CN115607573B - 一种用于调节杀伤性t细胞活性的方法、药物及其应用 - Google Patents
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Abstract
本发明提供一种用于调节杀伤性T细胞活性的药物及其应用,具体的,本发明首次公开了幽门螺杆菌感染对外泌体表面抗原以及免疫逃逸之间的关系,为免疫功能抑制的疾病发生及干预提供依据,当在肿瘤免疫治疗无效同时合并幽门螺杆菌感染时,可考虑通过阻断幽门螺杆菌感染来调控外泌体所导致的免疫功能失活的状态,从而促进机体免疫功能恢复。
Description
技术领域
本发明涉及生物医药领域,更具体的,本发明涉及一种用于调节杀伤性T细胞活性的药物及其应用。
背景技术
体内免疫细胞的正常功能是维持机体平衡的基本保障。但在某些病理情况下,体内免疫细胞的功能长期处于耗竭和失活状态,影响了机体的免疫平衡,导致疾病的发生,并可能导致免疫治疗的疗效不佳。如在肿瘤免疫治疗无效同时合并幽门螺杆菌感染时,可考虑通过阻断幽门螺杆菌感染来调控外泌体所导致的免疫功能失活的状态,从而促进机体免疫功能恢复。
幽门螺杆菌是一种革兰氏阴性菌,呈螺旋状,可在胃表面黏液细胞定植,造成黏膜损伤及胃癌的发生。更多研究认为幽门螺杆菌可能与多种疾病相关。然而幽门螺杆菌感染及其机制较为复杂,特别是幽门螺杆菌对于T细胞的调节作用和相关机制还鲜有报道。
发明内容
发明人在进行CAR-T治疗研究中以外的发现,幽门螺杆菌感染后,会明显上调胃黏膜细胞释放的外泌体表面PD-L1分子的表达,从而抑制人外周血单个核细胞(PBMCs)中T细胞的功能,使T细胞处于耗竭状态。基于此,本发明提供如下的技术方案:
本发明的第一个方面,提供一种胃黏膜细胞外泌体用于制备调节T细胞功能的药物中的应用,所述外泌体来自于幽门螺杆菌感染个体的胃黏膜细胞。
在一种实施方案中,所述T细胞为杀伤性T细胞。
本发明的第二个方面,提供一种用于提升幽门螺杆菌感染患者T细胞活性的药物,其中,所述药物中包含抑制患者胃黏膜细胞外泌体表面PD-L1分子的表达的制剂。
在一种实施方式中,所述制剂选自抗体、siRNA、miRNA等。
本发明的第三个方面,提供一种用于辅助诊断免疫治疗疗效的试剂盒,其中所述试剂盒包含用于检测外泌体表面PD-L1分子的表达水平的试剂,所述外泌体来自患者的胃黏膜细胞。
在一种实施方式中,所述免疫治疗是指CAR-T疗法。
在一种实施方式中,所述辅助诊断的诊断标准为:当患者胃黏膜细胞释放的外泌体表面PD-L1分子的表达显著增加时,CAR-T治疗的效果较差。
相对于现有技术,本发明获得了如下突出的技术效果:
本发明首次剖析了幽门螺杆菌感染对外泌体表面抗原以及免疫逃逸之间的关系,为免疫功能抑制的疾病发生及干预提供依据,当在肿瘤免疫治疗无效同时合并幽门螺杆菌感染时,可考虑通过阻断幽门螺杆菌感染来调控外泌体所导致的免疫功能失活的状态,从而促进机体免疫功能恢复,为肿瘤免疫治疗提供新的启迪。
附图说明
附图用来提供对本发明的进一步理解,并且构成说明书的一部分,与本发明的实施例一起用于解释本发明,并不构成对本发明的限制。在附图中:
图1为幽门螺杆菌与胃黏膜细胞GES-1共培养0/6/12/24/48小时后,real-timePCR结果显示PD-L1基因CD274的mRNA表达变化情况。
图2为幽门螺杆菌与胃黏膜细胞GES-1共培养0/6/12/24/48小时后,western blot结果显示PD-L1蛋白的mRNA表达变化情况。
图3为双免疫荧光染色和激光共聚焦扫描显微镜实验结果,与未感染幽门螺杆菌的细胞相比,感染幽门螺杆菌后GES-1细胞的PD-L1原位蛋白表达上调,并与膜蛋白CD63共定位。
图4为western blot结果,与未感染幽门螺杆菌的细胞相比,在幽门螺杆菌感染后GES-1细胞的PD-L1不仅在细胞中表达上调,而且在GES-1细胞的外泌体中表达上调。
