结核病疫苗的抗结核免疫机制的研究进展
丁菁芸, 郭翰翔, 雒静, 许建华, 邵萌, 吴芳
石河子大学医学院,石河子 832002
通讯作者:吴 芳,Email: wufang@163.com; ORCID:0000-0001-5320-7134
摘要

结核病是由结核分枝杆菌( Mycobacterium Tuberculosis,MTB)所引起的一种慢性传染病,严重危害人类健康,是目前全球范围内,尤以发展中国家为首,是受危害最为严重的慢性传染病之一。目前,预防结核病最常见且有效的疫苗是卡介苗(Bacillus Calmette-Guérin,BCG),但由于其对成人肺部结核保护作用的不确定性,再加上外界因素的改变也使卡介苗难以满足人类预防结核病的迫切需求,因此,新型抗结核疫苗的研发显得格外紧迫和重要。本文将介绍减毒活疫苗VPM1002疫苗,蛋白质/佐剂疫苗H4/H56:IC31疫苗,病毒载体疫苗腺病毒载体疫苗和其他已经进入临床试验的疫苗,以及一些尚在研究的抗结核免疫机制的研究现状,为以后的结核病防治提供参考。

关键词: 结核病; 结核分枝杆菌; 抗结核免疫机制; 结核病疫苗
中图分类号:R378.91 文献标志码:A 文章编号:1002-2694(2020)11-0940-09
Research progress on the anti-tuberculosis immune mechanisms of tuberculosis vaccines
DING Jing-yun, GUO Han-xiang, LUO Ling, XU Jian-hua, SHAO Meng, WU Fang
Shihezi University School of Medicine, Shihezi 832002, China
Corresponding author:Wu Fang, Email: wufang@163.com
Abstract

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB), which severely endangers human health. Tuberculosis is one of the major infectious diseases causing harm and death to people globally. China has among the highest burden of TB worldwide. China’s TB prevention and control efforts are facing many problems and challenges. The current TB prevention and control service system and control capacity in China cannot meet the prevention and control needs. At present, the most common and effective vaccine to prevent tuberculosis is Bacillus Calmette-Guérin (BCG). However, because of the relatively low protective effect of BCG against pulmonary tuberculosis infection in adolescents and adults, as well as changes in external factors, BCG faces challenges in meeting the urgent needs of preventing and controlling tuberculosis in humans. Currently, research and development of a new TB vaccine is particularly urgent and important. This article introduces the live attenuated vaccine VPM1002 vaccine, protein/adjuvant vaccine H4/H56:IC31 vaccine, viral vector vaccine, adenovirus vector vaccine and other vaccines that have entered clinical trials. It additionally describes the current status of research on anti-TB immune mechanisms to provide a reference for future tuberculosis control, and it discusses ideas for the future development of new TB vaccines. This article should have important reference value for the development and innovation of TB vaccines in China.

Key words: tuberculosis; Mycobacterium tuberculosis; anti-tuberculosis immune mechanism; tuberculosis vaccine

结核病流行的最新数据显示, 结核病仍然是最致命的传染病, 也是最大的单一感染性病原体致死原因。2018年, 全球有700万新发结核病, 感染人数约为17亿。其中57%的男性, 32%的女性和11%的儿童(年龄< 15岁)。所有国家和年龄组都有病例, 但总体上89%是成年人(年龄≥ 15岁)[1]。Bacillus Calmette-Gué rin(BCG)是目前唯一获得世界各国许可预防结核病的疫苗, 在预防婴幼儿结核病方面具有中等效力, 但在青少年和成年人中预防结核病方面并不可靠。目前正在进行临床Ⅱ b期试验的卡介苗再接种虽然对印度的成年人有一定的保护作用 , 但是在不同年龄组和不同地区结核病的发病率不一致, 使得卡介苗再接种对结核病的防护水平也不一致[3]。结核病的致病机制相对复杂, 目前, 中国也是全球9个结核病高负担国家之一。所以深入探究结核病疫苗的抗结核免疫机制对我们未来生产更高效, 毒性作用更小, 预防作用更好的结核病疫苗有着重要的作用。本文将对目前正在进行临床试验的疫苗和一些新的抗结核研究机制进行综述。

