Autologous adoptive immunotherapy without destruction of infected cells during the treatment of chronic hepatitis B

目的明确免疫活性细胞回输法治疗慢性乙型肝炎(CHB)时肝组织损害情况. 方法随机选择16例CHB患者用自体免疫活性细胞回输法治疗,追踪52周.治疗前后行两次肝穿刺获得肝组织,苏木精-伊红染色评价肝脏组织炎症情况,Masson染色评价肝组织纤维化情况,检测乙型肝炎病毒(HBV)复制指标以及肝功能,评价免疫治疗对肝组织的影响. 结果完整随访14例患者,4例患者治疗前后完成2次肝穿刺,其中1例患者结果显示治疗后肝细胞坏死和小叶内炎症程度明显减轻(G3→G1),纤维化程度改善(S2→S1).其余3例肝脏组织学变化不明显,但无加重或恶化.免疫活性细胞体外培养前后,进行免疫荧光抗体染色,经流式细胞仪分析,细胞表型有明显的改变,CD4+细胞比例逐渐下降,CD8+细胞比例从20%上升至60%～80%.回输治疗后52周的随访结果,HBV DNA阴转率为42.86%(6/14),乙型肝炎e抗原阴转并伴有抗-HBe阳性的血清转换率为42.86%(6/14),无1例发生乙型肝炎表原抗原阴转.丙氨酸氨基转移酶的复常率为42.86%(6/14).在回输治疗时以及治疗后的随访中未发生严重的不良反应. 结论免疫活性细胞回输法治疗CHB不引起肝组织损害,其免疫调节作用是通过非细胞毒机制途径达到对病毒抑制或清除的作用.To investigate the profile of liver histological damage after autologous adoptive immunotherapy with cytokine-induced killer cells (CIK cells) in patients with chronic hepatitis B (CHB).16 CHB patients were randomly enrolled and received autologous adoptive immunotherapy, then followed up 52 weeks. Liver samples were taken from the patients to evaluate the degree of inflammation and fibrosis. The markers of hepatitis B virus and liver function were also detected.4 patients had two liver-biopsied samples before therapy and after 52 weeks follow-up. One patient's histological assessment revealed a significant improvement in intralobular necroinflammation (G2 --> G1) and fibrosis (S2 --> S1). The others failed to show obvious changes in liver histology. After 10 days culture in vitro, phenotypic characterization of CIK cells changed significantly by flow cytometry. The percentage of CD4+ cells decreased gradually, while the percentage of CD8+ cells increased from 20% to 60% - 80%. After 52 weeks follow-up, HBV DNA was negative (HBV DNA<4pg/ml in serum) in 6 out of 14 patients. The rates of both HBeAg/anti-HBe seroconversion and alanine aminotransferase normalization were 42.86%(6/14). There was no HBsAg/anti-HBs seroconversion. There was few severe treatment-related adverse events.Autologous adoptive immunotherapy doesn't induce the damage of liver histology in chronic hepatitis B patients, which inhibits hepatitis B virus replication by a certain noncytotoxic mechanism.国家重点基础研究发展计划(973计划)PubMed中国科学引文数据库(CSCD)07391-3931