Liu Zilai, Hosomi Koji, Shimoyama Atsushi, Yoshii Ken, Sun Xiao, Lan Huangwenxian, Wang Yunru, Yamaura Haruki, Kenneth Davie, Saika Azusa, Nagatake Takahiro, Kiyono Hiroshi, Fukase Koichi, Kunisawa Jun
Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBIOHN), Ibaraki, Japan.
Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Front Pharmacol. 2021 Oct 22;12:763657. doi: 10.3389/fphar.2021.763657. eCollection 2021.
We previously identified spp. as a commensal bacterium that resides in lymphoid tissues, including Peyer's patches. We found that -derived lipopolysaccharide acted as a weak agonist of Toll-like receptor four due to the unique structure of lipid A, which lies in the core of lipopolysaccharide. This feature allowed the use of chemically synthesized lipid A as a safe synthetic vaccine adjuvant that induces Th17 polarization to enhance systemic IgG and respiratory IgA responses to T-cell-dependent antigens (e.g., ovalbumin and pneumococcal surface protein A) without excessive inflammation. Here, we examined the adjuvant activity of lipid A on a influenzae B conjugate vaccine that contains capsular polysaccharide polyribosyl ribitol phosphate (PRP), a T-cell-independent antigen, conjugated with the T-cell-dependent tetanus toxoid (TT) antigen (i.e., PRP-TT). When mice were subcutaneously immunized with PRP alone or mixed with TT, lipid A did not affect PRP-specific IgG production. In contrast, PRP-specific serum IgG responses were enhanced when mice were immunized with PRP-TT, but these responses were impaired in similarly immunized T-cell-deficient nude mice. Furthermore, TT-specific-but not PRP-specific-T-cell activation occurred in mice immunized with PRP-TT together with lipid A. In addition, coculture with lipid A promoted significant proliferation of and enhanced antibody production by B cells. Together, these findings suggest that lipid A exerts an adjuvant activity on thymus-independent Hib polysaccharide antigen in the presence of a T-cell-dependent conjugate carrier antigen.
我们之前鉴定出[具体菌种名称]为一种共生细菌，存在于包括派尔集合淋巴结在内的淋巴组织中。我们发现，由于脂多糖核心部位脂质A的独特结构，[该菌种]衍生的脂多糖作为Toll样受体4的弱激动剂。这一特性使得化学合成的[该菌种]脂质A能够用作安全的合成疫苗佐剂，可诱导Th17极化，增强对T细胞依赖性抗原（如卵清蛋白和肺炎球菌表面蛋白A）的全身IgG和呼吸道IgA反应，且不会引发过度炎症。在此，我们研究了[该菌种]脂质A对一种B型流感嗜血杆菌结合疫苗的佐剂活性，该疫苗包含与T细胞依赖性破伤风类毒素（TT）抗原（即PRP-TT）偶联的荚膜多糖多聚核糖基核糖醇磷酸（PRP），一种T细胞非依赖性抗原。当小鼠皮下单独免疫PRP或与TT混合免疫时，[该菌种]脂质A不影响PRP特异性IgG的产生。相比之下，当小鼠用PRP-TT免疫时，PRP特异性血清IgG反应增强，但在同样免疫的T细胞缺陷裸鼠中这些反应受损。此外，在用PRP-TT和[该菌种]脂质A一起免疫的小鼠中发生了TT特异性而非PRP特异性的T细胞激活。另外，与[该菌种]脂质A共培养促进了B细胞的显著增殖并增强了其抗体产生。总之，这些发现表明，在T细胞依赖性偶联载体抗原存在的情况下，[该菌种]脂质A对胸腺非依赖性b型流感嗜血杆菌多糖抗原发挥佐剂活性。
