Zhu Danming, Liu Longchao, Yang Dan, Fu Sherry, Bian Yingjie, Sun Zhichen, He Junming, Su Lishan, Zhang Liguo, Peng Hua, Fu Yang-Xin
Institute of Biophysics-University of Texas Group for Immunotherapy, Chinese Academy of Sciences Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China;
Institute of Biophysics-University of Texas Group for Immunotherapy, Chinese Academy of Sciences Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China;
J Immunol. 2016 Apr 1;196(7):3079-87. doi: 10.4049/jimmunol.1502061. Epub 2016 Mar 2.
Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection has been challenging because of HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface Ag in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti-HBsAg Ab in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4(+) T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8(+) T cells induced by the addition of a TLR agonist resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral Ag with neutralizing Abs followed by vaccination.
由于乙肝病毒（HBV）诱导的免疫耐受，开发控制慢性HBV感染的治疗性疫苗/策略一直具有挑战性。在本研究中，我们探索了打破耐受并恢复耐受小鼠对HBV表面抗原免疫反应的策略。我们证明，免疫耐受状态归因于HBV携带者模型中循环HBsAg的水平和持续时间。在耐受小鼠中用单克隆抗HBsAg抗体清除循环中的HBsAg可逐渐降低耐受性，并重新建立对后续重组酵母乙肝疫苗（Engerix-B）接种的B细胞和CD4(+) T细胞反应，产生保护性IgG。此外，添加TLR激动剂诱导的HBsAg特异性CD8(+) T细胞可导致血清和肝脏中的HBV清除。因此，通过用中和抗体清除细胞外病毒抗原，然后进行疫苗接种，可以实现保护性免疫的产生。
