Passive immunization to outer membrane proteins MLP and PAL does not protect mice from sepsis
Passive immunization to outer membrane proteins MLP and PAL does not protect mice from sepsis
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DOI：
10.2119/2006-00065.valentine
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发表时间：
2006-09-01
影响因子：
5.7
通讯作者：
Warren, H. Shaw
中科院分区：
文献类型：
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作者：
Valentine, Catherine H.;Hellman, Judith;Warren, H. Shaw
多项较早的研究报道，针对粗糙突变细菌的免疫球蛋白，如E。coliJ5，对革兰氏阴性菌的异源菌株的攻击提供广泛的保护。这种保护最初被认为是通过免疫球蛋白与细菌脂多糖（LIPS）的结合而发生的，然而，已经投资数亿美元试图开发临床有效的抗LPS单克隆抗体而没有成功，并且没有研究表明来自这种抗血清的IgG结合LIPS。保护机制的鉴定将有助于开发用于治疗脓毒症的广泛保护性人单克隆抗体。来自该抗血清的IgG结合2种细菌外膜蛋白：胞壁素脂蛋白（MLP）和肽聚糖相关脂蛋白（PAL），这两种外膜蛋白都是高度保守的，具有锚定在细菌膜中的脂质结构域，与LPS一起从细菌中脱落，并通过Toll样受体2激活细胞。我们在当前工作中的目标是确定针对MLP和PAL的被动免疫是否保护小鼠免受革兰氏阴性脓毒症。针对MLP或PAL的单克隆或多克隆IgG在3种不同的脓毒症模型中均不赋予存活保护：盲肠结扎和穿刺，感染的烧伤模型，和模拟腹膜炎的感染的纤维蛋白凝块模型，我们的结果不支持这样的假设，即抗MILP或抗PAL IgG是先前描述的抗粗糙突变体细菌抗血清中的保护性抗体。这些研究表明，涉及不同的保护机制。
Multiple older studies report that immunoglobulin directed to rough mutant bacteria, such as E. coli J5, provides broad protection against challenge with heterologous strains of Gram-negative bacteria. This protection was initially believed to occur through binding of immunoglobulin to bacterial lipopolysaccharide (LIPS), However, hundreds of millions of dollars have been invested in attempting to develop clinically-effective anti-LPS monoclonal antibodies without success, and no study has shown that IgG from this antiserum binds LIPS. Identification of the protective mechanism would facilitate development of broadly protective human monoclonal antibodies for treating sepsis. IgG from this antiserum binds 2 bacterial outer membrane proteins: murein lipoprotein (MLP) and peptidoglycan-assocated lipoprotein (PAL), Both of these outer membrane proteins are highly conserved, have lipid domains that are anchored in the bacterial membrane, are shed from bacteria in blebs together with LPS, and activate cells through Toll-like receptor 2. Our goal in the current work was to determine if passive immunization directed to MLP and PAL protects mice from Gram-negative sepsis, Neither monoclonal nor polyclonal IgG directed to MLP or PAL conferred survival protection in 3 different models of sepsis: cecal ligation and puncture, an infected burn model, and an infected fibrin clot model mimicking peritonitis, Our results are not supportive of the hypothesis that either anti-MILP or anti-PAL IgG are the protective antibodies in the previously described anti-rough mutant bacterial antisera. These studies suggest that a different mechanism of protection is involved.