Yoshino Naoto, Takeshita Ryosuke, Kawamura Hanae, Murakami Kazuyuki, Sasaki Yutaka, Sugiyama Ikumi, Sadzuka Yasuyuki, Kagabu Masahiro, Sugiyama Toru, Muraki Yasushi, Sato Shigehiro
Division of Infectious Diseases and Immunology, Department of Microbiology, School of Medicine, Iwate Medical University, Yahaba-cho, Japan.
Department of Obstetrics and Gynecology, School of Medicine, Iwate Medical University, Morioka, Japan.
Scand J Immunol. 2018 Aug;88(2):e12698. doi: 10.1111/sji.12698.
Cyclic lipopeptides such as surfactin and polymyxin have potent mucosal adjuvant properties. Cyclic lipopeptides are tensioactive compounds, but the relationship between adjuvanticity and surface activity is unknown. Here, we show that the critical micelle concentration (cmc) of surfactant and particle size of the surfactant-protein complex are important determinants of cyclic lipopeptide adjuvanticity. We found that the diameter of cyclic lipopeptide-ovalbumin (OVA) complex particles was significantly larger than that in the solutions of OVA alone at cyclic lipopeptide concentrations above the cmc. OVA-specific antibody titres in mice immunized intranasally with OVA and a cyclic lipopeptide at concentrations above its cmc were significantly higher than those in mice immunized with OVA plus the same dose of the cyclic lipopeptide but administered with formulations in which cyclic lipopeptide concentration was below the cmc. Thus, the concentration of the cyclic lipopeptide in the formulation at immunization, but not its overall dose, was critical for its adjuvanticity. Furthermore, two types of aggregates, the cyclic lipopeptide simplex micelles and the cyclic lipopeptide-OVA complex micelles, were found in formulations with SF concentrations above its cmc. Degranulation of mast cells exposed to SF simplex micelles was more pronounced when SF concentration was above the cmc. In conclusion, our study showed that surface activity properties, such as the cmc and the size of surfactant-protein complex, contribute to the adjuvanticity of cyclic lipopeptides. Our study proposes a novel idea that cmc is a key parameter for tensioactive adjuvants.
诸如表面活性素和多粘菌素等环脂肽具有强大的黏膜佐剂特性。环脂肽是表面活性化合物，但佐剂活性与表面活性之间的关系尚不清楚。在此，我们表明表面活性剂的临界胶束浓度（cmc）和表面活性剂 - 蛋白质复合物的粒径是环脂肽佐剂活性的重要决定因素。我们发现，在环脂肽浓度高于cmc时，环脂肽 - 卵清蛋白（OVA）复合颗粒的直径明显大于仅OVA溶液中的颗粒直径。用高于其cmc浓度的OVA和环脂肽经鼻免疫的小鼠中，OVA特异性抗体滴度显著高于用OVA加相同剂量环脂肽但以低于cmc的环脂肽浓度制剂给药的小鼠。因此，免疫制剂中环脂肽的浓度而非其总剂量对其佐剂活性至关重要。此外，在SF浓度高于其cmc的制剂中发现了两种聚集体，即环脂肽单纯胶束和环脂肽 - OVA复合胶束。当SF浓度高于cmc时，暴露于SF单纯胶束的肥大细胞脱颗粒更为明显。总之，我们的研究表明，诸如cmc和表面活性剂 - 蛋白质复合物大小等表面活性特性有助于环脂肽的佐剂活性。我们的研究提出了一个新观点，即cmc是表面活性佐剂的关键参数。