1 减毒活疫苗

VPM1002是将单核细胞李斯特菌hly整合至BCG[4]的重组卡介苗(rBCG)。它可以通过诱导体液免疫和细胞免疫应答使机体产生强烈的抗结核免疫效果。与普通BCG相比较, 重组卡介苗产生的免疫更为持久, 因此, 重组卡介苗可以在胎儿分娩后的任何时间进行接种。VPM1002即使在SCID(重症联合免疫缺陷)小鼠中也具有较高的安全性, 并提供了显著增强针对结核分枝杆菌的保护[5]。首先, VPM1002疫苗可以促进细胞凋亡和自噬, 并促进分枝杆菌抗原释放到细胞质中, 增加细胞质中抗原的负载以增强引发MHC I限制性 CD8+T细胞的表达, CD8+T细胞通过该途径识别、吸附吞噬细胞的结核杆菌抗原[6, 7]。其次, 其诱导高于卡介苗的抗原特异性记忆 CD4+T细胞的数量和比例, 具有CXCR5和CCR7表型[8]。VPM1002疫苗接种后显著增加抗原特异性 CD4+T细胞和IL-2的产生, 肺和脾细胞中的IL-17(在抗结核免疫中具有重要作用), IFN-γ 和粒细胞-巨噬细胞集落刺激因子(GM-CSF)产量提高。其中分泌细胞因子IL-17的细胞中, γ δ T细胞所占比例最高。在分泌IFN-γ 的细胞中, 自然杀伤细胞(natural killer cell, NK)所占比例最高。因此, VPM1002免疫诱发并加强Th1和Th17细胞因子反应, 并在肺和脾脏中持续存在长时间[9]。虽然 VPM1002疫苗和BCG均可诱导IL-17应答。但是, 在接种的第16周和第6个月的时间点上, 接种VPM1002疫苗导致IL-17CD8+ T细胞增加[10]。此外, 受到VPM1002感染的巨噬细胞中的囊泡通过骨髓来源的树突状细胞(Dendritic Cells, DC)亚群诱导更多Th17极化细胞因子IL-6和IL-23以及免疫调节细胞因子IL-10的产生[7]。VPM1002感染与黑色素瘤2 (AIM2)炎症小体缺失强化激活、半胱天冬酶激活增强、IL-1β 和IL-18的产生以及AIM2依赖性和干扰素基因刺激因子(STING)依赖性自噬的诱导有关[11]

与VPM1002疫苗思路相同, 但是CysVac2是由早期分泌抗原CysD和Ag85B融合而成。Counoupas等人构建的过表达CysVac2的重组BCG菌株(rBCG:CysVac2)与亲代BCG相比较, rBCG:CysVac2皮内接种导致机体内的单核细胞/巨噬细胞召募增加, 抗原特异性 CD4+T细胞启动增强, 进而产生更强的诱导特异性IFN-γ 分泌细胞的作用, 而且用CysVac2融合蛋白加强BCG的保护效果也得到类似的改善[12]。另有研究表明, 加入适当佐剂可以提高特异性多功能(IFN-γ + TNF-α + IL-2+) CD4+T细胞数目并提前启动特异性多功能 CD4+T细胞[13, 14]

MTBVAC疫苗是第1个也是目前唯一一个基于MTB的减毒活疫苗候选疫苗[15]。疫苗诱导强大的中枢记忆 CD4+T细胞反应并能长期维持 CD4+T细胞记忆, 进而促进机体表达高水平的IFN-γ , 可以有效控制结核杆菌感染[16, 17, 18]。这表明MTBVAC疫苗免疫反应比BCG的免疫反应持续时间更为长久。更为有效地诱导针对结核分枝杆菌引起人类结核病的特异性免疫[19]

