变应原特异性免疫治疗的研究进展
郭伟, 姜玉新
皖南医学院医学寄生虫学教研室,芜湖 241002
通讯作者:姜玉新,Email: jiangyx@wnmc.edu.cn;ORCID: 0000-0002-1133-495X
摘要

变应原特异性免疫治疗(Allergen-specific immunotherapy, ASIT)是现阶段唯一针对病因治疗且能长时间持续减轻过敏症状,改变自然病程的治疗方法。目前已在过敏性疾病的临床治疗中广泛应用,并取得良好的治疗效果。随着治疗药物和治疗途径的不断改良,ASIT在过敏性疾病的治疗中显示出不可比拟的优势。本文对ASIT作用机制、应用药物、给药途径和禁忌症方面进行综述,旨在为ASIT的临床治疗提供参考。

关键词: 过敏性哮喘; 变应原特异性免疫治疗; 变应原疫苗
中图分类号:R562.2 文献标志码:A 文章编号:1002-2694(2019)04-0334-04
Research advances of allergen-specific immunotherapy
GUO Wei, JIANG Yu-xin
Department of Medical Parasitology, Wannan Medical College, Wuhu 241002,China
Corresponding author: Jiang Yu-xin, Email: jiangyx@wnmc.edu.cn
Abstract

Allergen-specific immunotherapy (ASIT) is the only treatment that causes a long-lasting relief of symptoms and change the natural course at this stage. This treatment has been widely applied in allergic diseases and achieved successful clinical outcomes. With the development of treatment, ASIT demonstrated unparalleled advantages of allergic diseases. This review summarizes the advances in the mechanisms of ASIT, the application of drug and route of administration to provide a reference for ASIT.

Key words: allergic asthma; allergen-specific immunotherapy; allergen vaccine

过敏性哮喘是临床常见病和多发病, 近年来其发病率和患病率逐年增加[1, 2, 3, 4]。过敏性哮喘的发病机制较为复杂, 主要是由于机体免疫系统对环境中变应原应答过程中产生特异性IgE抗体、慢性气道炎症(嗜酸性粒细胞、中性粒细胞增多集聚, 粘液增多)和气道高反应性[5], 以及Th2细胞增多引起[6, 7, 8]免疫失衡等综合因素所引致。虽然临床上治疗哮喘的方法很多, 如应用糖皮质激素[9, 10]、β 2受体激动剂[11, 12]、氨茶碱[13, 14]等, 在短时间内改善过敏症状具有一定的效果, 但变应原特异性免疫治疗(Allergen-specific immunotherapy, ASIT)又称脱敏疗法(Desensitization), 是现阶段唯一针对病因的治疗措施, 能长时间持续减轻过敏症状, 改变自然病程的治疗方法[15, 16]。目前ASIT作用机制、治疗药物和安全性均得到很大发展, 本文就现阶段ASIT发展和应用情况做一综述, 旨在为ASIT的临床治疗提供借鉴。

1 变应原特异性免疫治疗的机制

ASIT是在临床上确定过敏性疾病患者的变应原后, 将该变应原制备出变应原提取物并不同浓度稀释, 使得该变应原与患者反复接触(经注射或其他给药途径), 逐步增加变应原的浓度和剂量, 从而提高患者对该种变应原的免疫耐受, 达到当再次接触该种变应原时, 不再产生过敏症状或症状减轻的现象[17, 18]。其具体的作用机制包括:1) 调节Th1/Th2细胞的平衡、调节IgE和IgG抗体的生成及影响免疫效应细胞等。有效的免疫治疗可以减少血清IL-4水平、增加IFN-γ 含量, 诱导选择性Th2型免疫应答向Th1应答偏移, 从而使IL-4、IL-5等Th2细胞的细胞因子减少, 并显著减低单核细胞中IL-4、IL-5表达, 增加IFN-γ 表达, 抑制嗜酸性粒细胞增生、活化和聚集; 2) IL-4分泌减少, 下调了B细胞合成IgE, 同时血清总IgG增多(特别是IgG4), 竞争性阻断了变应原与肥大细胞表面IgE结合, 避免了肥大细胞的激活和炎症介质释放, 改善临床症状; 3) 减少局部肥大细胞、嗜酸性粒细胞和嗜碱性粒细胞等的数量, 影响粘附因子、趋化因子和促炎因子的生成, 降低气道上皮的生物反应性。目前研究表明[5, 8, 16, 19, 20, 21, 22, 23, 24], ASIT主要是通过上述3种作用机制改善临床症状, 达到治疗效果。

