CN111450244B - 一种防治冠状病毒感染的细胞组合及其应用 - Google Patents
一种防治冠状病毒感染的细胞组合及其应用 Download PDFInfo
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Abstract
本发明提供了一种防治冠状病毒感染的细胞组合及其应用。具体而言，本发明提供了DC细胞和/或NP蛋白在制备用于预防和/或治疗冠状病毒感染的免疫细胞组合物和/或试剂盒中的应用，还提供了一种负载NP抗原的DC细胞，还提供了负载NP抗原的DC细胞诱导产生的CTL细胞和NK细胞。本发明用DC细胞进行预防和治疗新冠病毒感染以及以DC诱导的T细胞和NK细胞进行治疗新冠病毒感染。
Description
技术领域
本发明是关于一种防治(预防和/或治疗)冠状病毒感染的技术，具体而言，是关于一种防治冠状病毒感染的细胞、包含所述细胞的组合物及其制备方法和相关应用。
背景技术
2019新型冠状病毒(或称SARS-CoV-2)是2019年发现的一种新型冠状病毒，该病毒与肺上皮细胞上的CEA2蛋白结合后侵染该细胞，造成肺部炎症，严重的可引发呼吸衰竭，进而死亡。
越来越多的研究表明2019新型冠状病毒除了人类，还可以猫、狗等动物作为宿主，可引起更大范围的传播。同时，2019新型冠状病毒被发现存在于自来水和空气中，这为该病毒的防控带来更大的麻烦。
总体来说，防治2019新型冠状病毒的药物开发思路有两种，一是阻止病毒和宿主细胞结合，二是阻止新冠病毒在宿主细胞内的产生。如果要阻止病毒和宿主细胞结合，作用的靶点应是病毒的刺突蛋白Spike或者宿主细胞上的ACE2受体。据悉，全球现有60个以上的新冠疫苗项目，涉及超100家生物企业和机构。研发产品包含核酸类疫苗、蛋白类疫苗、病毒载体疫苗以及减毒疫苗等，主要机制就是通过暴露病毒Spike蛋白给机体免疫系统，诱导B细胞产生中和抗体进而阻断病毒的侵袭。但Spike蛋白糖基化以及易突变的特点使得中和抗体难以在体内形成长期免疫保护。同时，对于已经潜入细胞内的病毒颗粒，或者已发生变异的病毒颗粒，中和抗体将无法发挥作用。如果要阻止新病毒的产生，作用的靶点则是RNA依赖性RNA聚合酶(RdRp)或者蛋白质水解酶，现正在进行临床试验的瑞德西韦、克力芝等药物则是基于上述作用靶点。但需知道，这类药物主要是抑制病毒的复制，降低病毒的滴度，但能否彻底清除细胞内的病毒或发生变异的病毒，则是当前药物研发需要关注的问题，否则，在机体免疫系统功能较差时，残余病毒极有可能卷土重来。
发明内容
本发明的一个目的在于提供一种预防和/或治疗冠状病毒感染的新技术。
本发明提出以SARS-COV-2病毒核衣壳蛋白(nucleoprotein，NP)作为靶点，应用细胞免疫的方式进行预防和/或治疗冠状病毒感染。
SARS-COV-2病毒NP蛋白具有如SEQ ID No.2所示氨基酸序列。
本发明中以NP作为靶点，一方面，NP蛋白特异性的T细胞不会因为病毒的变异而丢失掉作用靶点；另一方面，NP蛋白特异性的T细胞不仅可以杀死新冠病毒感染的细胞，对于和其结构蛋白有高度相似性的SARS病毒或其它未被识别的结构相似病毒，也能发挥很好的清除作用，在治疗当前感染病毒的同时，还可以预防未来可能出现的一些病毒感染疾病。更重要的是，以往的抗原选择，多属于计算预测获取的几个抗原肽分子的联合应用，具有抗原的不确定性等问题。本发明将完整的NP蛋白通过天然的免疫反应呈递方式进行处理，由此获取多个与HLA相匹配的短肽，进而介导特异性T细胞的激活和抗病毒作用。
根据本发明的具体实施方案，本发明提供的预防和/或治疗冠状病毒感染的技术，以DC细胞负载新冠病毒NP抗原制备DC疫苗预防冠状病毒感染，通过注射负载NP抗原的DC细胞至健康人体内，使患者自发产生抗病毒免疫反应，体内诱导病毒特异性T细胞和NK细胞的产生。本发明的负载NP蛋白的DC细胞能够同时诱导扩增NP特异性T细胞(CTL细胞)和NK细胞，通过注射所述的CTL细胞和NK细胞的组合，可迅速改善患者体内的免疫状况，减少非特异性炎症反应，清除病毒感染细胞。
从而，一方面，本发明提供了DC细胞和/或NP蛋白在制备用于预防和/或治疗冠状病毒感染的免疫细胞组合物和/或试剂盒中的应用。所述的免疫细胞组合物可作为或进一步制备药物或疫苗。
