免疫活性物质:结核病和非结核分枝杆菌病治疗的新选择

doi:10.19982/j.issn.1000-6621.20220239

摘要/Abstract

摘要：

结核病不仅是一种传染性疾病,也是一种免疫性疾病。免疫疗法是一种潜在的结核病和非结核分枝杆菌病治疗手段,可以通过影响和调节人体的免疫系统来抑制甚至清除结核分枝杆菌和非结核分枝杆菌。本文中,笔者就治疗结核病和非结核分枝杆菌病的免疫活性物质如细胞因子、抗体、小分子活性肽、溶菌酶及免疫阻滞剂等的研究进展进行总结和凝练,以期为结核病和非结核分枝杆菌病的治疗提供新思路。

关键词: 结核, 分枝杆菌感染, 免疫疗法, 主动, 佐剂, 免疫, 总结性报告(主题)

Abstract:

Tuberculosis (TB) is not only an infectious disease, but also an immune disease. As a new potential treatment for diseases caused by the Mycobacterium tuberculosis (MTB) and nontuberculous mycobacteria (NTM), immunotherapy can inhibit or even eliminate MTB and NTM by influencing and regulating the immune system of the human body. In this article, we summarized the research progress of immunologically active substances such as cytokines, antibodies, small molecule active peptides, lysozyme, and immunoblockers in the treatment of MTB and NTM infections. This study will provide new ideas for TB and NTM treatment.

Key words: Tuberculosis, Mycobacterium infections, Immunotherapy, active, Adjuvants, immunologic, Consensus development conferences as topic

中图分类号:

R392
R52

龚文平, 米洁, 吴雪琼. 免疫活性物质:结核病和非结核分枝杆菌病治疗的新选择[J]. 中国防痨杂志, 2022, 44(11): 1107-1121. doi: 10.19982/j.issn.1000-6621.20220239

Gong Wenping, Mi Jie, Wu Xueqiong. Immunologically active substances: novel treatment options for tuberculosis and nontuberculous mycobacteriosis[J]. Chinese Journal of Antituberculosis, 2022, 44(11): 1107-1121. doi: 10.19982/j.issn.1000-6621.20220239

