替比夫定对T细胞免疫调节作用的实验性研究

Experimental study on immunomodulatory effect of tebivudineon T cells

目的探索核苷类药物替比夫定的免疫调节作用。方法选择6-8周健康雄性BALB/c小鼠,每日灌胃替比夫定,对照组每日灌胃等量0.9%氯化钠溶液。14 d后取小鼠脾脏细胞,检测记忆性T细胞表型,调节性T细胞比例,T细胞中IL-2、TNF-α及IFN-γ表达水平,并以羟基荧光素二醋酸盐琥珀酰亚胺脂（CFSE）染色法检测T细胞的增殖能力。结果与对照组相比,替比夫定灌胃组小鼠脾脏中T细胞分泌细胞因子IL-2、TNF-α及IFN-γ的水平,和由TCR/CD3作用下的细胞增殖能力均无显著性差异,但脾脏T细胞的亚群分布发生明显改变,初始T细胞比例明显升高,效应T细胞比例明显降低,且调节性T细胞的比例也明显降低。结论替比夫定导致的外周初始T细胞的比例升高和调节性T细胞比例的降低有利于增强免疫系统对外界抗原的应答能力,替比夫定不仅可以通过直接抑制病毒复制发挥药效,同时还有可能通过调节患者的免疫功能发挥间接抗病毒作用。

Objective To investigate the immunomodulatory effect of nucleotide anologues （telbivudine） .Methods Healthy male BALB/c mice of 6‐8 weeks old were given a gavage of telbivudine for 14 days as experimental group ,while mice were given a gavage of saline of the same volume with the drug as control group .Mice were sacrificed for analysis of memory T cells subset distribution ,regulatory T cells population in spleen ,and levels of interleukin‐2 （IL‐2） ,tumor necrosis factor‐α （TNF‐α） ,interferon‐γ （IFN‐γ） secreted from T cells by flow cytometry .The proliferation of T cells in spleen was detected by 5 ,6‐carboxyfluorescein diacetate succinimidyl ester （CFSE） staining .Results When compared to those in control group ,cytokine profiling of IL‐2 ,TNF‐α,IFN‐γand proliferation of T cells in spleen ,which stimulated by T cell receptor （TCR）/CD3 ,showed no significant difference in experimental group .However ,compared with those in control group ,T cells subset distribution in spleen in experimental group showed obviously changed ,such as significant increase of naive T cells frequency and significant dicrease of effector/memory and regulatory T cells . Conclusion Stimulated by telbivudine ,up‐regulation of peripheral naive T cells and down‐regulation of regulatory T cells might enhance immune responses to external antigens .Thus long‐term treatment with telbivudine might play dual roles in chronic hepatitis B through directly viral inhibition and indirectly immunomodulatory effect .