根据本发明的具体实施方案，本发明的上述应用中，所述NP蛋白为SARS-COV-2病毒NP蛋白。
根据本发明的具体实施方案，本发明的上述应用中，对所述DC细胞的具体性能无特殊要求。例如，可以采用能够体外培养扩增的DC细胞。
根据本发明的具体实施方案，本发明的上述应用中，所述冠状病毒为SARS-COV-2病毒。
另一方面，本发明还提供了一种负载NP抗原的DC细胞。
另一方面，本发明还提供了所述的负载NP抗原的DC细胞的制备方法，该方法包括：构建含有NP基因慢病毒载体，转染DC细胞。
根据本发明的具体实施方案，本发明中，所述NP基因为编码NP蛋白的基因。优选地，所述NP基因为编码SEQ ID No.2所示氨基酸序列的基因。更优选地，所述NP基因具有SEQID No.1第13位至第1269位碱基所示序列。更优选地，所述NP基因具有SEQ ID No.1所示序列。
另一方面，本发明还提供了所述的负载NP抗原的DC细胞在制备用于预防冠状病毒感染的免疫细胞组合物中的应用。所述的免疫细胞组合物可作为或进一步制备药物或疫苗。
另一方面，本发明还提供了一种免疫细胞，其是由所述的负载NP抗原的DC细胞诱导产生的。优选地，所述免疫细胞包括CTL细胞和/或NK细胞。
另一方面，本发明还提供了所述的免疫细胞在制备用于治疗冠状病毒感染的免疫细胞组合物中的应用。所述的免疫细胞组合物可作为或进一步制备药物或疫苗。
另一方面，本发明还提供了一种试剂盒，其包括：DC细胞和/或NP蛋白，负载NP抗原的DC细胞，和/或由所述的负载NP抗原的DC细胞诱导产生的免疫细胞(CTL细胞和/或NK细胞)。优选地，所述试剂盒还可包括冻存液或其他常规试剂。例如，所述细胞在试剂盒中保存于冻存液中，所述冻存液优选含10％DMSO和20％人血清。本发明的试剂盒可用于深入研究NP蛋白上特有肽段用于免疫治疗的可行性，也可用于冠状病毒感染的预防和/或治疗。
另一方面，本发明还提供了一种防治冠状病毒感染的免疫细胞组合物，其包括：本发明所述的负载NP抗原的DC细胞，和/或本发明所述的免疫细胞(包括CTL细胞和/或NK细胞)。优选地，所述免疫细胞组合物还可进一步包括用于重悬细胞的含1％人血白蛋白的生理盐水。
另一方面，本发明还提供了一种预防和/或治疗冠状病毒感染的方法，其包括：
将本发明的负载NP蛋白的DC细胞施予健康个体；和/或
将由本发明的负载NP蛋白的DC细胞诱导产生的CTL细胞和NK细胞施予冠状病毒感染个体。
综上所述，本发明以保守的NP抗原为靶点，以高活性DC细胞进行递呈，主要通过诱导机体产生NP抗原特异性T细胞，起到预防作用。经本发明的DC细胞诱导产生的T细胞，其特异性杀伤作用很强，在2:1低效靶比作用下的杀伤效果可以达到文献报道的其他抗原特异性T细胞25:1～100:1情况下的杀伤效果，具有意想不到的效果。本发明联合应用抗原特异性T细胞和NK细胞可治疗新冠病毒感染。本发明的技术方案，新冠病毒的防治，防具有防的有效性，考虑了病毒抗原变异的因素；治强调治疗的彻底性，考虑了病毒残留等问题。细胞免疫反应中，既有特异性的T细胞反应，又有天然的NK细胞反应，是最理想的抗新冠病毒的细胞组合。
附图说明
图1显示SARS-COV-2病毒与SARS病毒NP蛋白氨基酸序列的比较情况。
图2显示DC细胞和靶细胞内NP蛋白的表达情况。
图3显示DC-NP诱导产生的免疫细胞表型。
图4显示分选后的T细胞免疫表型。
图5显示NP抗原特异性CTL细胞产生颗粒酶和穿孔素的情况。
图6显示NP抗原特异性CTL细胞分泌干扰素γ的情况。
图7显示DC细胞诱导的NK细胞对靶细胞的杀伤作用。
图8显示DC-NP诱导产生的CTL细胞对靶细胞的杀伤作用。
具体实施方式
为了更清楚地理解本发明，现参照下列实施例及附图进一步描述本发明。实施例仅用于解释而不以任何方式限制本发明。
实施例中未注明具体条件的实验方法为所属领域熟知的常规方法和常规条件，或按照制造商所建议的条件。
实施例1、负载NP抗原的DC细胞和靶细胞
本发明中，以SARS-COV-2病毒核衣壳蛋白NP作为靶点，提供应用细胞免疫方式防治冠状病毒感染的方案。
NP结构基因相对保守，根据序列比对，SARS-COV-2病毒NP蛋白(SEQ ID No.2)与2003年出现的SARS病毒的NP蛋白(SEQ ID No.3)同源性达91％。可参见图1。图1中灰色背景部分，为标识的两个病毒NP蛋白序列中连续的≥9个氨基酸相同的地方。理论上，本发明的以灰色背景部分序列为靶点的CTL细胞，对SARS病毒感染也会起效。