图/表 4

图1

表1

细胞因子在结核病治疗方面的研究进展

名称	功能	结核病治疗	适应人群	参考文献
IFN-γ/TNF-α	IFN-γ主要由T淋巴细胞产生,TNF-α主要由活化的巨噬细胞、NK细胞及T淋巴细胞产生。两者都是一种高效的抗感染生物活性物质,又是一种具有广泛免疫调节作用的细胞因子	1.控制MTB感染的关键性Th1型细胞因子 2.在对抗MTB感染中扮演保护性细胞因子的角色 3.在结核病患者和动物模型上均可以刺激巨噬细胞的杀菌活性 4.雾化吸入IFN-γ可以治疗耐多药结核病	活动性结核病和耐多药结核病患者	[12⇓⇓⇓⇓-17]
IL-2	IL-2主要由活化T淋巴细胞产生,具有免疫应答和抗感染作用,能激活巨噬细胞,刺激T淋巴细胞、NK细胞和B淋巴细胞增殖,促进细胞因子和抗体产生	1.明显抑制MTB的生长 2.改善耐多药结核病患者的预后 3.改善结核病患者的痰培养和涂片阴转率	活动性结核病和耐多药结核病患者	[18⇓-20]
IL-7	IL-7是由骨髓基质细胞分泌的糖蛋白,其靶细胞主要为淋巴细胞,对来自人或小鼠骨髓的B祖细胞、胸腺细胞及外周成熟的T淋巴细胞等均有促生长活性	1.激活巨噬细胞发挥杀菌作用,诱导Th1型免疫应答,促进IFN-γ的分泌,抑制Th2型免疫应答 2.延长MTB感染小鼠的生存期限,提高卡介苗接种效果 3.分枝杆菌和分枝杆菌细胞壁成分诱导单核细胞IL-7受体表达,IL-7促进单核细胞来源的巨噬细胞体外杀灭分枝杆菌	活动性结核病患者	[21⇓⇓-24]
IL-12	IL-12是由树突状细胞和吞噬细胞产生的一种细胞因子,可刺激活化型T淋巴细胞增殖,促进Th0细胞向Th1细胞分化;诱导细胞毒性T淋巴细胞和NK细胞的细胞毒性并促进其分泌IFN-γ、TNF-α、GM-CSF等细胞因子;促进NK细胞和IL-2Rα、TNF受体及CD56分子的表达,增强对肿瘤细胞的抗体依赖细胞介导的细胞毒性作用	1.诱导Th1型免疫应答,促进IFN-γ的分泌,杀灭或清除MTB 2.IL-12治疗可提高CD4⁺ T淋巴细胞缺陷型小鼠的存活率并减少MTB载量,但对野生型小鼠无明显作用 3.上调感染局部部位MTB特异性IL-21的表达,可能在结核感染的局部免疫反应中起重要作用 4.应用大剂量的IL-12治疗结核病的不良反应较大	结核性胸膜炎患者	[25-26]
IL-15	IL-15是新近发现的一种因子,可由活化的单核-巨噬细胞、表皮细胞和成纤维细胞等多种细胞产生。发挥类似IL-2的生物学活性,是连接固有免疫和特异性免疫的桥梁	1.在分枝杆菌感染的保护性免疫中发挥作用 2.促进T淋巴细胞增殖和Th1细胞因子的分泌,并且可以明显降低小鼠肺脏中MTB菌量	活动性结核病患者	[23,27 -28]
IL-24	IL-24主要由黑色素瘤细胞和巨核细胞产生,是一种免疫调节分子,主要表现为对Th1型细胞因子的诱导,具有抗肿瘤作用和抗感染作用	1.可诱导Th1型免疫应答能力,增强小鼠动物模型对MTB标准株H37Rv感染的抗性 2.MTB的感染可以抑制人体IL-24的表达,进而增加结核易感性并促进慢性结核病的发展 3.可调节结核病患者IFN-γ的表达 4.与结核分枝杆菌潜伏感染者相比,结核病患者外周血单个核细胞分泌的IL-24和IFN-γ水平更低	活动性结核病患者	[29⇓-31]
名称	功能	结核病治疗	适应人群	参考文献
IL-32	IL-32是参与固有免疫和特异性免疫反应的一种重要的分泌性蛋白,发挥着促炎性细胞因子和细胞内细胞因子调节子的作用	1.可增强人类单核细胞来源的巨噬细胞清除MTB的能力 2.转基因小鼠Ⅱ型肺泡上皮细胞表达的人类IL-32能够明显减少肺部MTB菌量 3.有助于预防MTB感染	活动性结核病患者和结核分枝杆菌潜伏感染者	[32⇓-34]
GM-CSF	GM-CSF是一种由巨噬细胞、T细胞、肥大细胞、NK细胞、内皮细胞和成纤维细胞分泌的单体糖蛋白,具有细胞因子的功能	1.利用重组GM-CSF和阿奇霉素/阿米卡星联合治疗小鼠,可以明显降低小鼠脏器中分枝杆菌载量,提高小鼠生存率 2.利用重组人GM-CSF联合化疗辅助治疗活动性肺结核患者,4周时痰涂片阴转率无差异,但在治疗8周时有痰菌阴转较快的趋势 3.可被用于预防结核分枝杆菌潜伏感染或传播的再激活 4.对控制肉芽肿内MTB具有一定作用 5.在防止细胞死亡和维持宿主细胞对MTB感染的保护性分化和代谢状态方面起着关键作用	活动性结核病患者、结核性肉芽肿患者、结核分枝杆菌潜伏感染者	[33,35⇓⇓ -38]
G-CSF	G-CSF是由单核细胞、成纤维细胞和内皮细胞产生的一种造血生长因子,能与细胞表面的特定受体结合,促使中性粒细胞系造血祖细胞生长和分化,保护中性粒细胞避免凋亡并加强它们的功能	1.G-CSF与克拉霉素联合使用能抑制小鼠肺脏和脾脏中鸟分枝杆菌的菌量 2.G-CSF治疗小鼠能抑制或杀死鸟分枝杆菌的生长 3.重组G-CSF不能阻止鸟分枝杆菌感染的进程	鸟分枝杆菌感染者	[3⇓-5]

