Petersen T R, Buus S, Brunak S, Nissen M H, Sherman L A, Claesson M H
Laboratory of Cellular Immunology, The Department of Medical Anatomy, The Panum Institute, The University of Copenhagen, Blegdamsvej 3, Copenhagen 2200N, Denmark.
Scand J Immunol. 2001 Apr;53(4):357-64. doi: 10.1046/j.1365-3083.2001.00887.x.
The replacement of a suboptimal amino acid in a primary anchor position with an optimal residue improves human leucocyte antigen (HLA) binding and immunogenicity, while maintaining cytotoxic T lymphocyte (CTL) specificity. Using a neural network capable of performing quantitative predictions of peptide binding to HLA-A2 molecules, we identified three p53 protein-derived nonamer peptides with intermediate binding owing to suboptimal amino acids in the P2 anchor position. These peptides were synthesized along with the corresponding analogs, where the natural P2 residue had been replaced with the optimal leucine residue. All three modified peptides bound to and more efficiently stabilized HLA-A2 molecules than the corresponding nonmodified peptides. The HLA-A2 transgenic mice were used for immunization. Two of the epitopes were more immunogenic in their modified than in their natural versions. The CTLs raised against the modified peptides efficiently killed the target cells pulsed with the corresponding native peptide. In terms of sensitizing the targets cells for the CTL killing, the modified peptides were more efficient than native peptides. Finally, the CTLs induced by modified peptide killed HLA-A2 transgenic mouse fibrosarcoma cells transfected with human p53 DNA. The data suggest that modified self-peptides derived from overexpressed tumour-associated proteins can be used in vaccine development against cancer, and that quantitative predictions of HLA binding is of value in the rational selection and improvement of target epitopes recognized by CTLs.
将主要锚定位点的次优氨基酸替换为最优残基可改善人类白细胞抗原（HLA）结合和免疫原性，同时保持细胞毒性T淋巴细胞（CTL）特异性。利用能够对肽与HLA - A2分子的结合进行定量预测的神经网络，我们鉴定出三种源自p53蛋白的九聚体肽，由于P2锚定位点存在次优氨基酸，它们具有中等结合能力。这些肽与相应类似物一起合成，其中天然P2残基被最优亮氨酸残基取代。与相应的未修饰肽相比，所有三种修饰肽均能结合并更有效地稳定HLA - A2分子。使用HLA - A2转基因小鼠进行免疫。其中两个表位的修饰形式比天然形式具有更强的免疫原性。针对修饰肽产生的CTL能有效杀伤用相应天然肽脉冲处理的靶细胞。就使靶细胞对CTL杀伤敏感而言，修饰肽比天然肽更有效。最后，由修饰肽诱导的CTL杀死了转染人p53 DNA的HLA - A2转基因小鼠纤维肉瘤细胞。数据表明，源自过表达肿瘤相关蛋白的修饰自身肽可用于癌症疫苗开发，并且HLA结合的定量预测在合理选择和改进CTL识别的靶表位方面具有价值。
