低活性hTNF-α突变蛋白的免疫原性分析  

Immunogenicity of Low Activity Mutants of Human Tumor Necrosis Factor Alpha

作　　者：周福强 张丽[1] 邓立[1] 李荣秀[1] Zhou Fuqiang;Zhang Li;Deng Li;Li Rongxiu(State Key Laboratory of Microbial Metabolism,School of Life Sciences ＆ Biotechnology,Shanghai Jiao Tong University,Shanghai,20024)

机构地区：[1]上海交通大学生命科学技术学院微生物代谢国家重点实验室

出　　处：《基因组学与应用生物学》2018年第8期3641-3646,共6页Genomics and Applied Biology

基　　金：国家科技重大专项基金(2014ZX09101043-002)资助

摘　　要：肿瘤坏死因子-alpha（tumor necrosis factor alpha,TNF-α）在多种疾病如类风湿关节炎等自身免疫病发病机理上起着至关重要的作用。TNF-α生物抑制剂,在临床上具有很好的疗效。由于TNF-α是一种高活性的炎症因子,直接将其作为疫苗,会对机体产生很大的毒性副作用。故需要对天然的TNF-α进行点突变研究,找到生物活性很低的但同时保持良好的免疫原性的突变分子。本研究对人TNF-α活性部位4个关键氨基酸残基（K11,Y87,Y119,A145）进行了点突变和突变蛋白的免疫原性研究。发现Y119N、Y119G、Y87H、Y87H/A145R、K11Y、K11F这6个突变蛋白的生物活性较天然TNF-α下降90%以上,而免疫原性不受点突变的影响。Tumor necrosis factor alpha is a master regulator of inflammation and associated with many inflammatory diseases TNF-α biological inhibitors significantly improve clinical outcome of patients with some diseases such as rheumatoid arthritis.For vaccine design,it is necessary to identify mutant TNF-α with low biological activity as it is highly potent molecule,and toxic.In this study,we performed site directed mutagenesis on four amino acid residues critical function.We found that six mutants have activities reduced to less than 10% of its native molecule.The mutations have no effects on immunogenicity of TNF-α.

关 键 词：TNF-Α 点突变 生物活性 免疫原性 

分 类 号：R392[医药卫生—免疫学]