表1

表2

细胞因子及其阻滞剂治疗结核病临床试验研究进展

免疫活性物质	入组人群		样本量	试验方案和干预措施	临床试验阶段	注册号	研究进度
γ-干扰素	肺结核合并 HIV感染患者	美国西北州立医科大学,美国SPP Pharmaclon公司	78例	试验组1:接受皮下γ-干扰素(Ingaron ^®)50万IU与α-干扰素(Interal^®)300万IU交替治疗,间隔1d 试验组2:每天接受皮下注射γ-干扰素(Ingaron^®)50万IU和α-干扰素(Interal ^®)300万IU 对照组:所有参与者只接受基本的抗菌素治疗	Ⅰ/Ⅱ期	NCT05065905	已完成
γ-干扰素	耐多药结核病患者	美国国家过敏和传染病研究所,美国国立卫生研究院临床中心	30例	一项Ⅰ/Ⅱ期、对照、剂量增加的研究,以确定γ-干扰素给药对耐多药结核病患者的临床状况和免疫功能的耐受性、毒性和临床效果。入组患者每周皮下注射3次γ-干扰素,3种剂量水平0.025mg/m²、0.05mg/m²、0.1mg/m²,为期1年	Ⅰ/Ⅱ期	NCT00001407	已完成
白细胞介素-2	耐多药结核病患者	南京医科大学附属第一医院	500例	试验组:给予低剂量重组人白细胞介素-2加标准抗结核化疗4个疗程。采用重组人白细胞介素-2每隔1d皮下注射1次,共30d,分别于第1、3、5、7个月进行4个疗程。标准抗耐多药结核病化疗方案共24个月,其中6个月吡嗪酰胺+卡那霉素/阿米卡星或者卷曲霉素+对氨基水杨酸+丙硫异烟胺+左氧氟沙星为强化期治疗,18个月吡嗪酰胺+左氧氟沙星+丙硫异烟胺+对氨基水杨酸为巩固期治疗。随访36个月以上对照组:给予标准抗耐多药结核病化疗方案,共24个月,其中6个月吡嗪酰胺+卡那霉素/阿米卡星或者卷曲霉素+对氨基水杨酸+丙硫异烟胺+左氧氟沙星为强化期治疗,18个月吡嗪酰胺+左氧氟沙星+丙硫异烟胺+对氨基水杨酸为巩固期治疗。随访36个月以上	Ⅱ/Ⅲ期	NCT03069534	已完成
白细胞介素-2	肺结核患者	首都医科大学附属北京胸科医院	1100例	试验组:2H-R-Z-E-/4H-R(H:异烟肼;R:利福平;Z:吡嗪酰胺;E:乙胺丁醇)联合白细胞介素-2(500000IU/d,1个月皮下注射)。剂量:异烟肼300mg(1次/d),利福平450mg(体质量<50kg,1次/d)或600mg(体质量≥50kg,1次/d),吡嗪酰胺1500mg(体质量<50kg,1次/d)或30mg/kg(体质量≥50kg,1次/d),乙胺丁醇750mg(体质量<50kg,1次/d)或1000mg(体质量≥50kg,1次/d) 对照组:2H-R-Z-E-/4H-R。剂量:异烟肼300mg(1次/d),利福平450mg(体质量<50kg,1次/d)或600mg(体质量≥50kg,1次/d),吡嗪酰胺1500mg(体质量<50kg,1次/d)或30mg/kg(体质量≥50kg,1次/d),乙胺丁醇750mg(体质量<50kg,1次/d)或1000mg(体质量≥50kg,1次/d)	Ⅳ期	NCT04766307	招募志愿者
白细胞介素-17 阻滞剂	银屑病合并结核分枝杆菌潜伏感染患者	北京协和医院	300例	将纳入的银屑病患者根据基线筛查是否合并结核分枝杆菌潜伏感染分为两组,所有患者均给予白细胞介素-17阻滞剂,随访至少2年,观察两组活动性结核病的发病率	Ⅳ期	ChiCTR2100045823	招募志愿者
白细胞介素-4 阻滞剂 Pascolizumab	肺结核患者	新加坡国立大学附属医院,新加坡国立大学	32例	试验组:Pascolizumab单抗0.05~10mg/kg 对照组:生理盐水	Ⅱ期	NCT01638520	未知
γδT细胞	耐多药结核病患者	深圳市第三人民医院	45例	试验组:接受抗结核药物治疗,同时接受异基因γδT细胞治疗安慰剂对照组:仅接受抗结核药物治疗	Ⅰ期	NCT03575299	招募志愿者

