The ultra-potent and selective TLR8 agonist VTX-294 activates human newborn and adult leukocytes.
The ultra-potent and selective TLR8 agonist VTX-294 activates human newborn and adult leukocytes.
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DOI：
10.1371/journal.pone.0058164
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Levy O
中科院分区：
文献类型：
--
作者：
Dowling DJ;Tan Z;Prokopowicz ZM;Palmer CD;Matthews MA;Dietsch GN;Hershberg RM;Levy O
新生儿表现出独特的免疫反应，导致对感染的易感性和降低的疫苗反应。Toll样受体（TLR）激动剂可作为疫苗佐剂，当单独或联合使用时，但新生儿白细胞对许多TLR激动剂的反应会减弱。TLR 8激动剂在体外激活人新生儿白细胞方面比其他TLR激动剂更有效，但关于不同的TLR 8激动剂是否可以不同地激活新生儿白细胞知之甚少。我们表征了新型苯并氮杂卓类TLR 8激动剂VTX-294与激活TLR 8的咪唑并喹啉类（R-848;（TLR 7/8）CL 075;（TLR 8/7））在人新生儿和成人白细胞激活方面的体外免疫刺激活性。还评估了VTX-294和R-848与单磷酰脂质A（MPLA; TLR 4）组合的作用。使用表达NF-κB报告基因的TLR转染的HEK 293细胞评估TLR激动剂特异性。TLR激动剂诱导的细胞因子的生产，在人类新生儿脐带血和成人外周血中使用ELISA和多重测定。新生儿和成人单核细胞分化成单核细胞来源的树突状细胞（MoDC）和TLR激动剂诱导的激活细胞因子的产生（ELISA）和共刺激分子的表达（流式细胞术）进行评估。VTX-294对TLR 8转染的HEK细胞的活性比TLR 7转染的HEK细胞高100倍（EC 50，1050 nM vs. 105700 nM）。VTX-294诱导的TNF和IL-1β产生在新生儿脐带血和成人外周血中相当，而VTX-294在诱导TNF和IL-1β产生方面比MPLA、R848或CL 075更有效0.1 log。VTX-294和MPLA的组合比R-848和MPLA的组合诱导更大的血液TNF和IL-1β应答。VTX-294还有效诱导人新生MoDC中细胞因子和共刺激分子HLA-DR和CD 86的表达。VTX-294是一种新型超强效TLR 8激动剂，可激活新生儿和成人白细胞，是早期和成年期的候选疫苗佐剂。
Newborns display distinct immune responses that contribute to susceptibility to infection and reduced vaccine responses. Toll-like receptor (TLR) agonists may serve as vaccine adjuvants, when given individually or in combination, but responses of neonatal leukocytes to many TLR agonists are diminished. TLR8 agonists are more effective than other TLR agonists in activating human neonatal leukocytes in vitro, but little is known about whether different TLR8 agonists may distinctly activate neonatal leukocytes. We characterized the in vitro immuno-stimulatory activities of a novel benzazepine TLR8 agonist, VTX-294, in comparison to imidazoquinolines that activate TLR8 (R-848; (TLR7/8) CL075; (TLR8/7)), with respect to activation of human newborn and adult leukocytes. Effects of VTX-294 and R-848 in combination with monophosphoryl lipid A (MPLA; TLR4) were also assessed. TLR agonist specificity was assessed using TLR-transfected HEK293 cells expressing a NF-κB reporter gene. TLR agonist-induced cytokine production was measured in human newborn cord and adult peripheral blood using ELISA and multiplex assays. Newborn and adult monocytes were differentiated into monocyte-derived dendritic cells (MoDCs) and TLR agonist-induced activation assessed by cytokine production (ELISA) and co-stimulatory molecule expression (flow cytometry). VTX-294 was ∼100x more active on TLR8- than TLR7-transfected HEK cells (EC50, ∼50 nM vs. ∼5700 nM). VTX-294-induced TNF and IL-1β production were comparable in newborn cord and adult peripheral blood, while VTX-294 was ∼ 1 log more potent in inducing TNF and IL-1β production than MPLA, R848 or CL075. Combination of VTX-294 and MPLA induced greater blood TNF and IL-1β responses than combination of R-848 and MPLA. VTX-294 also potently induced expression of cytokines and co-stimulatory molecules HLA-DR and CD86 in human newborn MoDCs. VTX-294 is a novel ultra-potent TLR8 agonist that activates newborn and adult leukocytes and is a candidate vaccine adjuvant in both early life and adulthood.
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DOI：
10.4049/jimmunol.0901481
发表时间：
2009-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kollmann TR;Crabtree J;Rein-Weston A;Blimkie D;Thommai F;Wang XY;Lavoie PM;Furlong J;Fortuno ES 3rd;Hajjar AM;Hawkins NR;Self SG;Wilson CB
通讯作者：
Wilson CB
影响因子：
3.7
作者：
Itoh H;Tatematsu M;Watanabe A;Iwano K;Funami K;Seya T;Matsumoto M
通讯作者：
Matsumoto M
DOI：
10.1073/pnas.1013776108
发表时间：
2011-03-01
影响因子：
11.1
作者：
Cervantes, Jorge L.;Dunham-Ems, Star M.;Salazar, Juan C.
通讯作者：
Salazar, Juan C.
影响因子：
4.4
作者：
Dasari, Pallave;Zola, Heddy;Nicholson, Ian C.
通讯作者：
Nicholson, Ian C.
影响因子：
5.4
作者：
Demirjian, Alicia;Levy, Ofer
通讯作者：
Levy, Ofer