Activation of NF-κB by the intracellular expression of NF-κB-inducing kinase acts as a powerful vaccine adjuvant
Activation of NF-κB by the intracellular expression of NF-κB-inducing kinase acts as a powerful vaccine adjuvant
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DOI：
10.1073/pnas.0603493103
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发表时间：
2006-09-26
影响因子：
11.1
通讯作者：
Feldmann, M.
中科院分区：
文献类型：
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作者：
Andreakos, E.;Williams, R. O.;Feldmann, M.
目前迫切需要能提高基因疫苗效力的佐剂。这在癌症和传染病中尤其重要，如艾滋病毒和疟疾，迫切需要成功的疫苗。在这里，我们描述了一种增强免疫原性的方法，包括通过转基因表达细胞内信号分子NF-κ B诱导激酶（NIK）来激活NF-κ B。在体外，NIK通过有效地激活NF-κ B并因此上调细胞因子（TNF-α、IL-6、IL-10、IL-12、IL-14、IL-16、IL-18、IL-18、IL-18、IL-19、IL-19、IL-19、IL-19）的表达，在同种异体和抗原特异性T细胞增殖测定中增加树突状细胞抗原呈递。IL-12、IL-15和IL-18）、趋化因子[IL-8、RANTES（受活化调节，正常T细胞表达和分泌）、巨噬细胞炎性蛋白-Ia、单核细胞趋化蛋白-1和单核细胞趋化蛋白-3]、MHC抗原呈递分子（I类和II类）和共刺激分子（CD 80和CD 86）。在体内，NIK增强针对载体编码的抗原的免疫应答，并使其向辅助性T细胞1免疫应答转变，其中IgG 2a水平增加、T细胞增殖、IFN-γ产生和细胞毒性T淋巴细胞应答比完全弗氏佐剂（一种非常有效的辅助性T细胞1诱导佐剂）更有效。这些发现将NIK和其他可能的NF-κ B激活诱导剂定义为一种有效的佐剂策略，为基因疫苗的开发提供了巨大的潜力。
There is a pressing need for adjuvants that will enhance the effectiveness of genetic vaccines. This is particularly important in cancer and infectious disease such as HIV and malaria for which successful vaccines are desperately needed. Here, we describe an approach to enhance immunogenicity that involves the activation of NF-kappa B by the transgenic expression of an intracellular signaling molecule, NF-kappa B inducing kinase (NIK). In vitro, NIK increases dendritic cell antigen presentation in allogeneic and antigen-specific T cell proliferation assays by potently activating NF-kappa B and consequently up-regulating the expression of cytokines (TNF-alpha, IL-6. IL-12, IL-15, and IL-18), chemokines [IL-8, RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein-la, monocyte chemoattractant protein-1, and monocyte chemoattractant protein-3], MHC antigen-presenting molecules (class I and II), and costimulatory molecules (CD80 and CD86). In vivo, NIK enhances immune responses against a vector-encoded antigen and shifts them toward a T helper 1 immune response with increased IgG2a levels, T cell proliferation, IFN-gamma production, and cytotoxic T lymphocyte responses more potently than complete Freund's adjuvant, a very efficacious T helper 1-inducing adjuvant. These findings define NIK, and possibly other inducers of NF-kappa B activation, as a potent adjuvant strategy that offers great potential for genetic vaccine development.