趋化因子
免疫系统
免疫学
病毒复制
医学
HBeAg
乙型肝炎病毒
CD8型
乙型肝炎表面抗原
细胞因子
干扰素
先天免疫系统
乙型肝炎
病毒
病毒学
作者
Anthony T. Tan,Long Hoàng,Daniel J. Chin,Erik Rasmussen,Uri Lopatin,Stefan Hart,Hans Bitter,Tom Chu,Lore Gruenbaum,Palani Ravindran,Hua Zhong,Ed Gane,Seng Gee Lim,Wan Cheng Chow,Pei‐Jer Chen,Rosemary Petric,Antonio Bertoletti,Martin L. Hibberd
标识
DOI:10.1016/j.jhep.2013.08.020
摘要
Background & Aims The interaction between HBV replication and immune modulatory effects mediated by IFNα therapy is not well understood. We characterized the impact of HBV DNA replication on the early IFNα-induced immunomodulatory mechanisms. Methods We interrogated the transcriptional, serum cytokine/chemokine and cellular immune profiles of 28 patients with HBeAg+ chronic HBV infection (CHB) randomly assigned to one of 4 treatment cohorts (untreated n = 5, weekly dosing of 360 μg Pegasys® [PegIFNα] n = 11, daily dose of 300 mg Viread® [tenofovir disoproxil fumarate, TDF] n = 6, or a combination of both n = 6). Samples were characterized at multiple early time points through day 14 of therapy, after which all patients were given standard of care (180 μg Pegasys® injected subcutaneously, weekly). Results PegIFNα induced a distinct and rapid up-regulation of IFN signaling pathway that coincided with increase detection of distinct serum cytokines/chemokines (IL-15, IL-6, and CXCL-10) and the up-regulation of the frequency of proliferating NK and activated total CD8+ T cells. IFNα treatment alone did not result in rapid decay of HBV replication and was not able to restore the defective HBV-specific T cell response present in CHB patients. In addition, the IFNα immune-stimulatory effects diminished after the first dose, but this refractory effect was reduced in patients where HBV replication was simultaneously inhibited with TDF. Conclusions We present here the first comprehensive description of the early effects of IFNα treatment on immune and viral biomarkers in HBeAg+ CHB patients. Our results show that PegIFNα-induced innate immune activation directly benefits from the suppression of HBV replication. The interaction between HBV replication and immune modulatory effects mediated by IFNα therapy is not well understood. We characterized the impact of HBV DNA replication on the early IFNα-induced immunomodulatory mechanisms. We interrogated the transcriptional, serum cytokine/chemokine and cellular immune profiles of 28 patients with HBeAg+ chronic HBV infection (CHB) randomly assigned to one of 4 treatment cohorts (untreated n = 5, weekly dosing of 360 μg Pegasys® [PegIFNα] n = 11, daily dose of 300 mg Viread® [tenofovir disoproxil fumarate, TDF] n = 6, or a combination of both n = 6). Samples were characterized at multiple early time points through day 14 of therapy, after which all patients were given standard of care (180 μg Pegasys® injected subcutaneously, weekly). PegIFNα induced a distinct and rapid up-regulation of IFN signaling pathway that coincided with increase detection of distinct serum cytokines/chemokines (IL-15, IL-6, and CXCL-10) and the up-regulation of the frequency of proliferating NK and activated total CD8+ T cells. IFNα treatment alone did not result in rapid decay of HBV replication and was not able to restore the defective HBV-specific T cell response present in CHB patients. In addition, the IFNα immune-stimulatory effects diminished after the first dose, but this refractory effect was reduced in patients where HBV replication was simultaneously inhibited with TDF. We present here the first comprehensive description of the early effects of IFNα treatment on immune and viral biomarkers in HBeAg+ CHB patients. Our results show that PegIFNα-induced innate immune activation directly benefits from the suppression of HBV replication.
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