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含对硝基苯丙氨酸的B淋巴细胞刺激因子疫苗对狼疮肾炎模型小鼠的保护作用
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引用本文:戴辉腾,田浤,黄捷,陈超,蔡棣,高向东,姚文兵.含对硝基苯丙氨酸的B淋巴细胞刺激因子疫苗对狼疮肾炎模型小鼠的保护作用[J].中国药科大学学报(中文版),2017,48(4):483-489
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作者单位
戴辉腾 中国药科大学江苏省生物药物成药性研究重点实验室生命科学与技术学院 
田浤 中国药科大学江苏省生物药物成药性研究重点实验室生命科学与技术学院 
黄捷 中国药科大学江苏省生物药物成药性研究重点实验室生命科学与技术学院 
陈超 中国药科大学江苏省生物药物成药性研究重点实验室生命科学与技术学院 
蔡棣 中国药科大学江苏省生物药物成药性研究重点实验室生命科学与技术学院 
高向东 中国药科大学江苏省生物药物成药性研究重点实验室生命科学与技术学院 
姚文兵 中国药科大学江苏省生物药物成药性研究重点实验室生命科学与技术学院 
基金项目:国家自然科学基金资助项目(No.81273426,No.81673343)
中文摘要:考察含对硝基苯丙氨酸的B淋巴细胞刺激因子(BAFF)治疗BAFF过表达的自身免疫性疾病的效果。利用本研究前期构建的工程菌,表达纯化了B淋巴细胞刺激因子的可溶型突变体(smBAFF)以及在其65位定点引入了对硝基苯丙氨酸的改构体(pNO2Phe65smBAFF)。通过考察pNO2Phe65smBAFF体外促小鼠淋巴细胞增殖活性、免疫原性以及所诱导的抗血清对天然BAFF活性的抑制作用,评价了其用于治疗BAFF过表达的自身免疫性疾病的可行性;同时采用了cGVHD(graft-versus-host disease)诱导的狼疮肾炎小鼠模型评价了pNO2Phe65smBAFF的药理活性。结果表明:定点引入了对硝基苯丙氨酸的pNO2Phe65smBAFF不具有促进小鼠淋巴细胞增殖的能力;由于对硝基苯丙氨酸的引入显著增强了蛋白的免疫原性,诱导机体产生了可以抑制天然BAFF活性的交叉抗体;在cGVHD诱导的狼疮肾炎小鼠模型中,pNO2Phe65smBAFF可显著减轻疾病症状。定点引入了对硝基苯丙氨酸的pNO2Phe65smBAFF可以作为治疗BAFF过表达的自身免疫性疾病的候选分子。
中文关键词:B淋巴细胞刺激因子  对硝基苯丙氨酸  免疫原性  cGVHD
 
Protective effects of p-nitrophenylalanine-containing BAFF vaccine on lupus nephritis model mice
Abstract:In order to verify whether p-nitrophenylalanine-containing BAFF vaccine can be used as a candidate molecule for the treatment of autoimmune diseases with BAFF over-expression, a soluble mutant of B cell activating factor belonging to the TNF Family(smBAFF)and its pNO2Phe mutant(pNO2Phe65smBAFF), which site specific incorporated pNO2Phe at position 65 of smBAFF, were expressed and purified. In order to evaluate the feasibility of using pNO2Phe65smBAFF to treat BAFF-over-expressed autoimmune diseases, we investigate its Lymphocyte-stimulating capacity, immunogenicity and inhibitory effect of serum on biological activity of natural BAFF. The pharmacological activity of pNO2Phe65smBAFF was evaluated using a cGVHD(graft-versus-host disease)induced SLE mouse model. Results indicated that pNO2Phe65smBAFF, could bind to mouse lymphocytes but could not promote the proliferation of mouse lymphocytes. Moreover, the incorporation of pNO2Phe significantly increased the immunogenicity and induced cross-antibody, which can inhibit the biological activity of natural BAFF. In cGVHD induced SLE mouse model, pNO2Phe65smBAFF can significantly reduce the symptoms of the disease and play a therapeutic role. Therefore, pNO2Phe65smBAFF can be used as a candidate molecule for the treatment of autoimmune diseases with BAFF over-expression.
keywords:B cell activating factor belonging to the TNF family(BAFF)  p-nitrophenylalanine  immunogenicity  cGVHD
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