【摘要】 目的研究慢性乙型肝炎(CHB)患者经核苷(酸)类似物(NUCs)治疗前后肝内T细胞受体(TCR)文库变化特征。方法选取10例接受替比夫定(LdT)治疗的CHB患者,根据治疗104周后是否发生HBeAg血清学转换分为两组。通过高通量测序分析LdT治疗前后肝穿刺组织中TCRβCDR3区,并分析TCR文库特征及其与血清学参数相关性。结果经过104周NUCs治疗,发生HBeAg血清学转换的CHB患者肝内TCR文库不重复VJ组合(151.0比71.0,P=0.043)、CDR3克隆型(223.0比109.0,P=0.043),以及标准化香农熵(0.58比0.17,P=0.043)均表现为文库多样性显著下降,同时这些患者治疗前后HBsAg的变化程度与消失克隆型变化呈正相关(r=0.9,P=0.037)。结论 CHB患者口服NUCs治疗可引起肝内TCR文库发生有利于特定T细胞克隆增生的变化,这对于促进HBeAg血清学转换有重要意义,提示在NUCs抗病毒治疗的基础上联合免疫治疗可能会更有助于HBV的控制。更多还原

【Abstract】 Objective To investigate the dynamic changes of intrahepatic T cell receptor(TCR)repertoires before and after nucleos(t)ide analogues(NUCs)antiviral therapy in chronic hepatitis B(CHB)patients.Methods A total of ten CHB patients with tebivudine(LDT)based therapy were subdivided to two groups on HBeAg status after 104 treatment.The TCRβcomplementarity determining region 3(CDR3)of liver biopsies before and after 2-year NUCs treatment was analyzed by high-throughput sequencing.The TCR repertoire profiles and their correlations with serological parameters were analyzed.Results After LDT-based treatment for 104 weeks,the diversity of intrahepatic TCR repertoires in patients with HBeAg seroconversion decreased significantly on the number of unique VJ combinations(151.0比71.0,P=0.043),CDR3 clonotypes(223.0比 109.0,P=0.043),and the values of normalized Shannon diversity entropy(0.58 比 0.17,P=0.045).The decline of HBsAg levels in these patients was positively correlated with the elevation of ablated clonetype frequency(r=0.9,P=0.037).Conclusion NUCs antiviral therapy may induce changes of intrahepatic TCR repertoires.T cell clone expansion plays an important role in HBeAg seroconversion,suggesting that oral antiviral therapy combined with immunotherapy may be more conducive to the control of HBV.更多还原