Simultaneous immunisation with a Wilms鈥?Tumour 1 epitope and its ubiquitin fusions results in enhanced cell mediated immunity and tumour rejection in C57BL/6 mice

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• 作者：Nasir Saeedi Eslami^a ; Mohammad Ali Shokrgozar^b ; ^{mashokrgozar@pasteur.ac.ir} ; Asadollah Mousavi^c ; Kayhan Azadmanesh^d ; Alireza Nomani^e ; Vasso Apostolopoulos^f ; Stephanie Day^f ; Amir Amanzadeh^b ; Mohammad Hossein Alimohammadian^a ; ^{mhalimoh@pasteur.ac.ir}
• 关键词：Leukemia ; Cancer vaccine ; Ubiquitin ; Immunization
• 刊名：Molecular Immunology
• 出版年：2012
• 期刊代码：112_01615890
• 类别：bio
• 出版时间：July, 2012
• 卷：51
• 期：3-4
• 页码：325-331
• 文件大小：634 K

摘要

Protein fusion to ubiquitin results in its targeting to proteasome and processing through MHC class I pathway. We used this approach to induce cytotoxic T lymphocyte (CTL) response against a MHC class I epitope. Therefore, two known proteasome targeting systems, 鈥渦biquitin fusion degradation鈥?(UFD) and 鈥淣-end rule鈥? were used to immunise C57BL/6 mice. Two plasmids encoding an epitope from Wilms鈥?Tumour 1 (WT1-126), fused N-terminally to ubiquitin, were constructed. They were designated as 鈥減UbVVPT鈥?and 鈥減UbGRPT鈥? targeting the fused epitope to UFD and N-end pathways, respectively. A plasmid encoding WT1-126 without ubiquitin fusion (pPT) was also constructed as control. Three mice groups were immunised using these constructs (UGR, UVV and PT groups). Two other groups received mixed immunisations of pUbVVPT or pUbGRPT plus pPT plasmids (UVV + PT and UGR + PT). All mice received a WT1-126 peptide booster. Lymphoproliferative responses following stimulation with WT1-126 were observed in all immunisation groups, with mice receiving the mixture of plasmids eliciting the highest proliferation (UVV + PT > UGR + PT > PT). Moreover, In vivo cytotoxicity assay results revealed highest specific lysis of target cells in UVV + PT group. Tumour growth was decreased in all immunised groups, and was completely abrogated in UGR + PT group. In addition, T_H1 type cytokines patterns were detected from all immunised groups and WT1-126-specific IFN纬 producing lymphocytes were developed in them. These results suggest that the delivery of ubiquitin-fused epitopes along with epitopes alone can be used to optimise the effect of DNA vaccines on the induction of anti-tumour immunity.