2 蛋白质/佐剂疫苗

H4:IC31疫苗, 其中H4融合蛋白由两种免疫原性分枝杆菌抗原Ag85 B和TB10.4组成, 佐剂为IC31。IC31已被证明能诱导对多种多肽和抗原的有效和持续的细胞和体液反应并且在TB的动物模型中有效, 可诱导强效细胞反应[20]。其中, H4:IC31可以有效促进BCG诱导的免疫反应, 即诱导、促进、维持、保护机体内具有记忆和效应表型的多功能 CD4+T细胞, 进而增强和延长产生多种细胞因子的T细胞反应, 从而进一步增强和延长免疫应答。因此, H4:IC31作为BCG加强疫苗使用时, 可以在感染期间显示出诱导和维持对含有H4疫苗抗原的强烈反应的最高能力。此外, 这种针对疫苗抗原的应答, 尤其以具有多功能中枢记忆样表型的T细胞所支配。发生感染后, 这类T细胞将会被募集到感染部位发挥作用[21]。H4:IC31还诱导了较为持久的Th1反应, 并且抗原Ag85B和TB10.4特异性应答主要由多功能(IFN-γ + IL-2+ TNF-α +)和双功能(IL-2+ TNF-α +) CD4+T细胞亚群产生, 其中占主导地位的是抗原Ag85B产生的特异性T细胞(IFN-γ + IL-2+ TNF-α +)[22]。Hennie Geldenhuys[22]等人, Sepideh Aboutorabian[23]等人和Maria Norrby[24]等人都表明低剂量的H4抗原和高剂量的IC31佐剂能够有效的诱导最佳 CD4+T细胞免疫反应, 使H4:IC31最具免疫原性和保护性。另外Nemes E.等人证明卡介苗提供45.4%的疫苗功效(95%置信区间 6.4~68.1), 而 H4:IC31 提供 30.5%的疫苗功效(80%置信区间 3.0~50.2), 在 95%的置信区间水平上无统计学意义。这表明没有 MTB相关抗原, 可能降低持续QFT-GIT转化率, 这可能反映了持续的结核分枝杆菌感染, 这一发现为新疫苗提供新的思路[25]

与H4:IC31佐剂相同的另一种疫苗H56:IC31, 其中H56含有Ag85B和ESAT-6(这是在感染急性期分泌的两种结核分枝杆菌抗原)和营养胁迫诱导的抗原Rv2660c。研究表明在潜伏期/亚临床期感染的H56 / IC31对所有这3种疫苗抗原均具有疫苗促进和召回反应, 对ESAT-6和Rv2660c的应答非常明显(感染后1~3周), 与在H56刺激后对ESAT-6, Rv2660c和Ag85B产生了攻击前的IFN-γ 反应有关[26]。炎症标记物(ESR)的极低水平和对CFP10的低感染驱动反应, 阻止了抗肿瘤坏死因子(TNF)诱导的MTB的再激活, 可有效抑制潜在感染和控制细菌复制[26]。研究证明即使用不同剂量的疫苗, Ag85B和ESAT-6特异性 CD4+T细胞的功能和多功能评分也没有差异。但是较低剂量的H56:IC31诱导抗原特异性Th1细胞频率更为持久, 多功能Th1细胞数量更多, 这些细胞共同表达IFN-γ 、TNF-α 和(或)IL-2[27, 28]。遗憾的是表达细胞因子的细胞皆为特异性 CD4+ T细胞没有特异性 CD8+ T细胞[27, 28]。在H4:IC31和H56:IC31接种组中, 疫苗诱导的 CD4+ T细胞应答率最高的是那些识别Ag85B的人群, 接种疫苗后, H56:IC31组对ESAT-6的应答和H4:IC31组对TB10.4的应答也显着增加。二者均诱导血清IgG的 CD4+ T细胞反应[29]

M72/AS01E疫苗可以诱导多功能、持续的M72(Mtb32A和Mtb39A)特异性 CD4+ T细胞反应和强烈的体液反应, 促进机体产生IFN-γ 、TNF-α 、IL-2和IL-17以控制分枝杆菌感染[30, 31]。但是在受试者中, 观察到 CD4+ T细胞多功能性水平较低和 CD4+ T细胞表达的IL-17水平非常低, 且几乎没有检测到IL-13[30]。如果使用2剂M72/AS01E疫苗, 可以诱导产生较高数量的M72特异性抗体和Th1细胞因子, 提供的 CD4+ T细胞反应可长达一年[32]

