Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy.
Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy.
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DOI：
10.1016/j.vaccine.2009.03.034
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发表时间：
2009-05-18
期刊：
影响因子：
5.5
通讯作者：
Fahmy TM
中科院分区：
文献类型：
--
作者：
Demento SL;Eisenbarth SC;Foellmer HG;Platt C;Caplan MJ;Mark Saltzman W;Mellman I;Ledizet M;Fikrig E;Flavell RA;Fahmy TM
天然免疫系统的激活是启动有效的适应性免疫反应的关键步骤，因此，一类被称为模式识别受体(PRR)的天然病原体受体的激活是许多佐剂系统的核心特征。最近的研究表明，细胞内PRR的一个成员，NLRP3炎症体，可以被包括氢氧化铝和皂苷在内的许多经典佐剂激活。炎性小体的体外激活需要抗原提呈细胞中Toll样受体(TLR)和NLRP3的信号传递。在这里，我们提出了一类具有这两个信号的纳米材料，用于快速优化疫苗设计。我们使用一种简单的方法构建了这个系统，该方法将脂多糖(LPS)结合到由生物兼容的聚乳酸-乙醇酸(PLGA)构建的纳米颗粒表面，聚乳酸-乙醇酸(PLGA)负载了抗原。我们证明，与未包被的纳米颗粒相比，脂多糖修饰的颗粒优先被树突状细胞内化，并且当给小鼠注射该系统时，可以诱导出针对模型抗原卵清蛋白的强大体液和细胞免疫。用脂多糖修饰的纳米颗粒冲击野生型巨噬细胞，可以产生与炎症小体激活一致的促炎细胞因子IL-1β。相比之下，NLRP3缺陷和Caspase-1缺陷的巨噬细胞产生的IL-1β微乎其微。此外，当内吞作用和溶酶体失稳被抑制时，炎性小体的活动就会减少，这支持了纳米颗粒破坏溶酶体隔间并充当“危险信号”的观点。这种疫苗接种方法的通用性通过包裹重组西尼罗河囊膜蛋白进行测试，并通过对西尼罗河脑炎小鼠模型的保护来证明。这种抗原递送机制的设计能够刺激两条有效的先天免疫途径，代表了一种有效的同时递送抗原和佐剂的新途径。
Innate immune system activation is a critical step in the initiation of an effective adaptive immune response; therefore, activation of a class of innate pathogen receptors called pattern recognition receptors (PRR) is a central feature of many adjuvant systems. It has recently been shown that one member of an intracellular PRR, the NLRP3 inflammasome, is activated by a number of classical adjuvants including aluminum hydroxide and saponins. Inflammasome activation in vitro requires signaling of both the Toll-like receptor (TLR) and NLRP3 in antigen-presenting cells. Here we present a class of nanomaterials endowed with these two signals for rapid optimization of vaccine design. We constructed this system using a simple approach that incorporates lipopolysaccharides (LPS) onto the surface of nanoparticles constructed from a biocompatible polyester, poly (lactic-co-glycolic acid) (PLGA), loaded with antigen. We demonstrate that LPS-modified particles are preferentially internalized by dendritic cells compared to uncoated nanoparticles and the system, when administered to mice, elicits potent humoral and cellular immunity against a model antigen, ovalbumin. Wild type macrophages pulsed with LPS-modified nanoparticles resulted in production of the proinflammatory cytokine IL-1β consistent with inflammasome activation. In comparison, NLRP3-deficient and caspase-1-deficient macrophages showed negligible production of IL-1β. Furthermore, when endocytosis and lysosomal destabilization were inhibited, inflammasome activity was diminished, supporting the notion that nanoparticles rupture lysosomal compartments and behave as ‘danger signals’. The generality of this vaccination approach is tested by encapsulation of a recombinant West Nile envelope protein and demonstrated by protection against a murine model of West Nile encephalitis. The design of such an antigen delivery mechanism with the ability to stimulate two potent innate immune pathways represents a potent new approach to simultaneous antigen and adjuvant delivery.
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影响因子：
56.9
作者：
Blander, JM;Medzhitov, R
通讯作者：
Medzhitov, R
DOI：
10.1038/nrd1176
发表时间：
2003-09
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
O'Hagan DT;Valiante NM
通讯作者：
Valiante NM
影响因子：
4.4
作者：
Li, Hanfen;Willingham, Stephen B.;Ting, Jenny P. -Y.;Re, Fabio
通讯作者：
Re, Fabio
影响因子：
5.5
作者：
Peter, K;Men, Y;Corradin, G
通讯作者：
Corradin, G
影响因子：
3.1
作者：
PETROV, AB;SEMENOV, BF;DMITRIEV, BA
通讯作者：
DMITRIEV, BA