图5为real-time PCR结果。与未感染幽门螺杆菌的GES-1细胞相比,幽门螺杆菌感染后的GES-1细胞外泌体可使得健康人外周血单个核细胞(PBMCs)中干扰素γ(IFNG)和白介素2受体(IL2RA) 表达下调,而程序性细胞死亡受体1(PD-1)、细胞毒性T细胞相关蛋白4(CTLA4)和淋巴细胞相关基因3 (LAG3)的表达上调。
图6为流式细胞仪检测CD4+ T细胞结果。与未感染幽门螺杆菌的GES-1细胞相比,幽门螺杆菌感染后的GES-1细胞外泌体可显著增加PD-1+CD4+ T细胞占比。同时,CTLA4+CD4+ T细胞占比有增加趋势,IL-2R+CD4+ T细胞占比有下降趋势。
图7为流式细胞仪检测CD8+ T细胞结果。与未感染幽门螺杆菌的GES-1细胞相比,幽门螺杆菌感染后的GES-1细胞外泌体可显著增加PD-1+CD8+ T细胞占比。同时,IFN-γ+CD8+ T细胞占比有增加趋势,IL-2R+CD8+ T细胞占比有下降趋势。
具体实施方式
以下结合附图对本发明的优选实施例进行说明,应当理解,此处所描述的优选实施例仅用于说明和解释本发明,并不用于限定本发明。
实施例1 实验和方法
(1)幽门螺杆菌(H. pylori)体外感染胃黏膜上皮细胞GES-1细胞系。具体为:GES-1细胞培养于含10% FBS的 RPMI-1640培养液中,在37 ℃、5% CO2条件下培养,当细胞达到90%融合度时消化,按1:3的比例传代,处于对数生长期时,收集细胞,铺板。将冻存的H.pylori国际标准菌株26695复苏,接种于含10%羊血及4 g/ml两性霉素B、甲氧苄氨嘧啶、万古霉素的哥伦比亚琼脂平板上,置于37 ℃微需氧环境中(5% O2,10% CO2,85% N2)培养,48h后收集细菌,用磷酸盐缓冲液(PBS)洗2遍,收集菌沉淀,重悬于细胞培养液中,并用分光光度计调节细菌终浓度至1×108 CFU/ml。细胞铺板12h后,用PBS洗一遍,换新的细胞培养液,将细菌以MOI 100:1加入细胞培养液中,37°C、5% CO2条件下继续培养细胞。用未处理的GES-1细胞作为阴性对照。
(2)差速离心法提取细胞系分泌的外泌体。具体为:收集细胞的培养上清,4℃ 800×g离心5min,收集上清;4℃ 2000×g离心10min,收集上清;使用0.22μm滤膜过滤,将滤过的细胞培养上清加入到Beckman超速离心管中,超速离心管的液面距管口应不超过1mm。将装有细胞培养上清的超速离心管放入与Beckman SW40Ti配套的金属套管中并悬紧管盖,将离心套管挂置于SW40Ti水平转头上,离心前检查离心套管是否挂置妥当,位置正确;4℃100000×g离心2h,弃去上清液,将超速离心管倒置于滤纸上晾干,每个离心管中沉淀的外泌体使用预冷的PBS重悬,继续后续实验或者保存于-80℃。
(3)Real-time PCR检测与细菌共育0h、6h、12h、24h、48h后,GES-1细胞中CD274mRNA表达水平。具体为:用TRIzol法提取各样本总RNA,并逆转录为cDNA。采用实时荧光定量RT-PCR技术(SYRB Green)检测mRNA相对表达水平,分析其mRNA水平表达情况。定量引物:CD274 qF:5’-TGGCATTTGCTGAACGCATTT-3’,CD274 qR :5’T-GCAGCCAGGTCTAATTGTTTT-3’;ACTB qF:5’-TTGTTACAGGAAGTCCCTTGCC-3’,ACTB qR:5’-ATGCTATCACCTCCCCTGTGTG-3’。