除上述疫苗主要产生特异性 CD4+ T细胞免疫反应外, 有研究证明ID93/GLA-SE免疫可刺激机体产生大量 CD8+ T细胞, 这有助于提高感染者的保护作用[33]。ID93+GLA-SE是一种与Toll样受体激动剂佐剂GLA-SE结合的融合蛋白, 作为一种新型的抗结核疫苗候选株[34]。用ID93+GLA-SE疫苗可诱导高滴度的ID93(Rv3619-Rv1813-Rv3620-Rv2608)特异性抗体, 产生大量IgG1和IgG3亚类并增强Fc介导的巨噬细胞吞噬功能[35]。接种过ID93/GLA-SE的机体再接触病菌时, 肺和脾中会产生大量IFN-γ , 来对抗结核杆菌感染[36]

3 全细胞或提取物疫苗

母牛分枝杆菌(M.vaccae)来源于非结核分枝杆菌的热灭活疫苗, 可作为免疫调节剂用于增强细胞免疫并抵抗患者体内的抗结核分枝杆菌感染, 目前正在进行Ⅲ 期临床试验[37, 38]。与M. indicus pranii(MIP)和RUTI是目前已知进入临床试验仅有的三种治疗性疫苗, 这些结核病疫苗主要针对于耐多药结核病(MDR-TB)和多菌性麻风病(multibacillary leprosy)[39]M.vaccae的作用机制与细胞壁的肽聚糖部分有关, 肽聚糖遇到巨噬细胞和树突细胞后可以导致Th1细胞进一步活化, 并释放出大量标志性的保护性细胞因子IFN-γ , TNF-α 和IL-2[40]。另外, M.vaccae也可以诱导产生调节性T细胞并产生IL-10, 增强 CD4+ T细胞的记忆, 引起持续性小幅度的IL-10反应增加, 通过促进结核早期免疫应答, 进而有效预防结核分枝杆菌的潜伏性感染和复发[41]

印度支原体(M. indicus pranii, MIP)是由印度开发的一种非致病性细菌, 已获得印度药物监管机构、中央药物标准控制组织和美国食品药品管理局批准[42]。目前正在进行Ⅲ 期临床试验。结核分枝杆菌与MIP有大量相同的B细胞和T细胞表位[43]。 结核分枝杆菌感染后, MIP可协同刺激APC细胞和T细胞活化, 产生大量IL-2和IFN-γ , 提高Th1的保护性反应并降低体内结核杆菌生长[44, 45]。机体 CD4+ T和 CD8+ T细胞亚群均产生标志性的保护性细胞因子IFN-γ 、TNF-α 和IL-2。这种蛋白质还增强了 CD4+ T细胞的记忆, 在感染过程中可以作为第一道防线[46]。接种疫苗后, MIP诱导的Th1型细胞能有效地将保护性免疫转移到被结核分枝杆菌感染的患者肺部周围, 增强了肺局部记忆反应能力, 此举可以有效减轻肺部感染的程度[47, 48]。MIP诱导脾细胞和淋巴结细胞中TNF-α 、IL-12和IFN-γ 的分泌显著增加。激活了处于免疫抑制状态的巨噬细胞和树突状细胞[49]。MIP作为巨噬细胞一种有效的自噬诱导因子, 通过诱导MTB感染巨噬细胞自噬促进巨噬细胞吞噬溶酶体融合, 从而增强了感染巨噬细胞对结核分枝杆菌的清除, 随后, MIP通过自噬促进含结核分枝杆菌吞噬体的成熟, 进一步增强了机体内对感染巨噬细胞的清除作用以对抗感染。值得注意的是, 在这过程中, MIP感染的巨噬细胞维持总自噬通量[50, 51]。在免疫治疗早期, MIP组中的 CD8+ T细胞更多, 并且可以观察到较高比例的活化T细胞, 此外, 肉芽肿细胞内可以发现更高比例的 CD4+ T细胞, 这可以形成大的中央坏死核心[43]。后期, MIP主动杀死细菌的作用导致TNF-α 和IL-12表达水平增加, 再次给予MIP后IL-2的高表达可能是CCL5表达增加的原因, 并且CCL5高表达可能增强感染部位的T细胞募集[47]

