Mucosal Immunology Unit, Kings College London, Tower Wing Floor 28, Guy's Hospital, London SE1 9RT, United Kingdom.
Mucosal Immunology Unit, Kings College London, Tower Wing Floor 28, Guy's Hospital, London SE1 9RT, United Kingdom.
J Biol Chem. 2012 May 18;287(21):17152-17160. doi: 10.1074/jbc.M112.347179. Epub 2012 Apr 3.
The efficacy of a vaccine is generally dependent on an adjuvant, which enhances the immune functions and alum has been widely used in human immunization. Alum activates the intracellular stress sensors inflammasomes, but whether these are responsible for the adjuvanticity is controversial. The objectives of this investigation were to examine the hypothesis that alum-mediated adjuvanticity is a function of stress and conversely that stress agents will elicit adjuvanticity. The investigation was carried out in BALB/c mice by SC immunization with ovalbumin (OVA) mixed with alum. This elicited inflammasomes, with significant activation of caspase 1, production of IL-1β, and adjuvanticity, demonstrated by enhancing OVA-specific serum IgG antibodies, CD4(+) T cells, and proliferation. The novel finding that alum induced HSP70 suggests that stress is involved in the mechanism of adjuvanticity. This was confirmed by inhibition studies with PES (phenylethynesulfonamide), which disrupts inducible HSP70 function, and inhibited both inflammasomes and the adjuvant function. Parallel studies were pursued with an oxidative agent (sodium arsenite), K-releasing agent (Gramicidin) and a metal ionophore (dithiocarbamate). All 3 stress agents induced HSP70, inflammasomes, and the adjuvant functions. Furthermore, up-regulation of membrane associated IL-15 on DC and CD40L on T cells in the animals treated with alum or the stress agents mediate the interactions between splenic CD11c DC and CD4(+) or CD8(+) T cells. The results suggest that the three stress agents elicit HSP70, a hallmark of stress, as well as inflammasomes and adjuvanticity, commensurate with those of alum, which may provide an alternative strategy in developing novel adjuvants.
疫苗的功效通常取决于佐剂，佐剂可增强免疫功能，而明矾已广泛用于人体免疫。明矾激活细胞内应激传感器炎性体，但这些是否是佐剂的原因存在争议。本研究的目的是检验以下假设：明矾介导的佐剂作用是应激的功能，反之亦然，应激剂将引发佐剂作用。该研究在 BALB/c 小鼠中通过 SC 用卵清蛋白 (OVA) 与明矾混合进行免疫接种来进行。这引发了炎性体， caspase 1 显著激活，IL-1β产生，并且通过增强 OVA 特异性血清 IgG 抗体、CD4(+)T 细胞和增殖来证明佐剂作用。明矾诱导 HSP70 的新发现表明应激参与了佐剂作用的机制。这通过用苯乙酮 (phenylethynesulfonamide) 进行抑制研究得到证实，苯乙酮破坏诱导型 HSP70 功能，并抑制炎性体和佐剂功能。还进行了与氧化剂 (亚砷酸钠)、K 释放剂 (短杆菌肽) 和金属离子载体 (二硫代氨基甲酸盐) 的平行研究。所有 3 种应激剂都诱导 HSP70、炎性体和佐剂作用。此外，用明矾或应激剂处理的动物中，树突状细胞 (DC) 上膜相关的 IL-15 和 T 细胞上的 CD40L 的上调介导了脾 CD11c DC 与 CD4(+)或 CD8(+)T 细胞之间的相互作用。结果表明，这三种应激剂可诱导 HSP70、应激的标志性物质以及炎性体和佐剂作用，与明矾相当，这可能为开发新型佐剂提供一种替代策略。