(4)Western blot检测与细菌共育0h、6h、12h、24h、48h后,GES-1细胞中PD-L1蛋白表达水平。具体为:收集细胞并悬浮在含有蛋白酶抑制剂混合物的细胞裂解缓冲液中,在冰上摇匀30分钟。细胞裂解液4℃,15,000 × g离心10分钟,收集上清。使用BCA蛋白测定试剂盒(赛默飞世尔科技,Thermo Scientific)测定总蛋白浓度。蛋白质用10% (w/v)的SDS-PAGE分离并电泳转移到PVDF膜上。在5% (w/v)脱脂牛奶中,在含0.5% (v/v) Tween-20的tris缓冲盐水中,室温下封膜1小时,然后在4℃下与PD-L1抗体(1:1000,abcam,ab205921)和β-actin(1:1000, CST,3700S)的抗体孵育一夜。在含0.1% (v/v) Tween-20的PBS中洗涤3次15分钟后,将膜浸入二抗溶液山羊抗兔IRDye 680或山羊抗鼠IRDye 800CW(1:5000)孵育,室温1 h。用LI-COR Biosciences的Odyssey Imager红外荧光扫描成像系统扫膜,观察蛋白条带,保存图像。
(5)confocal观察PD-L1和CD63的共定位。采用荧光-激光共聚焦显微镜检测H. pylori感染对PD-L1和CD63的定位情况影响,H. pylori感染后,使用4%甲醛固定和3% BSA封闭后,先后加入PD-L1的一抗和CD63的一抗,在4℃孵育过夜,第二天加入TRITC/FITC 标记的二抗,室温1h,DAPI 染色细胞核,甘油封片。使用激光共聚焦显微镜观察PD-L1和CD63的丰度、分布及亚定位情况,对比两组间是否存在差异。
(6)外泌体WB:收集超速离心后的外泌体加入含有蛋白酶抑制剂混合物的细胞裂解缓冲液中,在冰上摇匀30分钟。细胞裂解液4℃,15,000 × g离心10分钟,收集上清。使用BCA蛋白测定试剂盒(赛默飞世尔科技,Thermo Scientific)测定总蛋白浓度。蛋白质用10%(w/v)的SDS-PAGE分离并电泳转移到PVDF膜上。在5% (w/v)脱脂牛奶中,在含0.5% (v/v)Tween-20的tris缓冲盐水中,室温下封膜1小时,然后在4℃下与PD-L1抗体(1:1000,abcam,ab205921)、CD63(1:1000,abcam,ab134045)和ALIX(1:200,Santa Cruz Biotechnology,sc-53540)的抗体孵育一夜。在含0.1% (v/v) Tween-20的PBS中洗涤3次15分钟后,将膜浸入二抗溶液山羊抗兔HRP(CST,7074)或山羊抗鼠HRP(CST,7076)(1:5000)孵育,室温1 h。用Tanon全自动化学发光图像分析系统扫膜,观察蛋白条带,保存图像。
(7)收集临床对象的全血分离PBMC,用GES-1细胞上清分泌的外泌体处理PBMC,通过RT-qPCR检测IFNG、IL2RA、PDCD1、CTLA4及LAG3的表达水平。PBMC分离使用人外周血淋巴细胞分离液(索莱宝,P8610),取新鲜抗凝血2 mL,与无血清1640培养基2:3 混匀后,小心加于4 mL分离液之液面上;以500 g离心20分钟,此时离心管中由上至下细胞分四层。第一层:为血浆层。第二层:为环状乳白色淋巴细胞层。第三层:为透明分离液层。第四层:为红细胞层。收集第二层细胞放入5 mL无血清1640培养基中,充分混匀后,以500 g离心10分钟,沉淀经2次洗涤后即得所需淋巴细胞。定量引物见表:
(8)流式细胞术检测PBMC中CD4+ 中IL-2R、PD-1及CTLA4表达情况,CD8+ T细胞IFNγ、IL-2R及PD-1表达情况。对各管PBMC计数,每管留取1×106细胞,然后每支流式检测管中加入100 μLCell Staining Buffer重悬细胞,进行流式染色分析,所有抗体均购自Biolegend,按照说明书按照1:50使用,分别加入Alexa Fluorreg 700 anti-human CD3、Alexa Fluorreg 488 anti-human CD4 Antibody、Brilliant Violet 570trade anti-human CD8a Antibody、PECyanine7 anti-human CD122 IL-2Rbeta Antibody、PerCPCyanine55 anti-human CD223 LAG-3 Antibody、Brilliant Violet 421tradeanti-human CD279 PD-1 Antibody及Alexa Fluorreg 647 anti-human CD152 CTLA-4Antibody抗体,4℃避光30 min进行细胞表面荧光染色。固定通透后,使用PE anti-humanIFN-gamma Antibody进行胞内染色30 min,加入2 mL Cell Staining Buffer,轻柔混匀洗涤细胞非特异染色抗体,室温350 g离心5 min后弃去上清液,重复洗涤过程两次。用500 μL2%的多聚甲醛固定液重悬细胞,使用Gallios流式细胞仪(美国贝克曼库尔特有限公司,Backman)检测并分析结果。
实施例2 实验结果
我们的研究表明,在感染幽门螺杆菌后,GES -1细胞程序性细胞死亡受体配体1(programmed cell death receptor ligand 1, PD-L1) mRNA(如图1所示)和蛋白表达上调(如图2所示)。采用双免疫荧光染色和激光共聚焦扫描显微镜证实,感染幽门螺杆菌的GES-1细胞PD-L1表达上调,与膜蛋白CD63共定位(如图3所示)。此外,收集有或无感染幽门螺杆菌的GES-1细胞外泌体,并检测PD-L1在GES-1细胞外泌体中的表达。我们的结果显示,在幽门螺杆菌感染后,PD-L1不仅在细胞中表达上调,而且在GES-1细胞外泌体中表达上调(如图4所示)。用健康人外周血单个核细胞(PBMCs)检测幽门螺杆菌感染对PD-L1的影响。结果显示,与没有幽门螺杆菌感染的GES-1细胞相比,幽门螺杆菌感染后的GES-1细胞外泌体可使得PBMCs中干扰素γ(IFNG)和白介素2受体(IL2RA) 表达下调,而程序性细胞死亡受体1(PD-1)、细胞毒性T细胞相关蛋白4 (CTLA4)和淋巴细胞相关基因3 (LAG3)的表达上调(如图5所示)。进一步,我们用流式细胞仪分析幽门螺杆菌感染后PBMCs中CD4+和CD8 + T细胞的状态。结果表明,与没有幽门螺杆菌感染的GES-1细胞相比,幽门螺杆菌感染后的GES-1细胞外泌体可显著增加PD-1阳性的CD4+ T和CD8+ T细胞的占比(如图6、7所示),这表明T细胞的数量和激活状态下降。同时,CTLA4或IL-2R阳性CD4+ T细胞、IFN-γ或IL-2R阳性CD8+ T细胞百分比变化趋势与耗竭T细胞的增加一致(如图6、7所示)。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (1)
1.一种用于辅助诊断免疫治疗疗效的试剂盒,其特征在于,所述试剂盒包含用于检测外泌体表面PD-L1分子的表达水平的试剂,所述外泌体来自患者的胃黏膜细胞,所述外泌体抑制T细胞功能,所述患者是幽门螺杆菌感染个体,与未感染幽门螺杆菌的GES-1细胞相比,幽门螺杆菌感染后的GES-1细胞外泌体使得健康人外周血单个核细胞(PBMCs)中干扰素γ和白介素2受体表达下调,而程序性细胞死亡受体1(PD-1)、细胞毒性T细胞相关蛋白4(CTLA4)和淋巴细胞相关基因3(LAG3)的表达上调,所述免疫治疗是指CAR-T疗法,所述辅助诊断的诊断标准为:当患者胃黏膜细胞释放的外泌体表面PD-L1分子的表达显著增加时,CAR-T治疗的效果较差。
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