A protective role of locally administered immunostimulatory CpG oligodeoxynucleotide in a mouse model of genital herpes infection
A protective role of locally administered immunostimulatory CpG oligodeoxynucleotide in a mouse model of genital herpes infection
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DOI：
10.1128/jvi.77.2.953-962.2003
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发表时间：
2003-01-01
影响因子：
5.4
通讯作者：
Holmgren, J
中科院分区：
文献类型：
--
作者：
Harandi, AM;Eriksson, K;Holmgren, J
细菌DNA中的未甲基化CpG二核苷酸或合成的寡脱氧核苷酸（ODN）被认为是免疫系统的有效激活剂和几种Th 1相关免疫调节细胞因子的诱导剂。因此，我们调查是否这样的含CpG的ODN（CpG ODN）给予粘膜在女性生殖道可以增强先天免疫和保护生殖器疱疹感染。在用正常致死剂量的单纯疱疹病毒2型（HSV-2）阴道内攻击之前2天或之后4小时，在不存在任何抗原的情况下，用CpG ODN或非CpG ODN对照阴道内处理C57 BL/6小鼠组。与未用CpG ODN处理的小鼠相比，用CpG ODN处理的小鼠在其阴道液中表现出显著降低的HSV-2滴度。此外，与非CpG ODN预处理相比，CpG ODN预处理显著防止疾病和死亡的发展。最引人注目的是，即使在病毒攻击后给予CpG ODN，也能保护患者免受疾病和死亡的侵害。CpG ODN诱导的保护作用与CpG ODN治疗后生殖道粘膜中γ干扰素（IFN-γ）、白细胞介素-12（IL-12）、IL-18和RANTES的快速产生有关。观察到的保护似乎依赖于IFN-γ、IL-12、IL-18和T细胞，因为CpG ODN预处理在IFN-γ、IL-12、IL-18或T细胞缺陷的小鼠中不赋予任何显著的保护。此外，在CpG ODN治疗的HSV-2攻击的小鼠中引发了对再感染的完全保护性免疫，这表明粘膜施用的CpG ODN除了有效刺激先天免疫外，还在诱导获得性免疫应答的发展中起作用。
Unmethylated CpG dinucleotides in bacterial DNA or synthetic oligodeoxynucleotides (ODNs) are known as potent activators of the immune system and inducers of several Th1-associated immunomodulatory cytokines. We therefore investigated whether such a CpG-containing ODN (CpG ODN) given mucosally in the female genital tract could enhance innate immunity and protect against genital herpes infection. Groups of C57BL/6 mice were treated intravaginally with either CpG ODN or a non-CpG ODN control in the absence of any antigen either 2 days before or 4 h after an intravaginal challenge with a normally lethal dose of herpes simplex virus type 2 (HSV-2). Mice treated with CpG ODN exhibited significantly decreased titers of HSV-2 in their vaginal fluids compared with non-CpG ODN-treated mice. Furthermore, CpG ODN pretreatment significantly protected against development of disease and death compared to non-CpG ODN pretreatment. Most strikingly, CpG ODN conferred protection against disease and death even when given after the viral challenge. The CpG ODN-induced protection was associated with a rapid production of gamma interferon (IFN-gamma), interleukin-12 (IL-12), IL-18, and RANTES in the genital tract mucosa following CpG ODN treatment. The observed protection appeared to be dependent on IFN-gamma, IL-12, IL-18, and T cells, as CpG ODN pretreatment did not confer any significant protection in mice deficient in IFN-gamma, IL-12, IL-18, or T cells. Further, a complete protective immunity to reinfection was elicited in CpG ODN-treated, HSV-2-challenged mice, suggesting a role for mucosally administered CpG ODN in inducing the development of an acquired immune response in addition to its potent stimulation of innate immunity.