Heat shock protein gp96 enhances humoral and T cell responses, decreases Treg frequency and potentiates the anti-HBV activity in BALB/c and transgenic mice.
Heat shock protein gp96 enhances humoral and T cell responses, decreases Treg frequency and potentiates the anti-HBV activity in BALB/c and transgenic mice.
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DOI：
10.1016/j.vaccine.2011.05.008
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发表时间：
2011-08
期刊：
影响因子：
5.5
通讯作者：
Saifeng Wang;Lipeng Qiu;Guang-ze Liu;Yang Li;Xiaojun Zhang;Wensong Jin;G. Gao;X. Kong;S. M
中科院分区：
文献类型：
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作者：
Saifeng Wang;Lipeng Qiu;Guang-ze Liu;Yang Li;Xiaojun Zhang;Wensong Jin;G. Gao;X. Kong;S. M
全世界有超过3.5亿人慢性感染乙型肝炎病毒（HBV）。广泛的病毒库和强大的hbv特异性T细胞反应被认为在病毒控制和清除中起关键作用。先前的研究和我们的研究表明，热休克蛋白gp96作为佐剂可诱导抗原特异性T细胞反应，但其抗病毒特性尚不清楚。在此，我们研究了gp96介导的细胞免疫和体液免疫在HBV转基因小鼠抗病毒作用中的作用。用HBV表面（HBsAg）和核心（HBcAg）抗原联合制剂与gp96免疫可诱导针对HBsAg和HBcAg的强效抗病毒t细胞和抗体免疫。与未免疫对照组相比，gp96佐剂疫苗免疫后，血清HBs水平和肝细胞中HBc表达最高分别下降45%和90%，并在末次免疫后4周将血清HBV-DNA水平降至低于或接近检出限，显示出治疗效果。与未处理相比，gp96处理显著增强了转基因小鼠肝脏对HBcAg的细胞应答，增加了CD8+ T细胞的浸润（P<0.05或0.01）。用gp96治疗能够使treg总体减少30-40%。gp96诱导的优越免疫应答与接种HBsAg和HBcAg后抗病毒效果的提高有关。我们得出结论，gp96可能至少部分通过下调Treg来增强转基因小鼠的抗病毒免疫。HBcAg可能作为Th1应答的有效佐剂。我们的研究揭示了gp96在免疫调节中的新特性及其在慢性HBV感染免疫治疗中打破免疫耐受的潜在应用。
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.