SARS-COV-2病毒NP序列(SEQ ID No.2)：
MSDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQRRPQGLPNNTASWFTALTQHGKEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTLLPAADLDDFSKQLQQSMSSADSTQA
SARS病毒NP序列(SEQ ID No.3)：
MSDNGPQSNQRSAPRITFGGPTDSTDNNQNGGRNGARPKQRRPQGLPNNTASWFTALTQHGKEELRFPRGQGVPINTNSGPDDQIGYYRRATRRVRGGDGKMKELSPRWYFYYLGTGPEASLPYGANKEGIVWVATEGALNTPKDHIGTRNPNNNAATVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRGNSRNSTPGSSRGNSPARMASGGGETALALLLLDRLNQLESKVSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKQYNVTQAFGRRGPEQTQGNFGDQDLIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYHGAIKLDDKDPQFKDNVILLNKHIDAYKTFPPTEPKKDKKKKTDEAQPLPQRQKKQPTVTLLPAADMDDFSRQLQNSMSGASADSTQA
本实施例中，制备了负载NP抗原的DC细胞和靶细胞。具体过程包括：
1、合成NP基因，构建慢病毒载体
(1)根据NCBI genebank内公布的新冠病毒的核酸序列，进行分析，进行密码子优化后合成。优化后合成序列如SEQ ID No.1所示。
NP人工序列(SEQ ID No.1)：
GAATTCGCCACCATGTCAGATAACGGACCTCAGAATCAGAGAAACGCACCTAGAATCACATTTGGAGGACCTTCAGATTCAACAGGATCAAACCAGAATGGCGAAAGATCAGGAGCAAGATCAAAGCAGCGCAGACCTCAAGGACTTCCTAACAACACAGCATCATGGTTTACAGCACTTACACAACACGGAAAGGAGGACCTTAAATTTCCTAGAGGACAAGGAGTGCCTATCAACACAAACTCATCACCTGATGATCAAATCGGATACTACAGAAGAGCAACAAGAAGAATCAGAGGAGGAGATGGAAAGATGAAGGATCTTTCACCTAGATGGTACTTCTATTATCTTGGAACAGGACCTGAAGCAGGACTTCCTTACGGAGCAAACAAAGATGGAATCATCTGGGTGGCAACAGAAGGAGCACTTAACACACCTAAAGATCACATCGGAACAAGAAACCCTGCAAACAACGCAGCAATCGTGCTTCAACTTCCTCAAGGAACAACACTTCCTAAAGGATTCTATGCGGAAGGATCAAGAGGAGGATCACAAGCTTCTTCGCGTTCGTCCAGTCGGTCCCGGAACAGTTCGAGAAATTCGACGCCAGGATCATCAAGAGGAACATCACCTGCAAGAATGGCAGGAAACGGAGGAGATGCAGCACTTGCACTTCTTCTTCTTGATAGACTTAACCAACTTGAATCAAAGATGAGTGGAAAGGGCCAGCAACAACAAGGACAGACCGTCACCAAGAAGTCGGCAGCAGAAGCATCAAAGAAGCCGCGCCAGAAGCGCACTGCAACAAAGGCGTATAACGTGACACAAGCATTTGGAAGAAGAGGACCTGAACAAACACAAGGAAACTTTGGAGATCAAGAACTTATCAGACAAGGAACAGATTACAAACACTGGCCTCAAATCGCACAATTTGCACCTTCAGCATCAGCATTCTTCGGTATGTCAAGAATCGGAATGGAAGTGACACCTTCAGGAACATGGCTTACATACACAGGAGCAATCAAACTTGATGATAAAGATCCTAACTTTAAAGATCAAGTGATCCTTCTTAACAAACACATCGATGCATACAAGACTTTCCCTCCTACAGAACCTAAGAAGGACAAGAAGAAGAAAGCGGACGAAACACAAGCACTTCCTCAAAGACAGAAGAAGCAGCAAACCGTAACGCTATTACCTGCAGCAGATCTTGATGATTTCAGCAAACAGCTCCAACAATCAATGTCATCAGCAGATTCAACACAAGCAGGATCC
(2)将目的基因与商业化pCDH慢病毒骨架载体分别进行EcoRⅠ和BamHⅠ双酶切。
(3)将酶切后产物与10×loading buffer混合，1％琼脂糖凝胶上样，130V，35min。
(4)切胶，分别回收NP片段以及慢病毒骨架载体。
(5)将目的基因和慢病毒载体按照摩尔比为1:3进行连接，室温静置2小时，所得连接产物将NP基因与载体上HA基因串联以实现融合表达。
(6)取50ul Stbl3感受态加入连接产物中，冰上放置20min。
(7)42℃，热激90s。迅速放回冰上，静置2min。
(8)向EP管内加入500ul LB液体培养基，置于37℃摇床内，180rpm，30min。
(9)取出转化后感受态细胞，5000rpm，3min。弃大部分上清，留底部100ul LB培养基以重悬转化后的感受态细胞。将感受态细胞转移至LB固体培养基平板上，涂布均匀。
(10)37℃培养箱，培养过夜。
(11)次日，挑取单克隆摇菌。
(12)收集菌体，按照质粒小提试剂盒的说明书，提取质粒。
(13)所得质粒以及原来的慢病毒骨架载体，分别用EcoRⅠ和BamHⅠ进行双酶切，跑胶验证。
(14)取条带位置正确的克隆质粒，测序。
(15)测序显示正确后，取目的质粒大提，备用。
2、NP抗原的慢病毒包装及浓缩
(1)复苏293细胞，培养传代；
(2)转染前一天胰酶消化，按照5×106个细胞/皿接种于10cm培养皿内，37℃，培养过夜；
(3)转染：pCDH慢病毒包装质粒与目的基因载体按照1:1质量比混合，加入转染试剂PEI，转染试剂：质粒质量比＝3:1，室温放置30min；
(4)用RPMI1640培养基替换培养皿内的培养基，将转染混合液轻轻加入培养皿内，轻柔混匀；
(5)4小时后，弃转染上清，替换成含FBS的培养基继续培养细胞；
(6)分别于24小时，48小时和72小时收集病毒；
(7)加入4×PEG8000病毒浓缩液，混匀后4℃冰箱静置过夜；
(8)3000rpm，4℃，1小时，弃上清，按照原体积1/10的量加入新鲜培养基重悬病毒，分装后储存于-80℃冰箱。
3、DC细胞和靶细胞负载NP抗原、蛋白表达鉴定
(1)取2-5×106个DC细胞或A549肺泡细胞(靶细胞)接种于6孔板内；
(2)配制500ul浓缩后的病毒液+500ul完全培养基+1ul 10mg/ml polybrene混合液，加入到细胞内培养过夜；
(3)次日，吸弃培养基上清，正常培养细胞至足够数量。
(4)配制10％SDS PAGE胶备用。
(5)收集慢病毒转染后的DC细胞和靶细胞，同时收集转染前的细胞作为对照。
(6)根据细胞总量加入一定比例的蛋白裂解液，冰上裂解细胞。
(7)裂解后蛋白经95℃高温煮20min，备用。
(8)蛋白上样，80V，30min。120V，60min。
(9)转膜，300mA，60min。
(10)一抗(anti-HA抗体，sigma)孵育，置于4℃摇床上过夜。
(11)次日，PBST洗涤膜3次，孵二抗(abbkine公司)，室温，1小时。
(12)PBST洗膜3次。加入ECL发光液，曝光。
(13)数据整理及分析。
按照上述操作，含有NP基因的慢病毒载体经过慢病毒包装生产后，用于感染志愿者来源的DC细胞(HLA-A02和HLA-A24阳性)和A549L 224细胞(A549细胞购自ATCC，实验室改造稳定表达Luciferase基因、HLA-A02和HLA-A24基因)，感染3天后，检测NP细胞的表达情况。结果如图2所示，DC细胞和A549细胞均表达NP蛋白。