表2

表3

小分子活性肽在结核病治疗方面的研究进展

活性肽	代表性物质	功能	结核病治疗效果	参考文献
转移因子	转移因子	转移因子是免疫特异性的小分子多肽,可以以免疫特异性的方式与抗原分子相互作用,提高T淋巴细胞活性,增强细胞免疫功能	1.协同化疗药物清除和杀灭结核分枝杆菌,从而明显提高治愈率,降低复发率 2.动物模型上,转移因子治疗可抑制结核分枝杆菌增殖 3.治疗复发肺结核患者,患者的临床症状得到改善,皮肤对结核菌素的反应性得到恢复,痰培养阴转	[84⇓-86]
抗菌肽	人中性粒细胞肽-1(HNP-1)、人β防御素-2(HBD-2)、HHC-10、LLKKK18、Magainin-Ⅰ模拟肽、先天防御调节肽(IDR)-HH2、IDR-1018	抗菌肽是昆虫体内经诱导而产生的一类具有抗菌活性的碱性多肽物质,具有强碱性、热稳定性及广谱抗菌性等特点	1.HNP-1、HBD-2或HNP-1/HBD-2联合治疗小鼠结核感染模型均可减少细菌载量并减轻肺部炎症 2.HHC-10和LLKKK18治疗可降低卡介菌、结核分枝杆菌和鸟分枝杆菌感染小鼠模型的细菌载量 3.Magainin-Ⅰ模拟肽通过阻止结核分枝杆菌抑制吞噬体-溶酶体融合和凋亡,而使活菌数明显减少,增强了宿主防御机制 4.IDR-HH2和IDR-1018在动物模型中降低了结核分枝杆菌菌量,尤其是IDR-1018可诱导小鼠肺部病变明显减少	[87⇓⇓-90]
胸腺肽	小牛胸腺素、胸腺肽-β4	胸腺肽是胸腺组织分泌的具有生理活性的一组多肽,其诱导T淋巴细胞分化成熟、增强细胞因子的生成和增强B淋巴细胞的抗体应答	1.小牛胸腺素治疗逆转了在卡介苗感染的骨髓重建小鼠体质量逐渐减轻的趋势,并可以减少脏器中分枝杆菌的菌量 2.胸腺肽能够体外改善肺结核患者的T淋巴细胞活性 3.胸腺肽联合抗结核药物治疗结核病,可改善症状,促进痰菌阴转和病灶吸收	[91⇓⇓⇓-95]
保尔佳	保尔佳	保尔佳是从动物脾脏中提取的低分子活性肽类物质,能激活免疫系统,促使白细胞介素-2和γ-干扰素释放,增加T淋巴细胞活化并刺激细胞分裂抑制素增加,提高机体免疫力	保尔佳辅助抗结核药物化疗,可改善结核病患者症状,用药后患者无肝、肾功能改变及不良反应的发生	[96]

表3

参考文献 111

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