摘要
背景:来自不同来源的质粒编码的蛋白质聚集多肽已被提议作为DNA疫苗的基因佐剂。我们报道了一个包含A型血管性血友病 (vWA/A) 结构域的炭疽毒素受体(ANTXR-1,别名TEM8,肿瘤内皮标志物8)的DNA序列的质粒(pATRex),通过诱导不溶性细胞内的聚集物的形成和随后的细胞死亡作为强有力的免疫佐剂。目的:在本研究中我们讨论作为基因佐剂是否有任何与自身聚集蛋白的利用相关的的免疫毒性的实质性问题。方法和结果:本研究里,通过组织学、放射线、骨标本的分子检查,我们报道了意外的发现,对小鼠肌肉注射pATRex触发了本身的、严重的骨质流失(骨质疏松),而不受被治疗动物的性别和基因型的影响。结论:虽然研究表明蛋白质的“粘性”佐剂是不可能达到可行性的疫苗接种,所获得的信息是有价值的,ATREX注射可以提供额外的、简化的、骨质疏松症的小鼠模型。而且,我们的研究结果提供了对蛋白毒性聚合物慢性激活了与淀粉样蛋白及聚集物相关的疾病的先天性免疫系统这一假设的实验性支持。
关键词: DNA疫苗,佐剂,蛋白质聚集体,慢性炎症,骨重塑,骨质疏松
Current Gene Therapy
Title:Administration of DNA Plasmid Coding Protein Aggregating Domain Induces Inflammatory Bone Loss
Volume: 16 Issue: 2
Author(s): Dimitrios Agas, Fabio Concetti, Melania Capitani, Giovanna Lacava, Antonio Concetti, Luigi Marchetti, Fulvio Laus and Andrea Marchegiani, Vasco Azevedo, Maria Giovanna Sabbieti, Franco Maria Venanzi
Affiliation:
关键词: DNA疫苗,佐剂,蛋白质聚集体,慢性炎症,骨重塑,骨质疏松
摘要: Background: Plasmids coding protein aggregation polypeptides from different sources have been proposed as genetic adjuvants for DNA vaccines. We reported that a plasmid (pATRex), encompassing the DNA sequence for the von Willebrand A (vWA/A) domain of the Anthrax Toxin Receptor-1 (ANTXR-1, alias TEM8, Tumor Endothelial Marker 8), acts as strong immune adjuvant by inducing formation of insoluble intracellular aggregates and subsequent cell death. Objective: In the present study we addressed the question of whether there is any substantial immunotoxicity associated with the use of self-aggregating proteins as genetic adjuvants. Methods & Results: Here we report, by mean of histology, X-ray and molecular examinations of bone specimens, the unexpected finding that intramuscular injection of pATRex in mice triggers, per se, severe bone loss (osteoporosis) independently from the sex and genotype of the treated animals. Conclusion: Even though the study suggests that proteinaceous “sticky “ adjuvants are unlikely to find their way into practical vaccination, the information gained is of value as ATRex injections could provide an additional, simplified, mouse model of osteoporosis. Moreover, our results provide experimental support to the hypothesis that proteotoxic aggregates chronically activate the innate immune system in amyloid and aggregosome associated disorders.
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Dimitrios Agas, Fabio Concetti, Melania Capitani, Giovanna Lacava, Antonio Concetti, Luigi Marchetti, Fulvio Laus and Andrea Marchegiani, Vasco Azevedo, Maria Giovanna Sabbieti, Franco Maria Venanzi , Administration of DNA Plasmid Coding Protein Aggregating Domain Induces Inflammatory Bone Loss, Current Gene Therapy 2016; 16 (2) . https://dx.doi.org/10.2174/1566523216666160331125355
DOI https://dx.doi.org/10.2174/1566523216666160331125355 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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