Glucopyranosyl Lipid Adjuvant (GLA), a Synthetic TLR4 Agonist, Promotes Potent Systemic and Mucosal Responses to Intranasal Immunization with HIVgp140
Glucopyranosyl Lipid Adjuvant (GLA), a Synthetic TLR4 Agonist, Promotes Potent Systemic and Mucosal Responses to Intranasal Immunization with HIVgp140
复制标题
DOI：
10.1371/journal.pone.0041144
复制
发表时间：
2012-07-19
期刊：
影响因子：
3.7
通讯作者：
Shattock, Robin J.
中科院分区：
文献类型：
--
作者：
Arias, Mauricio A.;Van Roey, Griet A.;Shattock, Robin J.
成功的艾滋病毒疫苗开发可能需要在全身和粘膜区室中诱导强烈、持久的体液和细胞免疫应答。基于上呼吸道和泌尿生殖道之间已知的免疫学联系，我们探索了鼻佐剂增强免疫的潜力，以诱导对gp 140的阴道和全身免疫应答。用HIV gp 140连同合成TLR 4激动剂、吡喃葡萄糖基脂质佐剂（GLA）的胶束和乳液制剂鼻内免疫小鼠，并将应答与TLR 7/8激动剂R848或非TLR佐剂壳聚糖进行比较。与单独的抗原相比，GLA和壳聚糖而不是R848大大增强了血清免疫球蛋白水平。GLA和壳聚糖均诱导鼻和阴道灌洗液和粪便中的高IgG和伊加滴度。阴道灌洗液中的高伊加和IgG滴度与生殖道中大量gp 140特异性抗体分泌细胞相关。虽然GLA和壳聚糖都诱导T细胞对免疫的应答，但GLA诱导更强的Th 17应答，而壳聚糖诱导更偏向Th 2的应答。我们的研究结果表明，GLA是一种非常有效的鼻内佐剂，大大增强体液和细胞免疫反应，无论是系统和粘膜。
Successful vaccine development against HIV will likely require the induction of strong, long-lasting humoral and cellular immune responses in both the systemic and mucosal compartments. Based on the known immunological linkage between the upper-respiratory and urogenital tracts, we explored the potential of nasal adjuvants to boost immunization for the induction of vaginal and systemic immune responses to gp140. Mice were immunized intranasally with HIV gp140 together with micellar and emulsion formulations of a synthetic TLR4 agonist, Glucopyranosyl Lipid Adjuvant (GLA) and responses were compared to R848, a TLR7/8 agonist, or chitosan, a non TLR adjuvant. GLA and chitosan but not R848 greatly enhanced serum immunoglobulin levels when compared to antigen alone. Both GLA and chitosan induced high IgG and IgA titers in nasal and vaginal lavage and feces. The high IgA and IgG titers in vaginal lavage were associated with high numbers of gp140-specific antibody secreting cells in the genital tract. Whilst both GLA and chitosan induced T cell responses to immunization, GLA induced a stronger Th17 response and chitosan induced a more Th2 skewed response. Our results show that GLA is a highly potent intranasal adjuvant greatly enhancing humoral and cellular immune responses, both systemically and mucosally.