2 新型ASIT药物

ASIT传统治疗药物是变应原粗制提取物, 其成分复杂, 难以标准化, 容易产生严重的系统或局部副作用, 或产生新的过敏反应[25, 26, 27]。一些高纯度的新型变应原疫苗被应用的临床治疗中。同传统变应原相比, 前者具有成分单一、容易量化、副作用小、低变应原性、高免疫原性等特点, 大大提到了ASIT的安全性。具有代表性的药物有以下几种:1) 重组变应原疫苗:将变应原在外源宿主中进行表达, 纯化后可获得成分单一, 量化精准的变应原。此方法制备的变应原疫苗能显著减少ASIT的副作用。Govindaraj等[28]利用基因重组技术表达出变应原蛋白Per a 10。临床应用证明, 此重组变应原能降低IgE结合能力, 减少组胺释放并且无蛋白水解活性; Myrset等[29]重组出分子量与结构均同野生型相似的重组蛋白, 可以应用于未来诊断和免疫治疗; Berdas-Le等[30]重组尘螨2类变应原, 表达出的重组蛋白Der p 2适用于临床过敏性疾病的诊断和治疗。目前越来越多的重组变应原被应用的临床和科研中。2) 低变应原性疫苗:利用DNA Shuffling或其他突变技术, 筛选出即破坏编码B细胞表位的基因序列, 同时保留编码T细胞表位的基因序列的嵌合基因, 使得表达出的嵌合蛋白即保留了T细胞免疫原性又减低变应原性, 减少IgE抗体的生成。郭伟等[31]利用此技术重组尘螨1类变应原基因, 表达出嵌合蛋白R8在ASIT中的效果优于重组的两亲本; Gafvelin等[32]重组表达了害嗜鳞螨变应原, 同样显示了低IgE结合能力, 同时又保留了免疫原性; Wallner等[33]利用DNA shuffling技术对Betv1家族14个基因进行突变, 筛选出2个低IgE结合、高免疫原性的嵌合蛋白, 使得ASIT的安全性进一步提高。3) DNA疫苗:通过注射(肌肉注射或皮内注射)编码变应原的治疗DNA, 诱导Th1类型的免疫应答, 促进IFN-γ 的生成, 调节IgG1/IgG2a[34]等效果。李国平等[35]验证了Der p 2的DNA疫苗对小鼠哮喘模型具有很好的治疗作用, 降低了IgE水平, 减轻气道炎症; Hartl等[36]利用实验证明Betv1 DNA疫苗, 可促进IFN-γ 的生成, 降低了IgE水平, 调节Th1/Th2细胞的平衡; Wang等[37]也证明DNA疫苗在过敏性疾病中具有潜在的治疗作用。DNA 疫苗具有使用方便、剂量精准、安全性高等优点, 但是其长期影响尚未明确, 因此在临床上ASIT中的应用也不如前二者广泛。4) 其他包括去除IgE表位的疫苗肽[38, 39]、主要重组变应原混合疫苗[40]、变应原偶联粒子[41]等。越来越多的ASIT药物应用于临床, 使得患者可以针对自身的情况合理选择, 制定个性化的治疗方案, 提高了ASIT的疗效和安全性。

3 给药途径

为了使ASIT药物更好地发挥药效, 不同药物的给药途径也不尽相同, 最常见的给药途径有:1) 皮内注射:将小剂量的药物注射入表皮和真皮之间使之产生免疫效应。Rotiroti等[42]应用变应原皮内注射, 抑制皮肤对变应原的迟发性应答, 诱导保护性抗体的生成; Esposito等[43]为提高皮内注射的安全性, 对皮内注射剂量进行具体的研究。2) 舌下腺免疫治疗:变应原制备成溶液或片剂, 被舌粘膜上皮层的树突状细胞摄取, 调节淋巴细胞分化和抗体生成, 形成免疫应答。Fleischer等[44]应用花生变应原进性免疫治疗, 验证了此疗法是安全的, 并具有长时间持续的治疗效果; Yamada等[45]通过对过敏模型的舌下腺免疫治疗, 证明了其能诱导Treg细胞表达IL-10。3) 肌肉注射:是应用DNA疫苗进行ASIT最常用的给药途径。Toda等[46]肌肉注射DNA疫苗在动物模型上验证了很好的疗效, 且无副作用。4) 其他:如淋巴管内给药, 将变应原直接注射入淋巴结内[47]

4 ASIT禁忌症

美国哮喘变态反应与免疫学学会(American Academy of Aergy Asthma Immunology, AAAAI)、全球变态反应和哮喘欧洲协作网对ASIT的禁忌症进行了细致的阐述。具体包括:1) 正在使用β 受体阻滞剂, 因为其可能使支气管痉挛, 对过敏反应具有促进作用; 2) 正在使用ACE抑制剂; 3) 哮喘发作期; 4) 心血管功能不全; 5) 严重的免疫缺陷性疾病; 6) 恶性肿瘤; 7)5岁以下 的儿童; 8) 妊娠期内起始ASIT; 9)急慢性感染性疾病[48, 49]

5 展 望

ASIT的安全性一直以来都是其应用的障碍。随着分子生物技术的飞速发展, ASIT的药物安全性已得到很大提高, 但遗憾的是, 对于患者变应原的准确诊断和药物副作用仍不理想。理想的ASIT疫苗应具有有一下特征:成分单一、能诱导免疫耐受, 减少IgE的生成, 产生更多的保护性抗体、容易制备、副作用小、疗效持久, 以及临床应用中容易监测等特点, 具有上述特征的ASIT疫苗将是未来变应原特异性免疫治疗的研究方向。

利益冲突:无

编辑:林丹

The authors have declared that no competing interests exist.

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