实施例2、NP蛋白抗原特异性CTL及NK细胞的制备
本实施例中，按照以下方法制备NP蛋白抗原特异性CTL及NK细胞：
(1)取负载抗原的志愿者来源的DC细胞和同一个志愿者的PBMC细胞(该志愿者细胞为HLA-A02和HLA-A24阳性)，计数。
(2)用含5％人血清的X-VIVO培养基，按照DC细胞：PBMC＝1:5～1:500的量混合DC细胞和PBMC细胞，静置培养过夜。
(3)次日，向培养体系内加入200～1000unit/ml的白介素2，混合后培养。
(4)根据细胞生长状况，添加适量的培养基和白介素2。
(5)第12-14天时，收集部分细胞进行流式分析。
(6)取1-5x105个细胞，2500rpm，离心5min。
(7)PBS洗涤2次，2500rpm，离心5min。
(8)向细胞内加入100ul含BSA的封闭液，冰上封闭10-15min。
(9)将细胞分成两份，一份加入CD3+CD56抗体，另一份加入两个抗体的同型对照抗体，冰上孵育30min。
(10)PBS洗涤3次，2500rpm，5min。
(11)500ul PBS重悬细胞，过滤后上流式细胞仪检测。
(12)检测结果显示CD3-CD56-区域细胞少于3％时，收集细胞进行磁珠分选。
(13)根据细胞密度和CD3细胞比例，取足量的细胞置于15ml离心管内，1000rpm，3min。
(14)弃上清，PBS洗涤，1000rpm，3min。
(15)弃上清，500ul X-VIVO15培养基重悬细胞，加入100ul CD3磁珠，混匀。
(16)放置细胞悬液于摇床上，室温，低速运行15min。
(17)向细胞悬液内加入5mlPBS，充分颠倒混匀后置于磁力架上，静置2min。
(18)小心将上清转移至干净的15ml离心管内，将原离心管从磁力架上取下，加入5ml PBS，颠倒混匀以洗涤磁珠。
(19)重复(18)步骤1次。
(20)将转移出的上清离心，用含5％人血清X-VIVO15培养基重悬细胞，加入200unit/ml IL2培养，即得到纯化后的NK细胞。
(21)用含5％人血清的X-VIVO15培养基重悬磁珠，加入200unit/ml IL2，置于6孔板内培养过夜。
(22)收集孔板内磁珠于离心管内，充分吹打磁珠，置于磁力加上以使T细胞和磁珠分离。
(23)收集并合并上清，1000rpm，5min。
(24)用含5％人血清的X-VIVO15培养基细胞继续培养，此细胞即为T细胞。
(25)待NK细胞和T细胞数量足够后，用于后续研究。
按照上述操作，将HLA-A02和HLA-A24阳性的PBMC细胞与负载NP抗原的DC细胞(HLA-02和HLA-A24)进行共培养，在第14天时，取部分细胞进行流式检测，结果如图3所示，负载NP抗原的DC细胞同时诱导CD3阳性的T细胞和CD56阳性的NK细胞产生，T细胞占比约80％，NK细胞占比17.2％。
在经过CD3磁珠分选后，将NK细胞和T细胞分别进行培养，并对培养后的T细胞进行流式分析，结果如图4所示，磁珠分选后，T细胞的纯度约为95％，还有约5％的NK细胞残留。此T细胞以CD8+阳性的T细胞，即CTL细胞为主，几乎都是Tα/β细胞。
实施例3、NP抗原特异性CTL细胞表达穿孔素及颗粒酶的分析
取部分实施例2中分选后的T细胞(CTL细胞)，经western blot的方式检测T细胞内穿孔素和颗粒酶的表达情况。检测方法与NP蛋白表达的检测方法一致。
结果如图5所示，CTL细胞可显著表达穿孔素和颗粒酶。
实施例4、NP抗原特异性CTL细胞分泌IFNγ的检测
本实施例主要是ELISA检测经DC诱导产生的CTL细胞的IFNγ分泌情况。具体按照如下操作进行：
(1)取磁珠分选后的T细胞，计数，按照1×106/ml的浓度接种细胞于12孔板内，加入200unit/ml IL2，培养24小时。
(2)24小时后，收集细胞，计数，1000rpm，离心5min，吸取上清用于ELISA检测。
(3)取上清50ul，1×PBS稀释10倍。
(4)将稀释后的待检上清、对照上清按照100ul样本加入样本孔，每个样本3复孔。同时将标准品以100ul/孔加入标准孔准备制作标准曲线，Dilution Buffer(1X)作为空白对照。
(5)以50ul/孔加入Biotinylated antibody工作液。混匀后盖上封板模，室温孵育2小时。
