CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Vaccine. 2011 Aug 26;29(37):6342-51. doi: 10.1016/j.vaccine.2011.05.008. Epub 2011 May 19.
More than 350 million people worldwide are chronically infected with hepatitis B virus (HBV). Broad repertoire and strong magnitude of HBV-specific T cell responses are thought to play key roles for virus control and clearance. Previous studies together with ours showed that heat shock protein gp96 as adjuvant induces antigen specific T cell responses, yet little is known for its anti-viral properties. Here, we investigated the role of gp96 mediated cellular and humoral immunity in antiviral effects in HBV transgenic mice. Immunization with HBV surface (HBsAg) and core (HBcAg) antigens combined formulation along with gp96 induced robust antiviral T-cell and antibody immunity against HBsAg and HBcAg. Compared with non-immunized control, immunization with gp96 adjuvant vaccine led to decrease of serum HBs level and HBc expression in hepatocyte by 45% and 90% at maximum, respectively, and decreased serum HBV-DNA level to below or close to the detection limit 4 weeks after the last immunization, suggesting the therapeutic effect. A significant enhancement in cellular responses towards HBcAg and increased infiltration of CD8+ T cells in liver of transgenic were observed under treatment with gp96 compared with no treatment (P<0.05 or 0.01). Treatment with gp96 was capable of reducing Tregs by overall 30-40%. The superior immune responses induced with the aid of gp96 correlated with improved antiviral effect by vaccination with HBsAg and HBcAg. We conclude that gp96 may contribute to enhanced antiviral immunity in transgenic mice at least partly by Treg down-regulation. HBcAg may act as potent adjuvant for Th1 response. Our study reveals the novel property of gp96 in immune modulation and its potential use for breaking immunotolerance in immunotherapy of chronic HBV infection.
全球有超过 3.5 亿人患有慢性乙型肝炎病毒（HBV）感染。人们认为广泛的乙型肝炎病毒特异性 T 细胞反应库和强烈的反应幅度对于控制和清除病毒起着关键作用。以前的研究和我们的研究都表明，热休克蛋白 gp96 作为佐剂可诱导抗原特异性 T 细胞反应，但对其抗病毒特性知之甚少。在这里，我们研究了 gp96 介导的细胞和体液免疫在乙型肝炎病毒转基因小鼠抗病毒作用中的作用。与 HBV 表面（HBsAg）和核心（HBcAg）抗原联合制剂一起免疫 gp96 可诱导针对 HBsAg 和 HBcAg 的强大抗病毒 T 细胞和抗体免疫。与未免疫的对照组相比，gp96 佐剂疫苗免疫导致血清 HBs 水平最大下降 45%，HBc 表达最大下降 90%，最后一次免疫后 4 周内血清 HBV-DNA 水平降至检测限以下或接近检测限，表明具有治疗效果。与未治疗相比，gp96 治疗可观察到针对 HBcAg 的细胞反应显著增强，转基因小鼠肝内 CD8+T 细胞浸润增加（P<0.05 或 0.01）。gp96 治疗可使 Tregs 总体减少 30-40%。在 HBsAg 和 HBcAg 疫苗接种的帮助下诱导的免疫反应增强与 gp96 治疗的抗病毒效果改善相关。我们得出结论，gp96 通过下调 Treg 可能至少部分有助于增强转基因小鼠的抗病毒免疫。HBcAg 可能作为 Th1 反应的有效佐剂。我们的研究揭示了 gp96 在免疫调节中的新特性及其在慢性乙型肝炎病毒感染免疫治疗中打破免疫耐受的潜在用途。