RUTI疫苗是目前临床上为数不多的候选疫苗之一, 作为一种治疗性结核病疫苗。正在进行IIa期临床试验。该疫苗由纯化的结核分枝杆菌(MTB)细胞片段和脂质体细胞片段组成[52]。RUTI增加了IFN-γ 、TNF-α 、IL-4、IL-10、IL-12p40、一氧化氮合酶(iNOS)和调节激活正常T细胞表达和分泌细胞因子(RANTES)的mRNA表达。同时, RUTI诱导脾脏特异性 CD4+CD8+效应T细胞和IFN分泌细胞数量增加以限制结核分枝杆菌在肺部的传播, 进而控制分枝杆菌的生长[53]。与单用IFN-γ 治疗相比, RUTI治疗导致小鼠骨髓来源树突状细胞(BMDC)上所有激活标记物的表达显著增加。值得注意的是, RUTI处理的骨髓来源树突状细胞表面CCR7表达增加, 表明RUTI疫苗可能增加DC的迁移能力[54]

除上述表达3种预防性疫苗外, 还有一种由达特茅斯学院研发的DAR-901。它是一种热灭活的非结核分枝杆菌疫苗加强剂[1]。它代表了SRL172的一种新的可扩展的制造方法, 诱导了大量较为长期的对结核分枝杆菌溶胞产物的IFN-γ 反应和对LAM(脂阿拉伯甘露聚糖)的抗体反应[55]。其中Th1 应答占主导地位, 大多数应答细胞均表现出多功能效应记忆表型。DAR-901诱导低频的抗原特异性(IFN-γ +、TNF-α + 、IL-2+)多功能/双功能 CD4+ T细胞, 未诱导大量或持续的 Th17/Th22 细胞因子反应, 但对 MTB裂解物的应答频率较高[56], 在引发IFN-γ 反应方面比抗体反应更有效, 且当作为 BCG 致敏动物的加强疫苗接种时, 与同源 BCG 加强疫苗相比, 对气溶胶肺结核的机体保护性得到了增强[57]

4 病毒载体疫苗

AdAg85A是一种可以表达免疫显性MTB抗原Ag85A与腺病毒的重组疫苗, 通过黏膜免疫增强的保护作用是黏膜给药产生MTB抗原特异性T细胞, 足够的抗原特异性T细胞募集到气道腔中。虽然气道给药可以将功能强大的T细胞募集到气道腔并恢复免疫保护, 但这些细胞, 特别是 CD8+ T细胞及相关保护作用只能在有限的时间内持续存在于气道管腔内。有趣的是, 抗原特异性 CD4+ T细胞通过持续时间的急性炎症进入气道腔, 与 CD8+ T细胞对应物不同, 表明气道腔 CD8+ T细胞具有重要的保护作用, CD4+ T和 CD8+ T细胞可能具有不同的机制[58]。Ad5Ag85A是以5型腺病毒(Ad5)为载体与结核杆菌特异性抗原Ag85A进行重组的一种疫苗。在小型动物模型中进行的研究表明, 用Ad5构建体加强免疫后, 可以将免疫反应范围扩大到包括Ag85A以外的分枝杆菌抗原(例如Rv0288), 以增强机体对结核病的抵抗作用[59]。有研究结果表明, 用Ad5-85A增强 BCG诱导的保护作用与Ag85A特异性 CD4+ T细胞的频率增加有关, 但是没有更高的亲和力, 而且用Ad5-85A增强BCG可使抗原决定簇扩散降至最低[60]。另有研究称加强接种后机体获得的 Ag85A 特异性 CD4+ T细胞系差异并不明显。然而, 与病毒加强之前获得的 CD4+ T细胞系相比, 加强后机体获得的Ag85A 特异性 CD4+ T细胞系可分泌更多的具有抗炎特性的免疫调节细胞因子IL-10[61]。但是Ag85A的表达仅限于感染的早期阶段, 后期数量变少[61]。ChAdOx185A-MVA85A疫苗, 其中ChAdOx185A是一种猿腺病毒, MVA85A是一种重组痘病毒, 它们均表达Ag85A。牛津大学的研究表明:黑猩猩身上进行鼻内接种的ChAdOx185A可以促进肺中诱导分泌 IFN-γ 的 Ag85A 特异性 CD8+ T细胞频率显著升高, TNF-α 和 IL-17 的应答率更高, 在脾脏中, ChAdOx185A诱导全身性IFN-γ , TNF-α 和IL-2的 CD8+ T细胞。皮内注射MVA85A后, 肺和脾脏 CD4+ T细胞分泌的细胞因子TNF-α 和IL-2的分泌水平显著增高, 但不会增加IFN-γ 的应答且 CD4+ T细胞应答不强烈。可在接种 BCG 的健康成人中使用 MVA85A 作为初免-加强治疗的方法[62]。IL-2, IL-17, Ag85A特异性IgG反应也由ChAdOx185A诱导并由MVA85A增强。据牛津大学的另一份研究表明在成人身上进行ChAdOx185A和MVA85A疫苗接种后会产生大量的Ag85A特异性(IFN-γ +、TNF-α + ) CD8+ T细胞。可预防和降低结核病的风险[63]