(6)孵育完成后，去除孔内液体，再加入300ul washing buffer工作液，停留1min后去除液体。重复3次，每次再干净滤纸上扣干。
(7)按照100ul/孔加入streptavidin-HRP工作液。盖上封膜板室温孵育20min。
(8)洗板，重读步骤(6)。
(9)显色，100ul/孔加入TMB溶液，室温避光孵育20min。
(10)终止反应，加入100ul stop solution。
(11)酶标仪450nm波长检测读数。
(12)用标准品拟合浓度曲线，计算样本IFNγ浓度。
按照以上操作，取部分实施例2中分选后的CTL细胞，测得每1×106个CTL所分泌的干扰素γ的量为672pg/ml(图6)。
实施例5、NK细胞对靶细胞的杀伤作用
以肺腺癌细胞A549作为靶细胞，检测经DC诱导的NK细胞对靶细胞的杀伤作用。具体按照如下操作进行：
(1)消化肺腺癌细胞A549L，计数，按照1x105个细胞/孔接种于24孔板内，贴壁3小时；
(2)细胞计数，按照效应细胞：靶细胞分别为2:1和5:1的比例将效应细胞加入到靶细胞内，混合培养4小时；
(3)吸弃悬浮的T细胞，PBS轻柔洗涤1～3次以去除漂浮的死亡靶细胞，吸干孔内液体；
(4)每孔加入100ul的细胞裂解液，冰上裂解，使细胞释放出luciferase蛋白；
(5)转移裂解液至1.5ml EP管内，3000rpm，离心3min；
(6)取luciferase报告基因底物100ul加至酶标板内，分别取裂解液上清20ul加入底物中；
(7)样品上机检测，根据荧光强度计算靶细胞杀伤效率。
按照上述操作，将DC细胞诱导产生的NK细胞与A549L细胞按照2:1和5:1的效靶比共孵育4小时，通过荧光强度检测反应NK细胞杀伤A549L细胞的量。结果如图7所示，由本发明的方法产生的NK细胞在2:1的效靶比情况下就可以长生约60％的杀伤作用，杀伤作用非常强。
实施例6、抗原特异性CTL细胞对靶细胞的杀伤作用
分别消化肺癌细胞A549L224细胞和A549L244 NP细胞，计数，按照1x105个细胞/孔接种于24孔板内，贴壁3小时；其余操作与NK细胞杀伤试验的一致。
肺腺癌细胞A549L经慢病毒感染后稳定表达HLA-A02和HLA-A24两类HLA分子，即A549L 224细胞，该细胞可以递呈HLA-A02和HLA-A24相关的抗原表位以供T细胞识别。A549L224NP细胞即为表达新冠病毒NP蛋白的靶细胞。
按照效靶比为2:1和5:1的条件进行两种靶细胞的杀伤测试，结果如图8所示，在2:1和5:1的情况下，对照细胞A549L 224细胞有部分比例的杀伤，是由少量的NK细胞造成的，在同等条件下，两条HLA分子匹配且表达NP蛋白的靶细胞A549L224NP对效应细胞的杀伤作用更加敏感，其检测数值具有统计学差异，说明了T细胞确实通过NP蛋白的识别而发挥作用，证明了NP特异性T细胞的存在以及高效的杀伤能力。
序列表
<110> 北京翊博普惠生物科技发展有限公司
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His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln
145 150 155 160
Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser
165 170 175
Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg Asn
180 185 190
Ser Ser Arg Asn Ser Thr Pro Gly Ser Ser Arg Gly Thr Ser Pro Ala
195 200 205
Arg Met Ala Gly Asn Gly Gly Asp Ala Ala Leu Ala Leu Leu Leu Leu
210 215 220
Asp Arg Leu Asn Gln Leu Glu Ser Lys Met Ser Gly Lys Gly Gln Gln
225 230 235 240
Gln Gln Gly Gln Thr Val Thr Lys Lys Ser Ala Ala Glu Ala Ser Lys
