Immunoprofiling toll-like receptor ligands Comparison of immunostimulatory and proinflammatory profiles in ex vivo human blood models
Immunoprofiling toll-like receptor ligands Comparison of immunostimulatory and proinflammatory profiles in ex vivo human blood models
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DOI：
10.4161/hv.6.4.10866
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发表时间：
2010-04-01
期刊：
影响因子：
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通讯作者：
David, Sunil A.
中科院分区：
文献类型：
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作者：
Hood, Jennifer D.;Warshakoon, Hemamali J.;David, Sunil A.
迫切需要开发新型、安全和有效的佐剂。病原体相关分子模式（PAMP）识别元件如Toll样受体、NOD样受体和RIG样受体的最近发现和表征使PAMP在桥接先天性和适应性免疫应答中的作用成为焦点，并且对免疫刺激性与促炎活性的详细理解可能导致有效佐剂的开发，单磷酰脂质A是一个很好的例子。在本文中，我们描述了一系列的分层分析，用于表征TLR激动剂在体外，包括初级TLR-报告基因分析，二级指标的免疫激活，和三级屏幕特征转录激活模式，以确定最佳的免疫刺激化学型。对已知的人TLR激动剂的代表性成员的评价表明，TLR 2、-4、-5和-7激动剂是免疫刺激性的。TLR 7激动剂具有极强的免疫刺激性，刺激几乎所有的淋巴细胞亚群，而不诱导促炎细胞因子反应。TLR 5激动剂鞭毛蛋白虽然具有免疫刺激作用，但也具有高度的促炎性。这些结果表明，TLR激动剂以外的脂质A样化学型可以开发成潜在的佐剂，这一系列的分层测定可以适应于快速确定在大型图书馆，化合物与佐剂的潜力，缺乏促炎反应。
There is a pressing need for the development of novel, safe and effective adjuvants. The recent discovery and characterization of pathogen-associated molecular pattern (PAMP)-recognizing elements such as the Toll-like, NOD-like and RIG-like receptors, has brought into sharp focus the role of PAMPs in bridging the innate and adaptive immune responses, and a detailed understanding of the immunostimulatory vis-a-vis proinflammatory activities could lead to the development of effective adjuvants, monophosphoryl lipid A being an excellent example. We describe in this paper a series of hierarchical assays that were employed to characterize TLR agonists in vitro including primary TLR-reporter assays, secondary indices of immune activation, and tertiary screens characterizing transcriptomal activation patterns to identify optimal immunostimulatory chemotypes. The evaluation of representative members of known human TLR agonists demonstrate that TLR2, -4, -5 and -7 agonists were immunostimulatory. TLR7 agonists were extremely immunostimulatory, stimulating nearly all subsets of lymphocytes without inducing proinflammatory cytokine responses. The TLR5 agonist, flagellin, while immunostimulatory, was also highly proinflammatory. These results suggest that TLR agonists other than lipid A-like chemotypes could be developed into potential adjuvants, and that this series of hierarchical assays could be adapted to rapidly identify in large libraries, compounds with adjuvantic potential that lack proinflammatory responses.