修回日期: 2005-10-27
接受日期: 2005-10-31
在线出版日期: 2005-12-15
炎国内外的研究都表明, 宿主对HBV各种抗原产生不同程度的免疫耐受, 目前治疗乙肝的药物疗效均有限. 过继免疫疗法因其有希望从源头上解决免疫耐受的问题, 故在慢性乙肝治疗上有很好的应用前景. 我们就过继免疫在乙肝治疗中的研究及其临床应用前景进行了回顾和展望.
引文著录: 高新生, 林菊生. 过继免疫疗法在慢性乙型肝炎治疗上的应用. 世界华人消化杂志 2005; 13(23): 2778-2782
Revised: October 27, 2005
Accepted: October 31, 2005
Published online: December 15, 2005
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13(23): 2778-2782
- URL: https://www.wjgnet.com/1009-3079/full/v13/i23/2778.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v13.i23.2778
目前, 多数学者认为HBV感染慢性化的主要机制是宿主对HBV各种抗原产生不同程度的特异性免疫无应答, 即免疫耐受. HBV可以经胎盘传染胎儿, 胎儿免疫系统尚未发育成熟, 体内HBV特异性T细胞因阴性选择而导致克隆清除. 多数实验结果表明成人感染HBV的免疫耐受主要机制为个体免疫系统不健全. 如Th1/Th2细胞失衡, HBV感染免疫细胞等. 总体来说, 乙肝慢性化与个体特异性免疫功能减弱有关. 过继免疫治疗(adoptive immunotherapy)是将体外激活的免疫活性细胞或细胞因子进行免疫性转移, 输给肿瘤或感染病毒的宿主, 使他们在体内产生协同作用, 由免疫活性细胞杀伤、溶解肿瘤或病毒感染的细胞, 直接或间接地介导机体的抗肿瘤或抗病毒效应. 过继免疫疗法因为可以借正常个体的免疫功能来协助或纠正有免疫功能障碍的患者, 故在慢性乙肝治疗上有较好的应用前景. 我们将对此进行综述.
既往临床观察表明, 一些合并HBV感染的血液病患者接受乙型肝炎表面抗体(抗-HBs)阳性供者骨髓后, 在造血和免疫功能重建的同时, 其体内的HBV也被清除. 近年来, 随着研究者对这一现象的认识逐渐深入, 有关研究报道不断增多[1-3]. Shouval et al[4]研究发现: 用重组的乙型肝炎表面抗原(HBsAg)免疫供者小鼠, 然后将其骨髓移植给免疫抑制的受者小鼠, 受者体内可检测到抗-HBs, 提示供者对乙型肝炎的免疫功能已转移到受者体内. Lau et al[5]报道21例合并HBV感染的患者, 其中5例接受抗-HBs/抗-HBc阳性的骨髓移植, 2例产生持续的HBsAg阴转和抗-HBs阳转, 这2例患者移植前HBeAg和HBV DNA均为阴性, 且均为成年人; 1例发生一过性阴转. 而2例未发生阴转者均为儿童, 且病毒为高复制, 其中1例患者与供者HLA抗原有2个位点不一致, 另1例接受经疫苗免疫产生抗-HBs的供者骨髓. 另16例接受抗-HBs阴性供者骨髓的患者, 无一例发生阴转, 说明过继免疫在HBV的清除中起重要作用, 但也可能存在其他因素的影响, 如病毒复制的水平, 获得免疫的方式等. 随后Lau et al[6]又观察了13例接受抗-HBs阳性供者的骨髓, 其中抗-HBs/抗-HBc阳性6例, 抗-HBc阳性7例, 4例HBsAg阴转, 抗-HBs转阳, 且全部都是接受抗-HBs/抗-HBc阳性骨髓的患者; 而7例接受仅抗-HBs阳性的患者无一例阴转, 故有人认为疫苗免疫对于HBV的清除是不足的, 而且发生清除的时间一般在BMT后3-6 mo. Lau et al[7]研究受体体内淋巴细胞后, 发现了受体体内T淋巴细胞来源于供体, 并且是针对核心C抗原, 而不是针对表面抗原, 这证明了上述现象发生的机制. 