The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination
The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination
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DOI：
10.1073/pnas.1319784110
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发表时间：
2013-12-24
影响因子：
11.1
通讯作者：
Seubert, Anja
中科院分区：
文献类型：
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作者：
Vono, Maria;Taccone, Marianna;Seubert, Anja
疫苗是控制感染的最有效的媒介。除了病原体抗原，疫苗还含有用于增强保护性免疫反应的佐剂。然而，大多数佐剂的分子作用机制尚不清楚，需要更好地了解佐剂的佐剂性质，以开发基于分子靶点的改进佐剂，进一步提高疫苗效力。这对结核病、疟疾、艾滋病和其他没有保护性疫苗的疾病尤其重要。内源性危险信号的释放与佐剂性有关；然而，细胞外ATP在疫苗接种过程中的作用从未被探索过。在这里，我们测试了ATP释放是否参与了四种常见佐剂的免疫增强作用：氢氧化铝、磷酸钙、不完全弗氏佐剂和水包油乳剂MF59。我们发现肌肉注射总是与ATP的微弱瞬时释放有关，MF59的存在极大地增强了这种释放，但并不是所有其他受试佐剂都能增强这种释放。局部注射ATP水解酶apyrase可抑制MF59诱导的肌肉细胞募集，但不能抑制明矾或不完全弗氏佐剂诱导的细胞募集。此外，apyrase强烈抑制流感特异性T细胞反应和血凝抑制滴度，对MF59佐剂三价流感疫苗的反应。这些数据表明，MF59诱导的先天和获得性免疫反应需要短暂的ATP释放，并将细胞外ATP与疫苗接种的增强反应联系起来。
Vaccines are the most effective agents to control infections. In addition to the pathogen antigens, vaccines contain adjuvants that are used to enhance protective immune responses. However, the molecular mechanism of action of most adjuvants is ill-known, and a better understanding of adjuvanticity is needed to develop improved adjuvants based on molecular targets that further enhance vaccine efficacy. This is particularly important for tuberculosis, malaria, AIDS, and other diseases for which protective vaccines do not exist. Release of endogenous danger signals has been linked to adjuvanticity; however, the role of extracellular ATP during vaccination has never been explored. Here, we tested whether ATP release is involved in the immune boosting effect of four common adjuvants: aluminum hydroxide, calcium phosphate, incomplete Freund's adjuvant, and the oil-in-water emulsion MF59. We found that intramuscular injection is always associated with a weak transient release of ATP, which was greatly enhanced by the presence of MF59 but not by all other adjuvants tested. Local injection of apyrase, an ATP-hydrolyzing enzyme, inhibited cell recruitment in the muscle induced by MF59 but not by alum or incomplete Freund's adjuvant. In addition, apyrase strongly inhibited influenza-specific T-cell responses and hemagglutination inhibition titers in response to an MF59-adjuvanted trivalent influenza vaccine. These data demonstrate that a transient ATP release is required for innate and adaptive immune responses induced by MF59 and link extracellular ATP with an enhanced response to vaccination.