摘要
背景:DNA疫苗具有良好的耐受性和安全性,但是普遍免疫效果不理想。我们先前报道过当肿瘤抗原TEM-8的血管性I/A区序列的编码质粒载体(pATRex)与肿瘤抗原的编码质粒结合时,可以作为一个功能强大的分子佐剂,增强抵抗乳腺瘤和黑色素瘤的免疫性。目的:本研究中我们解决了两个未解决的议题;pATRex的辅助作用是否会延至DNA疫苗抗传染病的范围?如果是,那么pATRex佐剂基于什么作用机制?结果:在此我们用小鼠疟疾疫苗模型展示,联合pATRex 用药可以加强由肌内注射疟原虫裂殖子表面蛋白4/5 (PyMSP4/5)编码质粒引起的抗体产生。pATRex佐剂增强 B细胞应答, 并诱导产生与DNA疫苗TH2型免疫应答极化一致的IgG1升高。为了探索佐剂作用机制,转移pATRex 细胞到体外,这也导致了不溶的细胞内聚集物和细胞凋亡的形成。采用结构模型方法,我们确定ATRex的一个短肽序列(α3-β4)是蛋白聚集的原因,并且确认自组装肽编码质粒的细胞转染类似于诱发细胞内聚集物、胱天蛋白酶激活及细胞凋亡。结论:促聚集区的编码质粒诱导胞内不溶聚集物的形成,这些聚集物会诱发胱天蛋白酶激活及细胞凋亡,从而导致先天免疫系统激活,因此在此可以充当基因佐剂。
关键词: 疫苗,佐剂,DNA疫苗,细胞凋亡,分子佐剂,质粒
Current Gene Therapy
Title:Plasmids Encoding Protein Aggregation Domains Act As Molecular Adjuvants for DNA Vaccines
Volume: 14 Issue: 3
Author(s): Melamia Capitani, Fadi Saade, Kristina M. Havas, Mauro Angeletti, Fabio Concetti, Dimitrios Agas, Maria G. Sabbieti, Antonio Concetti, Franco M. Venanzi and Nikolai Petrovsky
Affiliation:
关键词: 疫苗,佐剂,DNA疫苗,细胞凋亡,分子佐剂,质粒
摘要: Background: DNA vaccines provide high tolerability and safety but commonly suffer from suboptimal immunogenicity. We previously reported that a plasmid vector (pATRex), encoding the DNA sequence for the von Willebrand I/A domain of the tumor endothelial marker-8 (TEM8) when given in combination with plasmid-encoded tumor antigens acted as a powerful molecular adjuvant enhancing immunity against breast and melanoma tumors. Aims: In the present study we addressed two unsolved issues; would the adjuvant action of pATRex extend to a DNA vaccine against infectious disease and, if so, what is the mechanistic basis for pATRex adjuvant action? Results: Here we show in a murine malaria vaccine model that co-administration of pATRex potentiates antibody production elicited by an intramuscular injection of plasmid encoding Plasmodium yoelii merozoite surface protein 4/5 (PyMSP4/5). pATRex enhanced the B-cell response and induced increased IgG1 production consistent with TH2 polarization of the DNA vaccine response. To explore the mechanism of adjuvant action, cells were transfected in vitro with pATRex and this resulted in formation of insoluble intracellular aggregates and apoptotic cell death. Using a structural modeling approach we identified a short peptide sequence (α3-β4) within ATRex responsible for protein aggregation and confirmed that transfection of cells with plasmid encoding this self-assembling peptide similarly triggered intracellular aggregates, caspase activation and cell death. Conclusion: Plasmids encoding aggregationpromoting domains induce formation of insoluble intracellular aggregates that trigger caspase activation and apoptotic cell death leading to activation of the innate immune system thereby acting as genetic adjuvants.
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Capitani Melamia, Saade Fadi, Havas M. Kristina, Angeletti Mauro, Concetti Fabio, Agas Dimitrios, Sabbieti G. Maria, Concetti Antonio, Venanzi M. Franco and Petrovsky Nikolai, Plasmids Encoding Protein Aggregation Domains Act As Molecular Adjuvants for DNA Vaccines, Current Gene Therapy 2014; 14 (3) . https://dx.doi.org/10.2174/1566523214666140509114838
DOI https://dx.doi.org/10.2174/1566523214666140509114838 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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