A Simple Mycobacterial Monomycolated Glycerol Lipid Has Potent Immunostimulatory Activity1
A Simple Mycobacterial Monomycolated Glycerol Lipid Has Potent Immunostimulatory Activity1
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简单的分枝杆菌单分枝甘油脂质具有有效的免疫刺激活性1
作者：
C. Andersen;E. Agger;I. Rosenkrands;J. Gomes;Veemal Bhowruth;Kevin J. C. Gibson;Rune V. Petersen;D. Minnikin;G. Besra;P. Andersen
长期以来，人们认为牛分枝杆菌卡介苗和弗氏完全佐剂的强免疫刺激活性是由于特定的分枝杆菌细胞包膜成分，如脂质和多糖。涉及的分枝杆菌脂质包括，除其他外，所谓的脐带因子或海藻糖二霉菌酸酯，但有限的信息是关于负责与人类APC相互作用的刺激成分的精确分子性质。在这方面，大多数旨在鉴定和表征个体免疫刺激性分枝杆菌脂质的研究已经在小鼠系统中使用骨髓来源的树突状细胞进行。在这项研究中，它被证明，有效的免疫刺激活性在于芽孢杆菌Calmette-Gue 'rin非极性脂质类。这种活性可以被缩小到一个非常简单的单菌酰甘油（MMG）的能力，刺激人树突状细胞的活化标志物的表达增强和促炎细胞因子的释放进行评估。发现基于32个碳（C32）的MMG的合成类似物表现出相当水平的免疫刺激活性。使用阳离子脂质体作为递送载体，用MMG中的结核病候选疫苗Ag 85 B-ESAT-6或合成类似物免疫小鼠，发现产生显著的Th 1应答，其特征在于显著水平的IFN-γ。总之，这一发展开辟了生产一类新的化学定义的脂质佐剂的可能性，以提高新的疫苗制剂的活性，针对包括结核病在内的感染因子。
It is a long held belief that the strong immunostimulatory activity of the Mycobacterium bovis bacillus Calmette-Guérin vaccine and Freund’s complete adjuvant is due to specific mycobacterial cell envelope components, such as lipids and polysaccharides. Implicated mycobacterial lipids include, among others, the so-called cord factor or trehalose dimycolate, but limited information is available regarding the precise molecular nature of the stimulatory components responsible for the interaction with human APCs. In this regard, the majority of research aimed at identifying and characterizing individual immunostimulatory mycobacterial lipids has been performed in the murine system using bone marrow-derived dendritic cells. In this study, it is documented that potent immunostimulatory activity lies within the bacillus Calmette-Guérin nonpolar lipid class. This activity can be narrowed down to a remarkably simple monomycolyl glycerol (MMG) with the ability to stimulate human dendritic cells as assessed by enhanced expression of activation markers and the release of proinflammatory cytokines. A synthetic analog of MMG based on 32 carbons (C32) was found to exhibit comparable levels of immunostimulatory activities. Immunization of mice with the tuberculosis vaccine candidate, Ag85B-ESAT-6, in MMG or the synthetic analog using cationic liposomes as the delivery vehicle was found to give rise to a prominent Th1 response characterized by significant levels of IFN-γ. Together, this development opens up the possibility of producing a novel class of chemically defined lipid adjuvants to enhance the activity of new vaccine formulations, directed against infectious agents including tuberculosis.