吸附壳聚糖PLGA纳米/微球载口蹄疫核酸疫苗的黏膜免疫研究
摘要
呼吸道传播被认为是口蹄疫感染的一条重要途径,而黏膜免疫可以有效预防口蹄疫的呼吸道感染,因而研制口蹄疫黏膜免疫疫苗为口蹄疫的预防提供新的思路和可能性。
为了增强黏膜免疫疫苗的免疫效果,克隆了牛的IL-6基因,并通过生物信息学方法预测了其在大鼠体内的活性；将IL-6基因插入到真核表达载体PcDNA3.1(+)作为分子佐剂,使其位于口蹄疫的结构蛋白前和中间,构建了重组质粒Pc-P12A3C、Pc-IL2AP12A3C、pc-P12AIL3C;通过夹心ELISA方法、间接免疫荧光法检测体外转染细胞中口蹄疫结构蛋白的表达,透射电子显微镜观察口蹄疫空衣壳的组装。
为使口蹄疫核酸疫苗能够递呈至鼻及下呼吸道,并延长核酸疫苗的滞留时间,乳化扩散挥发法制备了吸附壳聚糖PLGA纳米/微球,并冷冻干燥制备成粉末。另外,还研究了壳聚糖浓度、pH对颗粒吸附质粒的影响,发现质粒的吸附率随着壳聚糖浓度的增加、pH的降低而提高。
以制备的吸附壳聚糖PLGA纳米/微米球载口蹄疫DNA疫苗通过鼻黏膜免疫豚鼠,检测血清口蹄疫特异性抗体、鼻洗液口蹄疫特异性IgA水平,以及进行动物攻毒保护试验。结果显示,pc-P12AIL3C、pc-P12A3C和pc-IL2AP12A3C三个免疫组均在豚鼠诱致口蹄疫特异性IgG、IgA抗体的产生,但抗体滴度依次降低；抗强毒攻击的免疫保护分别为1/5、0/5和3/5。因此,以牛IL-6基因作为黏膜分子佐剂,吸附壳聚糖PLGA纳米/微球载口蹄疫DNA疫苗通过鼻免疫豚鼠,结果表明能够促进口蹄疫DNA疫苗黏膜免疫。
In order to enhance the immunological effect of mucosal vaccine, the gene of bovine IL-6 was cloned, and predicted its reactivity on rat. IL-6 was inserted into eukaryotic expression plasmid PcDNA3.1 (+) located either before or in the gene P12A and 3C as adjuvant, recombinant plasmid Pc-P12A3C、Pc-IL2AP12A3C、pc-P12AIL3C were constructed. Subsequently, sandwich-ELISA, indirect immunoflurescent assay were used to detected the FMDV structure protein expressed in vitro, and FMDV capisid was observed by SEM.
Aerosol transmission of foot and mouth disease virus (FMDV) is believed to be an important route of infection, mucosal immunity establishes defence against FMDV entering the body via mucosal surfaces. Therefore, developing the mucosal vaccine provide new concept and possibility.
In order to delivery the DNA vaccine to nasal and lower resparatory tract, and improve the residence time, the chitosan coated PLGA nano/micro sphere were made by Emulsion-Diffusion-Evaporation technique, and freeze-dried into powder. In addition, the affect of chitosan concentration, pH on the asorbence of plasmid was studied, the asorbence of plasmid improved when chitosan concentration increased and pH decreased.
Guinea pigs were intranasally vaccinated the microparticles containing chitosan coated PLGA nanospheres loaded FMDV DNA vaccine, FMDV specific antibody in serum, FMDV specific IgA in nasal washing were detected, and animal challenge experiments were performed. The results shows that pc-P12AIL3C、pc-P12A3C and pc-IL2AP12A3C induced FMDV specific IgG,IgA in guinea pigs, and the antibody titer decreased systematically. The percent of animal protected against FMDV challenge immunized with pc-P12AIL3C、pc-P12A3C and pc-IL2AP12A3C were 1/5、0/5 and 3/5 respectively. Therefore, the results show the mucosal immune response against FMDV were enhanced through the bovine IL-6 as mucosal molecular adjuvant and chitosan coated PLGA nano/micro spheres loaded the DNA vaccine.
