Synthesis and immunological characterization of toll-like receptor 7 agonistic conjugates.
Synthesis and immunological characterization of toll-like receptor 7 agonistic conjugates.
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DOI：
10.1021/bc900054q
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发表时间：
2009-06
影响因子：
4.7
通讯作者：
Carson DA
中科院分区：
文献类型：
--
作者：
Chan M;Hayashi T;Kuy CS;Gray CS;Wu CC;Corr M;Wrasidlo W;Cottam HB;Carson DA
先天免疫系统细胞上toll样受体（TLR）的激活启动、放大和指导抗原特异性获得性免疫应答。因此，刺激TLR的配体代表潜在的免疫佐剂。在这项研究中，一个有效的TLR 7激动剂缀合到磷脂，聚（乙二醇）（PEG），或磷脂-PEG通过一个通用的苯甲酸官能团。与未修饰的TLR 7激动剂相比，每种缀合物在体外和体内显示出独特的免疫学特征。在小鼠巨噬细胞和人外周血单核细胞中，磷脂TLR 7激动剂缀合物的效力比游离TLR 7配体至少高100倍，而PEG-磷脂缀合物的效力与未修饰的TLR 7激动剂的效力相似。当在小鼠中全身给药时，与未修饰的TLR 7激活剂相比，磷脂和磷脂-PEG TLR 7缀合物诱导血清中促炎细胞因子水平的延长增加。当缀合物在疫苗接种期间用作佐剂时，仅磷脂TLR 7激动剂缀合物诱导Th 1和Th 2抗原特异性免疫应答。这些数据表明，TLR 7配体的免疫刺激活性可以通过缀合来放大和集中，从而拓宽了这些试剂的潜在治疗应用。
Activation of toll-like receptors (TLRs) on cells of the innate immune system initiates, amplifies, and directs the antigen-specific acquired immune response. Ligands that stimulate TLRs, therefore, represent potential immune adjuvants. In this study, a potent TLR7 agonist was conjugated to phospholipids, poly(ethylene glycol) (PEG), or phospholipid-PEG via a versatile benzoic acid functional group. Compared to the unmodified TLR7 agonist, each conjugate displayed a distinctive immunological profile in vitro and in vivo. In mouse macrophages and human peripheral blood mononuclear cells, the phospholipid TLR7 agonist conjugate was at least 100-fold more potent than the free TLR7 ligands, while the potency of PEG−phospholipid conjugate was similar to that of the unmodified TLR7 agonist. When administered systemically in mice, the phospholipid and phospholipid−PEG TLR7 conjugates induced prolonged increases in the levels of proinflammatory cytokines in serum, compared to the unmodified TLR7 activator. When the conjugates were used as adjuvants during vaccination, only the phospholipid TLR7 agonist conjugates induced both Th1 and Th2 antigen-specific immune responses. These data show that the immunostimulatory activity of a TLR7 ligand can be amplified and focused by conjugation, thus broadening the potential therapeutic application of these agents.
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DOI：
10.1073/pnas.0631696100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Lee, J;Chuang, TH;Cottam, HB
通讯作者：
Cottam, HB
影响因子：
46.9
作者：
Cho, HJ;Takabayashi, K;Raz, E
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Raz, E
影响因子：
82.9
作者：
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DOI：
10.1152/ajpregu.00527.2007
发表时间：
2008-07-01
影响因子：
2.8
作者：
Hayashi, Tomoko;Cottam, Howard B.;Corr, Maripat
通讯作者：
Corr, Maripat
影响因子：
2.2
作者：
KENNEY, JS;HUGHES, BW;ALLISON, AC
通讯作者：
ALLISON, AC