以上3种腺病毒只能较为有效的表达一种特异性T细胞免疫, 目前有一种正在进行对于潜伏性肺结核患者Ⅱ a期临床试验[1, 64]弱复制缺陷型流感病毒载体的黏膜载体疫苗, 可有效表达两种特异性T细胞免疫。TB/FLU-04L作为婴儿、青少年的预防性增强疫苗, 表达抗原Ag85A和ESAT-6。Ag85A参与脂质的积累和储存, 在MTB休眠中具有潜在的重要作用[65]。注射疫苗后, 病毒载体会引导机体产生强烈的Th1型细胞免疫应答, 从而使(IFN-γ +、IL-17+) CD4+和(IFN-γ +、IL-17+) CD8+ T细胞数量明显升高, 进而增强机体的抗结核能力[66]

5 探索新的免疫机制

通过浆细胞样树突状细胞中的toll样受体9(TLR-9)信号, 合成的CpG寡聚体Oligo-B可以诱导产生Th17细胞因子, 已知其在细胞因子中起重要作用。这些研究表明, CpG寡聚体是IFN-γ 和IL-17的良好诱导物并且可以重新激活机体产生获得性免疫。因此, Oligo-B可以通过IFN-γ 和IL-17来促进产生记忆T细胞。表明Oligo-B加强可以恢复 CD4+中TCM的数量, 并重新激活以前接种BCG的免疫衰老状态小鼠中对MTB感染的保护性免疫, 但IFN-γ 的产生需要超老龄小鼠中Oligo-B的3次增强才能重新激活[67]

纳米粒子(NPs)通过递送多种增强免疫调节化合物(IMC)的作用, 使细胞靶向, 改善抗原转染, 增强复合性和提供协同作用的机会[68]。表明基于NP的免疫治疗, 对于新的治疗和疫苗接种系统具有很大的前景。

IL-12和IL-10, 前者是一种关键的Th1极化细胞因子, 后者是Th1免疫中有效的免疫调节分子[69, 70]。有报道称, 发现人IL-18的产生显著增强了BCG诱导DC产生IL-10的能力, 这意味着人IL-18可能促进了DC与Th1细胞群之间的相关性[71]。rBCGhIL-18不能通过DC诱导IL-12, 但是能诱导显着更多的IL-10(与非重组BCG或PPD相比)。IL-10的主要来源是同属常规树突状细胞(conventional dendritic cells, cDCs)亚群, CD103+cDCs与CD11b+cDCs。在结核分枝杆菌感染后, CD103+cDCs通过产生免疫抑制性细胞因子IL-10直接调节非常需要CD11b+cDCs介导的Th1免疫激活反应。由此提供一种新的免疫抑制机制, 该机制由特定的cDCs亚群介导, 并且在引流淋巴结(dLN)中起作用, 这对于肺结核分枝杆菌感染后肺部整体延迟的Th1免疫有极大帮助[72]

