Intravacc, Bilthoven, The Netherlands; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Science Faculty, Utrecht University, The Netherlands.
Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
J Proteomics. 2018 Mar 20;175:144-155. doi: 10.1016/j.jprot.2017.12.021. Epub 2018 Jan 6.
Aluminum-based adjuvants are the most widely used adjuvants in human vaccines. A comprehensive understanding of the mechanism of action of aluminum adjuvants at the molecular level, however, is still elusive. Here, we unravel the effects of aluminum hydroxide Al(OH) by a systems-wide analysis of the Al(OH)-induced monocyte response. Cell response analysis by cytokine release was combined with (targeted) transcriptome and full proteome analysis. Results from this comprehensive study revealed two novel pathways to become activated upon monocyte stimulation with Al(OH): the first pathway was IFNβ signaling possibly induced by DAMP sensing pathways like TLR or NOD1 activation, and second the HLA class I antigen processing and presentation pathway. Furthermore, known mechanisms of the adjuvant activity of Al(OH) were elucidated in more detail such as inflammasome and complement activation, homeostasis and HLA-class II upregulation, possibly related to increased IFNγ gene expression. Altogether, our study revealed which immunological pathways are activated upon stimulation of monocytes with Al(OH), refining our knowledge on the adjuvant effect of Al(OH) in primary monocytes.
Aluminum salts are the most used adjuvants in human vaccines but a comprehensive understanding of the working mechanism of alum adjuvants at the molecular level is still elusive. Our Systems Vaccinology approach, combining complementary molecular biological, immunological and mass spectrometry-based techniques gave a detailed insight in the molecular mechanisms and pathways induced by Al(OH) in primary monocytes. Several novel immunological relevant cellular pathways were identified: type I interferon secretion potentially induced by TLR and/or NOD like signaling, the activation of the inflammasome and the HLA Class-I and Class-II antigen presenting pathways induced by IFNγ. This study highlights the mechanisms of the most commonly used adjuvant in human vaccines by combing proteomics, transcriptomics and cytokine analysis revealing new potential mechanisms of action for Al(OH).
铝基佐剂是人类疫苗中使用最广泛的佐剂。然而，在分子水平上全面了解铝佐剂的作用机制仍难以捉摸。在这里，我们通过对氢氧化铝（Al(OH)）诱导的单核细胞反应进行系统全面的分析，揭示了 Al(OH)的作用。通过细胞因子释放进行细胞反应分析，结合（靶向）转录组和全蛋白质组分析。这项综合研究的结果揭示了单核细胞受到 Al(OH)刺激后两种新的激活途径：第一条途径可能是通过 TLR 或 NOD1 激活等 DAMP 感应途径诱导 IFNβ 信号转导，第二条途径是 HLA Ⅰ类抗原加工和呈递途径。此外，还更详细地阐明了 Al(OH)佐剂活性的已知机制，如炎症小体和补体激活、稳态和 HLA-Ⅱ类上调，可能与 IFNγ基因表达增加有关。总之，我们的研究揭示了单核细胞受到 Al(OH)刺激后哪些免疫途径被激活，从而细化了我们对 Al(OH)在原代单核细胞中的佐剂作用的认识。
铝盐是人类疫苗中使用最广泛的佐剂，但在分子水平上全面了解明矾佐剂的作用机制仍难以捉摸。我们的系统疫苗学方法结合了互补的分子生物学、免疫学和基于质谱的技术，详细了解了 Al(OH)在原代单核细胞中诱导的分子机制和途径。确定了几种新的免疫相关细胞途径：潜在由 TLR 和/或 NOD 样信号诱导的 I 型干扰素分泌、炎症小体的激活以及由 IFNγ诱导的 HLA Ⅰ类和Ⅱ类抗原呈递途径。这项研究通过结合蛋白质组学、转录组学和细胞因子分析，突出了人类疫苗中最常用佐剂的作用机制，揭示了 Al(OH)的新潜在作用机制。
