TLR4 agonists as immunomodulatory agents
TLR4 agonists as immunomodulatory agents
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DOI：
10.1179/096805106x118753
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发表时间：
2006-10-01
期刊：
影响因子：
--
通讯作者：
Probst, Peter
中科院分区：
文献类型：
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作者：
Alderson, Mark R.;McGowan, Patrick;Probst, Peter
单磷脂A(MPL(R))是一种来自明尼苏达州沙门氏菌的有效疫苗佐剂，最近在欧洲获得许可，作为一种改进的乙肝疫苗(Fendrix((R)的成分。MPL就像它的来源脂多糖一样，通过TLR4/MD-2复合体发出信号。我们已经生产了一系列合成的Toll样受体4(TLR4)激动剂，这些激动剂基于MPL中包含的主要六酰化同系物的结构。这些TLR4激动剂被称为氨基烷基氨基葡萄糖磷酸盐(AGPs)，在体外刺激人外周血单核细胞产生各种细胞因子，并上调单核细胞、NK细胞和B细胞的表面标志。此外，当给予小鼠的上呼吸道时，AGPs可提供对病毒和细菌病原体攻击的非特异性抵抗力。构效关系研究表明，AGPs对天然免疫效应器的激活主要取决于次级酰链的长度和连接到苷元成分上的官能团的性质。此外，AGPs可以作为疫苗抗原粘膜给药的有效佐剂，增强抗原特异性抗体和细胞介导的免疫反应。因此，通过结合AGPs的佐剂和非特异性耐药诱导特性，有可能生产出在给药后立即提供先天保护和长期获得性免疫的粘膜疫苗。
Monophosphoryl lipid A (MPL (R)) is a potent vaccine adjuvant derived from Salmonella minnesota that was recently licensed in Europe as a component of an improved vaccine for hepatitis B (Fendrix((R))). MPL, like lipopolysaccharide from which it is derived, signals via the TLR4/MD-2 complex. We have produced a series of synthetic Toll-like receptor 4 (TLR4) agonists that are based upon the structure of the major hexa-acylated congener contained within MPL. These TLR4 agonists, termed the aminoalkyl glucosaminide phosphates (AGPs), stimulate the production of various cytokines by human peripheral blood mononuclear cells in vitro and up-regulate cell surface markers on monocytes, NK cells and B cells. In addition, AGPs provide non-specific resistance to challenge with viral and bacterial pathogens when administered to the upper airways of mice. Structure-activity relationship studies have shown that the activation of innate immune effectors by AGPs depends primarily on the length of the secondary acyl chains and the nature of the functional group attached to the aglycon component. Moreover, AGPs can act as potent adjuvants for mucosal administration of vaccine antigens, enhancing both antigen-specific antibody and cell-mediated immune responses. Thus, by combining the adjuvant and non-specific resistance induction properties of AGPs it may be possible to generate mucosal vaccines that provide innate protection immediately following administration together with long-term acquired immunity.