CD26又称二肽酶Ⅳ , 是在大鼠肾脏上皮细胞内发现的一种高度糖基化的Ⅱ 型跨膜糖蛋白, CD26可通过颗粒酶B(granzyme B)、TNF-α 以及IFN-γ 介导人类 CD8+ T细胞活化, 发挥 CD8+ T细胞毒性作用。此外, CD26介导的 CD8+ T细胞共刺激作用比CD28介导的 CD8+ T细胞共刺激作用更为强烈[73]。DPP4(CD26)可以负调节CXCR3介导的Th1细胞归巢, 使其到达结核分枝杆菌感染部位, 为宿主导向治疗提供了一个潜在的新机会[74]

一种通常在饮用水中的物种, 被发现后经过分离测序, 它被认为是一种新种, 称为非致病性定殖曼氏梭状芽胞杆菌(M.manresensis)[75]。口服治疗能够诱导结核菌素纯蛋白衍化物(PPD)特异性适应性调节性T细胞(Tregs)反应(包括记忆细胞)[76], 并在治疗两周产生IL-10以及与弱于PPD特异性整体免疫应答刺激相联系起来, 从而增加了IL-6 , TNF和IFN-γ 的产生。但在肺部, 这种治疗主要减少促炎细胞因子TNF, IFN-γ , IL-6和IL-17的产生, 从而降低了细菌负荷和肉芽肿浸润, 以达到降低人类从潜在感染发展为结核病的风险[77]。最新数据显示2015 / EU热灭活的曼氏分支杆菌作为新型食品(NF)在建议的使用条件下是安全的[78]

6 结语

近年来候选疫苗抗结核免疫机制的研究重点多在于如何提高IFN-γ , 如何提高 CD4+ T细胞数量。但是有研究结果表明, 刺激诱导更高水平的 CD4+ T细胞因子可能并不是候选抗结核疫苗加强剂的关键或先决条件[56], 外周血中疫苗特异性IFN-γ 应答的强度与保护之间并没有相关性[79]。但是对于其他的免疫机制我们还所知甚少, 需要我们进行不断的探索。美国俄勒冈健康与科学大学的 David Lewinsohn提出无限制供体T细胞(DURT)具有几乎全种分布不变的T细胞抗原受体(TCR), 可以产生非常规的免疫反应。这种免疫表达可以消除人体差异, 也可避免病原体通过改变抗原而逃逸[80]。目前已有研究证明此方案具有一定的保护作用[81]。Sara Suliman等人证明了先天性炎性细胞因子激活血液粘膜相关不变T细胞(MAIT)是针对结核的全细胞疫苗或分枝杆菌体外刺激对疫苗反应的主要机制。MAIT细胞是MHC相关蛋白1(MR1)限制的T细胞, 对结核分枝杆菌有反应, 而且尚未被开发为潜在的结核疫苗靶标[82]。据Perdomo C.等人的研究表明粘膜BCG接种可以诱导肺中产生TRM为肺结核提供保护[83], 另外Bull NC等人发现这与BCG诱导的肺组织驻留 CD4+ T细胞的新型种群相关[84]。也有学者称免疫机制也可不局限在T细胞上。Maziar Divangahi(加拿大麦吉尔大学)讨论了如何通过BCG诱导的造血干细胞(HSC)重新编程的“ 免疫训练” 来达到对结核病疫苗的先天免疫[85]。希望通过本篇综述了解现在正在进行临床试验疫苗的抗结核免疫机制, 熟悉一些疫苗设计的新思路, 供其参考。

利益冲突:

引用本文格式:丁菁芸, 郭翰翔, 雒静, 等. 结核病疫苗的抗结核免疫机制的研究进展[J].中国人兽共患病学报, 2020, 36(11):940-948. DOI:10.3969/j.issn.1002-2694.2020.00.151

编辑:张智芳

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