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In vitro cytokine induction by TLR-activating vaccine adjuvants in human blood varies by age and adjuvant

机译：TLR活化疫苗佐剂在人血中的体外细胞因子诱导作用因年龄和佐剂而异

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Most infections occur in early life, prompting development of novel adjuvanted vaccines to protect newborns and infants. Several Toll-like receptor (TLR) agonists (TLRAs) are components of licensed vaccine formulations or are in development as candidate adjuvants. However, the type and magnitude of immune responses to TLRAs may vary with the TLR activated as well as age and geographic location. Most notably, in newborns, as compared to adults, the immune response to TLRAs is polarized with lower Thi cytokine production and robust Th2 and anti-inflammatory cytokine production. The ontogeny of TLR-mediated cytokine responses in international cohorts has been reported, but no study has compared cytokine responses to TLRAs between U.S. neonates and infants at the age of 6 months. Both are critical age groups for the currently pediatric vaccine schedule. In this study, we report quantitative differences in the production of a panel of 14 cytokines and chemokines after in vitro stimulation of newborn cord blood and infant and adult peripheral blood with agonists of TLR4, including monophosphoryl lipid A (MPLA) and glucopyranosyl lipid Adjuvant aqueous formulation (GLA-AF), as well as agonists of TLR7/8 (R848) and TLR9 (CpG). Both TLR4 agonists, MPLA and GLA-AF, induced greater concentrations of Thl cytokines CXCL10, TNF and Interleukin (IL)-12p70 in infant and adult blood compared to newborn blood. All the tested TLRAs induced greater infant IFN-alpha 2 production compared to newborn and adult blood. In contrast, CpG induced greater IFN-gamma, IL-1 beta, IL-4, IL-12p40, IL-10 and CXCL8 in newborn than in infant and adult blood. Overall, to the extent that these in vitro studies mirror responses in vivo, our study demonstrates distinct age-specific effects of TLRAs that may inform their development as candidate adjuvants for early life vaccines. (C) 2016 Elsevier Ltd. All rights reserved.
机译：大多数感染发生在生命的早期，促使开发了新型佐剂疫苗来保护新生儿和婴儿。几种Toll样受体（TLR）激动剂（TLRA）是获得许可的疫苗制剂的组成部分，或正在开发中作为候选佐剂。但是，对TLRA的免疫反应的类型和强度可能会随激活的TLR以及年龄和地理位置而变化。最值得注意的是，在新生儿中，与成人相比，对TLRA的免疫反应与低Thi细胞因子产生，强健的Th2和抗炎细胞因子产生呈两极分化。在国际队列中已报道了TLR介导的细胞因子应答的个体存在，但尚无研究比较6个月大的美国新生儿和婴儿对TLRA的细胞因子应答。两者都是当前儿科疫苗时间表的关键年龄组。在这项研究中，我们报告了在用TLR4激动剂（包括单磷酰脂质A（MPLA）和吡喃葡萄糖基脂质佐剂水溶液）体外刺激新生儿脐带血以及婴儿和成人外周血后，一组14种细胞因子和趋化因子的产量存在定量差异。制剂（GLA-AF）以及TLR7 / 8（R848）和TLR9（CpG）的激动剂。与新生儿血液相比，TLR4激动剂MPLA和GLA-AF均可在婴儿和成人血液中诱导更高浓度的Th1细胞因子CXCL10，TNF和白介素（IL）-12p70浓度。与新生儿和成人血液相比，所有测试的TLRA诱导更大的婴儿IFN-alpha 2产生。相反，CpG诱导的新生儿IFN-γ，IL-1 beta，IL-4，IL-12p40，IL-10和CXCL8比婴儿和成人血液中更大。总体而言，在一定程度上，这些体外研究反映了体内反应，我们的研究表明TLRA具有不同的年龄特异性作用，这可能有助于TLRA成为早期疫苗候选佐剂的发展。 （C）2016 Elsevier Ltd.保留所有权利。

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