为了增强黏膜免疫疫苗的免疫效果,克隆了牛的IL-6基因,并通过生物信息学方法预测了其在大鼠体内的活性；将IL-6基因插入到真核表达载体PcDNA3.1(+)作为分子佐剂,使其位于口蹄疫的结构蛋白前和中间,构建了重组质粒Pc-P12A3C、Pc-IL2AP12A3C、pc-P12AIL3C;通过夹心ELISA方法、间接免疫荧光法检测体外转染细胞中口蹄疫结构蛋白的表达,透射电子显微镜观察口蹄疫空衣壳的组装。
为使口蹄疫核酸疫苗能够递呈至鼻及下呼吸道,并延长核酸疫苗的滞留时间,乳化扩散挥发法制备了吸附壳聚糖PLGA纳米/微球,并冷冻干燥制备成粉末。另外,还研究了壳聚糖浓度、pH对颗粒吸附质粒的影响,发现质粒的吸附率随着壳聚糖浓度的增加、pH的降低而提高。
以制备的吸附壳聚糖PLGA纳米/微米球载口蹄疫DNA疫苗通过鼻黏膜免疫豚鼠,检测血清口蹄疫特异性抗体、鼻洗液口蹄疫特异性IgA水平,以及进行动物攻毒保护试验。结果显示,pc-P12AIL3C、pc-P12A3C和pc-IL2AP12A3C三个免疫组均在豚鼠诱致口蹄疫特异性IgG、IgA抗体的产生,但抗体滴度依次降低；抗强毒攻击的免疫保护分别为1/5、0/5和3/5。因此,以牛IL-6基因作为黏膜分子佐剂,吸附壳聚糖PLGA纳米/微球载口蹄疫DNA疫苗通过鼻免疫豚鼠,结果表明能够促进口蹄疫DNA疫苗黏膜免疫。
In order to enhance the immunological effect of mucosal vaccine, the gene of bovine IL-6 was cloned, and predicted its reactivity on rat. IL-6 was inserted into eukaryotic expression plasmid PcDNA3.1 (+) located either before or in the gene P12A and 3C as adjuvant, recombinant plasmid Pc-P12A3C、Pc-IL2AP12A3C、pc-P12AIL3C were constructed. Subsequently, sandwich-ELISA, indirect immunoflurescent assay were used to detected the FMDV structure protein expressed in vitro, and FMDV capisid was observed by SEM.
Aerosol transmission of foot and mouth disease virus (FMDV) is believed to be an important route of infection, mucosal immunity establishes defence against FMDV entering the body via mucosal surfaces. Therefore, developing the mucosal vaccine provide new concept and possibility.
In order to delivery the DNA vaccine to nasal and lower resparatory tract, and improve the residence time, the chitosan coated PLGA nano/micro sphere were made by Emulsion-Diffusion-Evaporation technique, and freeze-dried into powder. In addition, the affect of chitosan concentration, pH on the asorbence of plasmid was studied, the asorbence of plasmid improved when chitosan concentration increased and pH decreased.
Guinea pigs were intranasally vaccinated the microparticles containing chitosan coated PLGA nanospheres loaded FMDV DNA vaccine, FMDV specific antibody in serum, FMDV specific IgA in nasal washing were detected, and animal challenge experiments were performed. The results shows that pc-P12AIL3C、pc-P12A3C and pc-IL2AP12A3C induced FMDV specific IgG,IgA in guinea pigs, and the antibody titer decreased systematically. The percent of animal protected against FMDV challenge immunized with pc-P12AIL3C、pc-P12A3C and pc-IL2AP12A3C were 1/5、0/5 and 3/5 respectively. Therefore, the results show the mucosal immune response against FMDV were enhanced through the bovine IL-6 as mucosal molecular adjuvant and chitosan coated PLGA nano/micro spheres loaded the DNA vaccine.
引文
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