245 250 255
Lys Pro Arg Gln Lys Arg Thr Ala Thr Lys Ala Tyr Asn Val Thr Gln
260 265 270
Ala Phe Gly Arg Arg Gly Pro Glu Gln Thr Gln Gly Asn Phe Gly Asp
275 280 285
Gln Glu Leu Ile Arg Gln Gly Thr Asp Tyr Lys His Trp Pro Gln Ile
290 295 300
Ala Gln Phe Ala Pro Ser Ala Ser Ala Phe Phe Gly Met Ser Arg Ile
305 310 315 320
Gly Met Glu Val Thr Pro Ser Gly Thr Trp Leu Thr Tyr Thr Gly Ala
325 330 335
Ile Lys Leu Asp Asp Lys Asp Pro Asn Phe Lys Asp Gln Val Ile Leu
340 345 350
Leu Asn Lys His Ile Asp Ala Tyr Lys Thr Phe Pro Pro Thr Glu Pro
355 360 365
Lys Lys Asp Lys Lys Lys Lys Ala Asp Glu Thr Gln Ala Leu Pro Gln
370 375 380
Arg Gln Lys Lys Gln Gln Thr Val Thr Leu Leu Pro Ala Ala Asp Leu
385 390 395 400
Asp Asp Phe Ser Lys Gln Leu Gln Gln Ser Met Ser Ser Ala Asp Ser
405 410 415
Thr Gln Ala
<210> 3
<211> 422
<212> PRT
<213> SARS
<400> 3
Met Ser Asp Asn Gly Pro Gln Ser Asn Gln Arg Ser Ala Pro Arg Ile
1 5 10 15
Thr Phe Gly Gly Pro Thr Asp Ser Thr Asp Asn Asn Gln Asn Gly Gly
20 25 30
Arg Asn Gly Ala Arg Pro Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn
35 40 45
Asn Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Glu
50 55 60
Leu Arg Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Gly
65 70 75 80
Pro Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Val Arg
85 90 95
Gly Gly Asp Gly Lys Met Lys Glu Leu Ser Pro Arg Trp Tyr Phe Tyr
100 105 110
Tyr Leu Gly Thr Gly Pro Glu Ala Ser Leu Pro Tyr Gly Ala Asn Lys
115 120 125
Glu Gly Ile Val Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys
130 135 140
Asp His Ile Gly Thr Arg Asn Pro Asn Asn Asn Ala Ala Thr Val Leu
145 150 155 160
Gln Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly
165 170 175
Ser Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg
180 185 190
Gly Asn Ser Arg Asn Ser Thr Pro Gly Ser Ser Arg Gly Asn Ser Pro
195 200 205
