Li Xiangming, Yang Xiaofeng, Li Liangwei, Liu Haibo, Liu Jing
School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
Vaccine. 2006 Apr 12;24(16):3321-31. doi: 10.1016/j.vaccine.2006.01.012. Epub 2006 Jan 19.
DNA vaccine represents an attractive approach to therapy of chronic hepatitis B virus (HBV) infection because of its ability to generate antigen-specific immunity; nevertheless, there is still a need to increase the potency of DNA vaccine. Mycobacterium tuberculosis heat shock protein70 (HSP70) has both chaperon and cytokine functions, and has been shown to act as an adjuvant when co-administered with peptide antigens or given as fusion proteins. Here we evaluated the effects of two truncated HSP70 molecules, N-terminal domain (HSP70(1-360), amino acids 1-360) and C-terminal domain (HSP70(359-610), amino acids 359-610) of mycobacterial HSP70, on the potency of antigen-specific immunity generated by a HBV DNA vaccination. We found that only the HSP70(359-610)-fused HBV DNA vaccination resulted in a significant increase in hepatitis B surface antigen (HBsAg)-specific humoral response, while the HSP70(1-360)- or the complete HSP70 molecule-fused vaccine did not. Moreover, HSP70(359-610)-fused DNA vaccine did not induce anti-HSP70 antibody. Interestingly, HSP70(359-610) not only enhanced HBsAg-specific cytotoxic lymphocytes (CTL) responses but also overcame the epitope suppression caused by L(d)-restricted epitope. Meanwhile, HSP70(369-610) mediated T helper (Th) cell balance towards Th1 pathway. In a HBV transgenic mouse model, the HSP70(359-610) fusion vaccine facilitated clearance of circulating HBsAg and down-regulation of HBV replication. These results suggested that the truncated mycobacterial HSP70 molecule, HSP70(359-610), might be a superior candidate to deliver the adjuvant function in HBV DNA vaccination instead of the complete HSP70 molecule.
DNA疫苗因其能够产生抗原特异性免疫，代表了一种有吸引力的慢性乙型肝炎病毒（HBV）感染治疗方法；然而，仍有必要提高DNA疫苗的效力。结核分枝杆菌热休克蛋白70（HSP70）兼具伴侣和细胞因子功能，并且已证明当与肽抗原共同给药或以融合蛋白形式给予时可作为佐剂。在此，我们评估了分枝杆菌HSP70的两个截短的HSP70分子，N端结构域（HSP70(1-360)，氨基酸1-360）和C端结构域（HSP70(359-610)，氨基酸359-610），对HBV DNA疫苗接种产生的抗原特异性免疫效力的影响。我们发现，只有与HSP70(359-610)融合的HBV DNA疫苗接种导致乙肝表面抗原（HBsAg）特异性体液反应显著增加，而与HSP70(1-360)或完整HSP70分子融合的疫苗则没有。此外，与HSP70(359-610)融合的DNA疫苗不会诱导抗HSP70抗体。有趣的是，HSP70(359-610)不仅增强了HBsAg特异性细胞毒性淋巴细胞（CTL）反应，还克服了由L(d)限制性表位引起的表位抑制。同时，HSP70(369-610)介导T辅助（Th）细胞平衡向Th1途径倾斜。在HBV转基因小鼠模型中，HSP70(359-610)融合疫苗促进了循环HBsAg的清除并下调了HBV复制。这些结果表明，截短的分枝杆菌HSP70分子HSP70(359-610)可能是在HBV DNA疫苗接种中发挥佐剂功能的更优候选者，而非完整的HSP70分子。
