Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry , Central China Normal University , Wuhan , Hubei 430079 , P. R. China.
Mol Pharm. 2019 Apr 1;16(4):1467-1476. doi: 10.1021/acs.molpharmaceut.8b01095. Epub 2019 Mar 11.
Peptides are generally needed as T-helper epitopes in nicotine vaccines to induce effective antibody responses, but the highly polymorphic property of major histocompatibility complex (MHC) molecules may limit opportunities of B cell to receive CD4 T-cell help. Invariant natural killer T (iNKT) cells recognize lipid antigens presented by the nonpolymorphic CD1d molecule that is conserved in mammals to a great extent. iNKT cells also display some similar functions to conventional CD4 T-helper cells, especially they license dendritic cells stimulate antibody isotype switching by B cells. Herein, α-galactosylceramide (αGalCer), a classical iNKT cell agonist, serves as an adjuvant in synthetic nicotine vaccine candidates absent of peptide or protein. Our study reveals that αGalCer displays better adjuvant activity than PamCSK (a commonly used lipopeptide TLR agonist). Remarkably, the covalent linker between the nicotine hapten and αGalCer is not critical. Self-assembly of the lipid-tailed nicotine and αGalCer into the liposome represents a structurally simple but immunologically effective way to develop nicotine vaccines. This is the first time to introduce the iNKT cell agonist as an adjuvant to an antidrug vaccine. This discovery may contribute to improving the efficacy of clinical candidate nicotine vaccines in the future.
肽通常作为尼古丁疫苗中的 T 辅助表位，以诱导有效的抗体反应，但主要组织相容性复合体 (MHC) 分子的高度多态性可能限制了 B 细胞接受 CD4 T 细胞帮助的机会。不变自然杀伤 T (iNKT) 细胞识别由非多态性 CD1d 分子呈递的脂质抗原，该分子在哺乳动物中具有很大程度的保守性。iNKT 细胞还表现出一些与传统 CD4 T 辅助细胞相似的功能，特别是它们授权树突状细胞通过 B 细胞刺激抗体同种型转换。在此，α-半乳糖神经酰胺 (αGalCer)，一种经典的 iNKT 细胞激动剂，作为缺乏肽或蛋白质的合成尼古丁疫苗候选物的佐剂。我们的研究表明，αGalCer 比 PamCSK（一种常用的脂肽 TLR 激动剂）具有更好的佐剂活性。值得注意的是，尼古丁半抗原和 αGalCer 之间的共价连接物并不关键。尼古丁尾部脂质和 αGalCer 自组装成脂质体代表了一种结构简单但免疫有效的开发尼古丁疫苗的方法。这是首次将 iNKT 细胞激动剂作为一种佐剂引入抗药物疫苗。这一发现可能有助于提高未来临床候选尼古丁疫苗的疗效。