Ala Arg Met Ala Ser Gly Gly Gly Glu Thr Ala Leu Ala Leu Leu Leu
210 215 220
Leu Asp Arg Leu Asn Gln Leu Glu Ser Lys Val Ser Gly Lys Gly Gln
225 230 235 240
Gln Gln Gln Gly Gln Thr Val Thr Lys Lys Ser Ala Ala Glu Ala Ser
245 250 255
Lys Lys Pro Arg Gln Lys Arg Thr Ala Thr Lys Gln Tyr Asn Val Thr
260 265 270
Gln Ala Phe Gly Arg Arg Gly Pro Glu Gln Thr Gln Gly Asn Phe Gly
275 280 285
Asp Gln Asp Leu Ile Arg Gln Gly Thr Asp Tyr Lys His Trp Pro Gln
290 295 300
Ile Ala Gln Phe Ala Pro Ser Ala Ser Ala Phe Phe Gly Met Ser Arg
305 310 315 320
Ile Gly Met Glu Val Thr Pro Ser Gly Thr Trp Leu Thr Tyr His Gly
325 330 335
Ala Ile Lys Leu Asp Asp Lys Asp Pro Gln Phe Lys Asp Asn Val Ile
340 345 350
Leu Leu Asn Lys His Ile Asp Ala Tyr Lys Thr Phe Pro Pro Thr Glu
355 360 365
Pro Lys Lys Asp Lys Lys Lys Lys Thr Asp Glu Ala Gln Pro Leu Pro
370 375 380
Gln Arg Gln Lys Lys Gln Pro Thr Val Thr Leu Leu Pro Ala Ala Asp
385 390 395 400
Met Asp Asp Phe Ser Arg Gln Leu Gln Asn Ser Met Ser Gly Ala Ser
405 410 415
Ala Asp Ser Thr Gln Ala
420
Claims (5)
1.一种负载NP抗原的DC细胞在制备用于预防冠状病毒感染的免疫细胞组合物中的应用，其中所述负载NP抗原的DC细胞是通过构建含有NP基因的慢病毒载体转染DC细胞而制备得到的，其中所述NP基因如SEQ ID No. 1所示；
所述免疫细胞组合物包括CD3阳性CD8+阳性的CTL细胞和CD56阳性的NK细胞，并且，所述CTL细胞显著表达穿孔素和颗粒酶。
2.一种免疫细胞组合物在制备用于治疗冠状病毒感染的免疫细胞组合物中的应用，其中，所述免疫细胞组合物是按照以下方法制备得到的：
利用一种负载NP抗原的DC细胞，诱导产生免疫细胞组合物；其中所述负载NP抗原的DC细胞是通过构建含有NP基因的慢病毒载体转染DC细胞而制备得到的，其中所述NP基因如SEQ ID No. 1所示；并且，所述免疫细胞组合物包括CD3阳性CD8+阳性的CTL细胞和CD56阳性的NK细胞，并且，所述CTL细胞显著表达穿孔素和颗粒酶。
3.根据权利要求2所述的应用，其中，用于治疗冠状病毒感染的免疫细胞组合物存在于试剂盒中。
4.根据权利要求3所述的应用，其中，所述细胞在试剂盒中保存于冻存液中，所述冻存液含10% DMSO和20%人血清。
5.根据权利要求2所述的应用，其中，用于治疗冠状病毒感染的免疫细胞组合物为一种防治冠状病毒感染的免疫细胞制剂，所述制剂还包括用于重悬细胞的含1%人血白蛋白的生理盐水。
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| CN113325177B (zh) * | 2021-06-04 | 2024-03-01 | 博奥赛斯(重庆)生物科技有限公司 | 一种包含新型冠状病毒突变抗原的中和抗体检测试剂盒及其应用 |
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