疫治疗d3起,与对照组相比,3组实验组抑制淋巴瘤生长率(%)分别为28.57、57.9、76.7(P<0.01)。进一步检测肿瘤相关免疫微环境实验发现,治疗后肿瘤内浸润性CTL及巨噬细胞(TIM)平均比率(%),EBV-CTL+CHOP组、EBV-CTL组、CHOP组及空白对照组分别为13.65±1.48、4.33%±1.04%,10.24±1.2%、3.82±0.54,6.83±0.16、0.95±0.07,6.32±0.18、1.96±0.24(P<0.05)。结论 EBV特异性CTL可能通过激活TIM增殖而间接促进肿瘤免疫应答。EBV-CTL免疫治疗能有效改善EBV相关NHL化疗疗效,或对EBV相关NHL的治疗起到一定指导作用。
Objective To investigate the effect of EBV-specific cytotoxic T-cell (CTL) immunotherapy on the chemotherapy effect of EBV-associated non-Hodgkin’s lymphoma (NHL) and its mechanism. METHODS: A large number of EBV-specific CTLs were successfully induced and amplified by cytology experiments; a Balb/c nude female animal model of human EBV-associated NHL was established; an EBV-CTL treatment group and a chemotherapy-only chemotherapy (CHOP) group were established. Immune therapy combined with EBV-CTL+CHOP treatment group and blank control group, 5 rats/group, observed the growth of tumors in each group of animals; After the end of treatment, the tumor tissue was peeled to detect the changes of immune cells in the tumor. RESULTS In vitro killing experiments showed that the EBV-CTL killing capacity gradually increased with an increase in the ratio of effector to target. When the effective target ratio was 2.5:1, 5.0:1, and 10:1, and 20:1 respectively, the killing efficiency (%) was obtained separately. The rates were 9.41±1.23, 19.45±3.54, 50.34±6.77, and 55.26±7.21 (P<0.01). Animal experiments showed that compared with the control group, the growth rate (%) of lymphoma inhibition in the three experimental groups was increased from the d3 of autoimmune treatment. It was 28.57, 57.9, 76.7 (P<0.01). Further examination of the tumor-associated immune microenvironment found that the average ratio (%) of invasive CTLs and macrophages (TIMs) after treatment was found in EBV-CTL+CHOP group, EBV-CTL group, CHOP group, and blank control group. 13.65±1.48, 4.33%±1.04%, 10.24±1.2%, 3.82±0.54, 6.83±0.16, 0.95±0.07, 6.32±0.18, 1.96±0.24 (P<0.05). Conclusion EBV-specific CTL may indirectly promote tumor immune response by activating TIM proliferation. EBV-CTL immunotherapy can effectively improve the efficacy of EBV-associated NHL chemotherapy, or play a guiding role in the treatment of EBV-associated NHL.