DAMP-Inducing Adjuvant and PAMP Adjuvants Parallelly Enhance Protective Type-2 and Type-1 Immune Responses to Influenza Split Vaccination
DAMP-Inducing Adjuvant and PAMP Adjuvants Parallelly Enhance Protective Type-2 and Type-1 Immune Responses to Influenza Split Vaccination
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DOI：
10.3389/fimmu.2018.02619
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发表时间：
2018-11-20
影响因子：
7.3
通讯作者：
Arima, Hidetoshi
中科院分区：
文献类型：
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作者：
Hayashi, Tomoya;Momota, Masatoshi;Arima, Hidetoshi
最近，有报道称，2-羟丙基- β -环糊精（hp - β - cyd）是一种常见的药物添加剂，可作为疫苗佐剂，通过诱导宿主源性损伤相关分子模式（DAMPs），增强对共同接种的季节性流感分裂疫苗的保护性2型免疫原性。然而，像大多数其他潮湿诱导佐剂如氢氧化铝（明矾）一样，hp - β - cyd可能不足以诱导保护性1型（细胞）免疫反应，因此留下了改进的空间。在这里，我们证明了hp - β - cyd与人源化TLR9激动剂K3 CpG-ODN（一种有效的病原体相关分子模式（PAMP））的结合，通过分别诱导抗原特异性2型和1型免疫反应，增强了共同接种的流感分裂疫苗的保护效果。此外，hp - β - cyd诱导的大量抗原特异性IgE，可引起免疫抗原的过敏反应，被K3 CpG-ODN的加入完全抑制。此外，hp - β - cyd -和K3 cpg - odn佐剂流感分离疫苗可以保护小鼠免受高剂量异源流感病毒的致命攻击，而单一佐剂疫苗不能保护小鼠。在基因缺陷小鼠的进一步实验中揭示了独特的体内免疫作用机制，联合佐剂增强的2型和1型免疫应答分别依赖于TBK1和TLR9，表明它们的信号通路平行。最后，引流淋巴结的免疫反应分析表明，hp - β - cyd促进浆细胞样树突状细胞和B细胞对K3 CpG-ODN的摄取，这可能有助于激活这些细胞并增强IgG2c的产生。综上所述，上述结果可能为damp诱导佐剂和PAMP佐剂联合使用，通过平行增强2型和1型免疫应答来提高疫苗的免疫原性和有效性提供了潜在的临床应用。
Recently, it was reported that 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD), a common pharmaceutical additive, can act as a vaccine adjuvant to enhance protective type-2 immunogenicity to co-administered seasonal influenza split vaccine by inducing host-derived damage-associated molecular patterns (DAMPs). However, like most other DAMP-inducing adjuvants such as aluminum hydroxide (Alum), HP-beta-CyD may not be sufficient for the induction of protective type-1 (cellular) immune responses, thereby leaving room for improvement. Here, we demonstrate that a combination of HP-beta-CyD with a humanized TLR9 agonist, K3 CpG-ODN, a potent pathogen-associated molecular pattern (PAMP), enhanced the protective efficacy of the co-administered influenza split vaccine by inducing antigen-specific type-2 and type-1 immune responses, respectively. Moreover, substantial antigen-specific IgE induction by HP-beta-CyD, which can cause an allergic response to immunized antigen was completely suppressed by the addition of K3 CpG-ODN. Furthermore, HP-beta-CyD- and K3 CpG-ODN-adjuvanted influenza split vaccination protected the mice against lethal challenge with high doses of heterologous influenza virus, which could not be protected against by single adjuvant vaccines. Further experiments using gene deficient mice revealed the unique immunological mechanism of action in vivo, where type-2 and type-1 immune responses enhanced by the combined adjuvants were dependent on TBK1 and TLR9, respectively, indicating their parallel signaling pathways. Finally, the analysis of immune responses in the draining lymph node suggested that HP-beta-CyD promotes the uptake of K3 CpG-ODN by plasmacytoid dendritic cells and B cells, which may contributes to the activation of these cells and enhanced production of IgG2c. Taken together, the results above may offer potential clinical applications for the combination of DAMP-inducing adjuvant and PAMP adjuvant to improve vaccine immunogenicity and efficacy by enhancing both type-2 and type-1 immune responses in a parallel manner.