MODE OF ACTION OF ANTI-LIPOPOLYSACCHARIDE-BINDING PROTEIN ANTIBODIES FOR PREVENTION OF ENDOTOXEMIC SHOCK IN MICE
MODE OF ACTION OF ANTI-LIPOPOLYSACCHARIDE-BINDING PROTEIN ANTIBODIES FOR PREVENTION OF ENDOTOXEMIC SHOCK IN MICE
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DOI：
10.1073/pnas.91.17.7922
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发表时间：
1994-08-16
影响因子：
11.1
通讯作者：
GLAUSER, MP
中科院分区：
文献类型：
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作者：
GALLAY, P;HEUMANN, D;GLAUSER, MP
脂多糖（LPS）结合蛋白（LBP）已被证明在体外调节单核细胞对LPS的反应。在以前的研究中，多克隆抗LBP IgG被发现保护D半乳糖胺致敏小鼠免受致死性内毒素血症休克诱导的低挑战的LPS或脂质A时，同时给予内毒素。在本研究中，我们研究了这些抗LBP IgG的作用模式。在体外，我们证明了它们以不同的方式干扰LPS与单核细胞或多形细胞的结合：通过仅仅阻止LPS与LBP的结合，从而阻止LPS与CD 14的结合，或者通过与LPS-LBP复合物反应，从而介导它们与单核细胞和多形细胞上的补体或Fc受体的结合。在体内，我们证明了抗LBP IgG通过两种机制之一提供对致死性内毒素血症休克的保护。首先，通过用抗LBP IgG预处理的LBP阻断允许针对低剂量LPS（100 ng）的保护。尽管血液中的LPS水平与对照小鼠相似，但在没有可检测到的肿瘤坏死因子（TNF）的情况下，仍发生了这种保护作用。这表明，抗LBP IgG可以阻断LPS攻击时LBP介导的TNF释放。相反，抗LBP IgG在未用D-半乳糖胺致敏且用高剂量LPS（1 mg）攻击的小鼠中不提供保护，证实高浓度的LPS可以独立于LBP途径刺激细胞。第二，与LPS攻击同时施用的抗LBP治疗保护小鼠免受低剂量和高剂量的LPS。与用抗LBP IgG预处理后不同，这种保护伴随着循环LPS的减少，表明在这些条件下，抗LBP IgG可能通过清除LPS-LBP复合物促进LPS的清除。这些数据以及LBP通过脂质A与所有LPS结合的事实表明，针对LBP的抗体可能是内毒素休克治疗策略的候选者。
Lipopolysaccharide (LPS)-binding protein (LBP) has been shown to regulate the response of monocytes to LPS in vitro. In a previous study, polyclonal anti-LBP IgGs were found to protect D galactosamine-sensitized mice against a lethal endotoxemic shock induced by a low challenge of LPS or lipid A when administered simultaneously with endotoxin. In the present study, we investigated the mode of action of these anti-LBP IgGs. In vitro, we demonstrated that they interfere with LPS binding to monocytes or polymorphonuclear cells in different ways: by the mere prevention of binding of LPS to LBP thus preventing the binding of LPS to CD14, or by reacting with LPS-LBP complexes thus mediating their binding to complement or Fc receptors an monocytes and on polymorphonuclear cells. In vivo, we demonstrated that anti-LBP IgGs afforded protection against lethal endotoxemic shock by one of two mechanisms. First, LBP blockade by pretreatment with anti-LBP IgG allowed protection against a low dose of LPS (100 ng). This protection occurred despite LPS levels in blood similar to those in control mice but in the absence of detectable tumor necrosis factor (TNF). This demonstrated that anti-LBP IgG could block the LBP-mediated TNF release upon LPS challenge. In contrast, anti-LBP IgG did not afford protection in mice not sensitized with D-galactosamine and challenged with high-dose LPS (1 mg), confirming that LPS at high concentrations could stimulate cells independently of the LBP pathway. Second, anti-LBP treatment administered simultaneously with LPS challenge protected mice against both low and high doses of LPS. Unlike after pretreatment with anti-LBP IgG, this protection was accompanied by a decrease of circulating LPS, suggesting that anti-LBP IgG in these conditions facilitated clearance of LPS probably by clearing LPS-LBP complexes. These data and the fact that LBP binds to all LPS through lipid A suggest that antibody directed to LBP could be a candidate for therapeutic strategies in endotoxemic shock.