Unique efficacy of Toll-like receptor 8 agonists in activating human neonatal antigen-presenting cells
Unique efficacy of Toll-like receptor 8 agonists in activating human neonatal antigen-presenting cells
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DOI：
10.1182/blood-2005-12-4821
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发表时间：
2006-08-15
期刊：
影响因子：
20.3
通讯作者：
Wessels, Michael R.
中科院分区：
文献类型：
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作者：
Levy, Ofer;Suter, Eugenie E.;Wessels, Michael R.
新生儿容易受到微生物感染，对多种抗原的记忆反应较差。我们之前已经证明，人类新生儿血单核细胞对大多数已知的TLR激动剂，包括纯TLR7激动剂咪喹莫特，表现出受损的TNIF-α反应。然而，令人惊讶的是，新生儿对咪喹莫特同系物R-848(TLR7/8)的肿瘤坏死因子-α反应完全完好无损。我们现在发现，TLR8激动剂，包括R-848(TLR7/8)、咪唑喹啉同系物3M-003(TLR7/8)和3M-002(TLR8)，以及单链病毒RNA(TLR8)，可以诱导新生儿抗原提呈细胞(APC)产生Thlpolating细胞因子TNF-α和IL-12，大大超过TLR-2、-4或-7(单独)激动剂诱导的反应。TLR8激动剂还有效地诱导共刺激分子CD40在新生儿和成人骨髓树突状细胞(DC)上表达上调。TLR8激动剂的强大活性与其诱导p38 MAP激酶磷酸化以及在新生儿和成人单核细胞中降解I kappa B-α有关。我们得出结论，TLR8激动剂在激活新生儿APC的共刺激反应方面是唯一有效的，并提示这些药物是有希望的增强新生儿免疫反应的候选佐剂。
Newborns are prone to microbial infection and have poor memory responses to multiple antigens. We have previously shown that human neonatal blood monocytes exhibit impaired TNIF-alpha responses to most known TLR agonists, including the pure TLR7 agonist imiquimod. Surprisingly, however, neonatal TNF-alpha responses to the imiquimod congener R-848 (TLR 7/8) were fully intact. We now show that TLR8 agonists, including R-848 (TLR7/8), the imiclazoquinoline congeners 3M-003 (TLR7/8) and 3M-002 (TLR8), as well as single-stranded viral RNAs (TLR8) induced robust production of the Thlpolarizing cytokines TNF-alpha and IL-12 from neonatal antigen-presenting cells (APCs) that substantially exceeds responses induced by TLR-2,-4, or -7 (alone) agonists. TLR8 agonists also effectively induced up-regulation of the costimulatory molecule CD40 on neonatal and adult myelold dendritic cells (DCs). The strong activity of TLR8 agonists correlates with their induction of p38 MAP kinase phosphorylation and with degradation Of I kappa B-alpha in both neonatal and adult monocytes. We conclude that TLR8 agonists are uniquely efficacious in activating costimulatory responses in neonatal APCs and suggest that these agents are promising candidate adjuvants for enhancing immune responses in human newborns.