The adjuvant effects of co-stimulatory molecules on cellular and memory responses to HBsAg DNA vaccination
The adjuvant effects of co-stimulatory molecules on cellular and memory responses to HBsAg DNA vaccination
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共刺激分子对 HBsAg DNA 疫苗接种的细胞和记忆反应的佐剂作用
DOI：
10.1002/jgm.1004
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Wang, Bin
中科院分区：
文献类型：
--
作者：
Du, Xiaogang;Zheng, Guoxing;Wang, Bin
由于DNA疫苗本身往往会在人体内诱导较弱的免疫反应，因此需要辅助性方法来提高其效力。共刺激分子4-1BBL、OX40L和CD70被证明能诱导强烈的T细胞活性，因此，在本研究中，我们研究了它们是否可以作为乙肝表面抗原DNA疫苗(PcDS2)的分子佐剂来激发强烈的细胞和记忆反应。与单独使用pcDS2免疫的小鼠相比，共刺激分子的加入促进了T细胞的增殖和以更高的IgG2a/IgG1比率为标志的乙肝表面抗原特异性抗体反应。重要的是，pcDS2加上这些共刺激分子，在CD4(+)T细胞中诱导出更高水平的干扰素-γ和IL-4，在CD8(+)T细胞中诱导出更高水平的干扰素-γ。此外，在pcDS2加4-1BBL、OX40L或CD70免疫组中，也观察到显著的抗原特异性细胞毒性T淋巴细胞(CTL)反应和长期记忆CD8(+)T细胞的产生。直到免疫后100天，pcDS2加这些共刺激分子免疫的小鼠仍可观察到bcl2、Spi2a、IL-7Ra和IL-15Ra的表达上调，提示这些组小鼠产生了记忆T细胞。综上所述，这些结果表明，共刺激分子4-1BBL、OX40L或CD70可以增强乙肝表面抗原DNA疫苗的免疫原性，导致强烈的体液、细胞和记忆反应。这一方法可能导致一种有效的慢性乙肝病毒感染的治疗性疫苗。版权所有(C)2007 John Wiley&Sons Ltd.
Because DNA vaccines on their own tend to induce weak immune responses in humans, adjuvant methods are needed in order to improve their efficacy. The co-stimulatory molecules 4-1BBL, OX40L, and CD70 have been shown to induce strong T cell activities; therefore, in this study, we investigated whether they may be used as molecular adjuvants for a hepatitis B surface antigen (HBsAg) DNA vaccine (pcDS2) in eliciting strong cellular and memory responses. Compared to mice immunized with pcDS2 alone, addition of the co-stimulatory molecules increased T cell proliferation and an HBsAg-specific antibody response that was marked with a higher ratio of IgG2a/IgG1. Importantly, pcDS2 plus these co-stimulatory molecules elicited a higher level of IFN-gamma and IL-4 in CD4(+) T cells and a higher level of IFN-gamma in CD8(+) T cells. In addition, a significantly robust antigen-specific cytotoxic T lymphocyte (CTL) response and the production of long-term memory CD8(+) T cells were also observed in the groups immunized with pcDS2 plus 4-1BBL, OX40L, or CD70. Consistently, as late as 100 days after immunization, upregulated expressions of BCL-2, Spi2A, IL-7Ra, and IL-15Ra were still observed in mice immunized with pcDS2 plus these co-stimulatory molecules, suggesting the generation of memory T cells in these groups. Together, these results suggest that the co-stimulatory molecules 4-1BBL, OX40L, or CD70 can enhance the immunogenicity of HBsAg DNA vaccines, resulting in strong humoral, cellular, and memory responses. This approach may lead to an effective therapeutic vaccine for chronic hepatitis B virus (HBV) infection. Copyright (c) 2007 John Wiley & Sons Ltd.