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The fundamental study for polymyxins as novel and safe mucosal adjuvants

多粘菌素作为新型安全粘膜佐剂的基础研究

基本信息

批准号：
23790543
负责人：
YOSHINO Naoto
金额：
$ 2.66万
依托单位：
Iwate Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2011
资助国家：
日本
起止时间：
2011 至 2012
项目状态：
已结题

项目摘要

There is currently an urgent need to develop safe and effective adjuvants for enhancing vaccine-induced antigen -specific immune responses. We demonstrate here that intranasal immunization with clinically used polypeptide antibiotics, polymyxin B (PMB) and colistin (CL), along with ovalbumin (OVA), increases OVA-specific humoral immune responses in a dose-depe ndently manner at both mucosal and systemic compartments. Enhanced immunity by boosting was found to persist during 8 months of observation. Moreover, mice intranasally immunized with OVA plus various doses of PMB or CL showed neither inflammatory responses in the nasal cavity and olfactory bulbs nor renal damages, compared to those given OVA alone. These data suggest that polymyxins may serve as novel and safe mucosal adjuvants to induce humoral immune responses. The polymyxin adjuvanticity was found to be independent of endotoxins liberated by its bactericidal activity, as indicated by similar enhancing effects of PMB in lipopolysaccharide (LPS)-hyporesponsive and LPS -susceptible mice. However, despite the presence of preexisting anti-PMB antibodies, we ob served no reduction in the adjuvant function of polymyxins when they were given intranasally. Furthermore, the titers of OVA-specific Abs in mice intranasally immunized with OVA plus PMB or CL were significantly higher than those in mice administered with polymyxin analogues, such as polymyxin B nonapeptide and colistin methanesulfonate. The levels of released β-hexosaminidase and histamine in mast cell culture supernatants stimulated by PMB or CL were also significantly higher than those stimulated by their analogues. These results suggest that both the hydrophobic carbon chain and hydrophilic cationic cyclic peptide contribute to the mucosal adjuvanticity of PMB and CL

目前迫切需要开发安全有效的佐剂来增强疫苗诱导的抗原特异性免疫反应。我们在此证明，临床使用的多肽抗生素、多粘菌素B （PMB）和粘菌素（CL）以及卵清蛋白（OVA）的鼻内免疫，在粘膜和全身隔室以剂量依赖性的方式增加OVA特异性体液免疫反应。在8个月的观察中发现，增强免疫持续存在。此外，与单独给予OVA的小鼠相比，经鼻内接种OVA加不同剂量PMB或CL的小鼠鼻腔和嗅球均未出现炎症反应，肾脏也未受到损害。这些数据表明，多粘菌素可以作为一种新的、安全的粘膜佐剂来诱导体液免疫反应。PMB对脂多糖（LPS）低反应小鼠和脂多糖敏感小鼠的增强作用表明，多粘菌素的佐剂性不依赖于其杀菌活性释放的内毒素。然而，尽管存在预先存在的抗pmb抗体，我们观察到当鼻内给予多粘菌素时，其辅助功能没有降低。此外，经鼻经OVA + PMB或CL免疫的小鼠体内OVA特异性抗体滴度显著高于多粘菌素类似物（如多粘菌素B非肽和甲磺酸粘菌素）免疫的小鼠。经PMB或CL刺激的肥大细胞培养上清中释放的β-己糖氨酸酶和组胺水平也显著高于其类似物。这些结果表明疏水碳链和亲水阳离子环肽都参与了PMB和CL的粘膜佐剂作用