Laboratory of Immunology, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Vaccine. 2011 Jan 10;29(3):417-25. doi: 10.1016/j.vaccine.2010.11.005. Epub 2010 Nov 16.
α-Galactosylceramide (α-GalCer) is a safe and effective adjuvant for nasal vaccines and induces protective immune responses against tumors and viral infections. In our previous study, the fatty acyl chains of α-GalCer were modified based on the CD1d/glycolipid structure to generate α-GalCer analogues with branched acyl chains. In this study, two α-GalCer analogues, KBC-007 and KBC-009, that have different branched chain lengths were prepared and evaluated for their efficacy as nasal influenza vaccine adjuvants. These analogues displayed improved solubility over α-GalCer and potently stimulated NKT cells in both murine and in vitro human systems. Examination of serum cytokines in vivo revealed that these analogues elicited different cytokine release profiles compared to α-GalCer. KBC-009 induced both Th1/Th2 cytokines, whereas KBC-007 induced a more Th2-polarized cytokine response with diminished IFN-γ production. We found that a single immunization of inactivated influenza virus A/PR/8/34 (PR8) combined with α-GalCer analogues enhanced PR8-specific humoral and cellular immune responses in both systemic and mucosal compartments. Notably, KBC-009 exhibited potent adjuvant effects, inducing significantly higher systemic IgG and mucosal IgA antibody titers and enhancing cytotoxic T lymphocyte generation when compared to immunization with inactivated PR8 alone. In contrast, addition of KBC-007 to inactivated PR8 only marginally increased PR8-specific immune responses. The protective effect of KBC-009 against challenge infection was comparable to the effect produced by α-GalCer. These results suggest that an α-GalCer analogue with a branched acyl chain could be used as an effective mucosal adjuvant for the induction of protective immune responses against influenza virus infection.
α-半乳糖神经酰胺（α-GalCer）是一种安全有效的鼻腔疫苗佐剂，可诱导针对肿瘤和病毒感染的保护性免疫应答。在我们之前的研究中，基于 CD1d/糖脂结构对 α-GalCer 的脂肪酸链进行了修饰，生成了具有支链酰基的 α-GalCer 类似物。在这项研究中，制备了两种具有不同支链长度的 α-GalCer 类似物 KBC-007 和 KBC-009，并评估了它们作为鼻腔流感疫苗佐剂的功效。与 α-GalCer 相比，这些类似物的溶解度得到了提高，并在小鼠和体外人系统中强力刺激了 NKT 细胞。体内检测血清细胞因子发现，与 α-GalCer 相比，这些类似物引起了不同的细胞因子释放谱。KBC-009 诱导了 Th1/Th2 细胞因子，而 KBC-007 诱导了更偏向 Th2 的细胞因子反应，IFN-γ 产生减少。我们发现，单次免疫灭活流感病毒 A/PR/8/34（PR8）与 α-GalCer 类似物联合使用增强了 PR8 特异性体液和细胞免疫应答，无论是在系统还是黏膜部位。值得注意的是，与单独免疫灭活 PR8 相比，KBC-009 表现出强大的佐剂作用，诱导了显著更高的系统 IgG 和黏膜 IgA 抗体滴度，并增强了细胞毒性 T 淋巴细胞的产生。相比之下，将 KBC-007 添加到灭活的 PR8 中仅略微增加了 PR8 特异性免疫应答。KBC-009 对挑战感染的保护作用与 α-GalCer 产生的作用相当。这些结果表明，具有支链酰基的 α-GalCer 类似物可用作诱导针对流感病毒感染的保护性免疫应答的有效黏膜佐剂。
