MHC class II-associated invariant chain linkage of antigen dramatically improves cell-mediated immunity induced by adenovirus vaccines
MHC class II-associated invariant chain linkage of antigen dramatically improves cell-mediated immunity induced by adenovirus vaccines
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DOI：
10.4049/jimmunol.180.5.3339
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发表时间：
2008-03-01
影响因子：
4.4
通讯作者：
Christensen, Jan Piravsgaard
中科院分区：
文献类型：
--
作者：
Holst, Peter Johannes;Sorensen, Maria Rathmann;Christensen, Jan Piravsgaard
理想的疫苗能诱导一种有效的保护性免疫反应，这种免疫反应应能迅速诱导、长期存在并具有广泛的特异性。重组腺病毒载体在给药数周内诱导针对转基因Ags的有效的Ab和CD8(+) T细胞反应，它们是目前最有效和最通用的Ag递送载体之一。然而，艾滋病毒和丙型肝炎病毒等慢性感染的影响强调需要进一步改善。在这项研究中，我们表明，通过将rAg系在MHC Ii类相关不变链（Ii）上，可以加速、增强、扩大和延长对腺病毒编码的疫苗Ag的保护性免疫反应。因此，在体内和体外，表达淋巴细胞性脉络丛脑膜炎病毒（LCMV）衍生的Ii型糖蛋白的腺病毒载体疫苗增加了CD4（+）和CD8(+) T细胞刺激能力。此外，小鼠接种单剂量表达lcmv衍生的Ii相关糖蛋白的腺病毒疫苗，可保护小鼠免受致命病毒诱导的绒毛膜脑膜炎、免疫显性T细胞表位突变菌株的致命攻击，以及高侵袭性菌株的全身感染。在治疗性肿瘤疫苗接种中，该疫苗与活的LCMV一样有效。相比之下，接种了表达未修饰糖蛋白的传统腺病毒疫苗的动物可以预防全身感染，但只能暂时预防致死性脉络丛脑膜炎，而且这种疫苗在肿瘤治疗中效率较低。
The ideal vaccine induces a potent protective immune response, which should be rapidly induced, long-standing, and of broad specificity. Recombinant adenoviral vectors induce potent Ab and CD8(+) T cell responses against transgenic Ags within weeks of administration, and they are among the most potent and versatile Ag delivery vehicles available. However, the impact of chronic infections like HIV and hepatitis C virus underscore the need for further improvements. In this study, we show that the protective immune response to an adenovirus-encoded vaccine Ag can be accelerated, enhanced, broadened, and prolonged by tethering of the rAg to the MHC class II-associated invariant chain (Ii). Thus, adenovirus-vectored vaccines expressing lymphocytic choriomeningitis virus (LCMV)-derived glycoprotein linked to Ii increased the CD4(+) and CD8(+) T cell stimulatory capacity in vitro and in vivo. Furthermore, mice vaccinated with a single dose of adenovirus-expressing LCMV-derived glycoprotein linked to Ii were protected against lethal virus-induced choriomeningitis, lethal challenge with strains mutated in immunodominant T cell epitopes, and systemic infection with a highly invasive strain. In therapeutic tumor vaccination, the vaccine was as efficient as live LCMV. In comparison, animals vaccinated with a conventional adenovirus vaccine expressing unmodified glycoprotein were protected against systemic infection, but only temporarily against lethal choriomeningitis, and this vaccine was less efficient in tumor therapy.