对于合并HBV感染的需移植者, 接受BMT后, 常需要大剂量的免疫抑制剂治疗, 这很可能诱发肝炎的活动, 甚至发生重型肝炎. Caselitz et al[8]研究认为在合并HBV感染的移植患者中, 由于肝衰竭引起死亡的可能性至少部分与HBV的再活动有关. Chen et al[9]报告了43例接受BMT的HBV感染者, 其中32例接受异基因BMT, 11例接受自体BMT. 随访1-11年, 接受异基因BMT的患者有26(81.3%)例发生肝功能损害, 5例发展为暴发型肝炎; 在接受自体BMT的患者有4(36.4%)例发生肝功能损害, 无一例发生暴发型肝炎, 提示自身移植的安全性较高. Lau et al[5]报道4例接受抗-HBs阳性供者的骨髓发生HBV清除的患者中, 虽然均出现不同程度的肝损害, 但没有出现暴发型肝炎, 原因可能与细胞毒性T淋巴细胞(CTL)的非细胞毒性作用机制有关. 反之, 乙肝抗体阳性的患者接受乙肝病毒携带者骨髓移植, 则有发生爆发型肝炎的报道[10].
不少研究者[11-13]发现: 骨髓移植致死性并发症中, 肝损害, 特别是在HBV阳性患者中, 是主要诱发因素. 如何防止和减少HBV感染者接受BMT后发生肝脏损害, 是目前需要解决的一个问题. Daily et al[14]报道, 应用丙种球蛋白肌注能起到预防作用. 最近, Lau et al[5]报道应用泛昔洛韦降低合并乙型肝炎的血液病患者的病毒水平, 可减少肝脏损害的发生率. 拉米夫定在防止骨髓移植肝损害及乙肝复发上, 作用最为肯定[15-18].
上述研究表明, 接受BMT后的HBsAg阴转率明显高于自发的转换率或应用干扰素后的阴转率, 在目前尚缺乏有效清除HBV治疗手段的情况下, BMT过继免疫给我们提供了一种治疗慢性乙肝的思路.
1970年后Morgan et al[19]发现白细胞介素-2(IL-2)对T淋巴细胞具有扩增和激活作用. 1982年Rosenberg et al[20]发现: 正常人和肿瘤患者的外周血单核细胞在含IL-2的培养基中, 经2-3 d时间培养后出现显著的杀伤活性, 后将这种细胞称为淋巴因子激活的杀伤细胞即LAK细胞. 1987年开始用于慢性乙肝的治疗,到目前已有18 a的历史. 总结其治疗经验后发现: 临床上有反复轻度肝功能受损, ALT轻度升高, HBeAg阳性或HBV-DNA阳性, 但滴度较低的患者效果较佳. 其HBeAg阴转率近期为44%, 远期为58%; DNA则分别为57%和70%. 应用LAK细胞治疗效果, 受个体免疫状态的影响, 免疫低下者效果差. 由于LAK细胞治疗中需要使用大量IL-2, 而IL-2可引起毛细血管渗透性增加综合征. 一般不良反应有发热, 恶心, 乏力, 肌肉酸痛, 严重的有败血症. 目前研究的方向是寻找更有效果的LAK前体细胞(脐血, 骨髓, TIL细胞等); 改善LAK细胞诱导方法(加入抗CD3, IL-7等); 改变LAK细胞的输注途径(通过肝动脉导管). 这些研究或多或少的提高了LAK细胞的疗效, 减轻了其治疗的副作用.
树突状细胞(dendritic cells, DCs), 顾名思义为一种边缘有树枝状突起的大细胞, 在体内含量极少, 但却发挥着非常重要的作用, 是机体识别外来抗原(病原体)和自身变异抗原(肿瘤抗原等)的最重要的抗原递呈细胞. 越来越多的证据表明由DC激活的细胞免疫, 特别是CTL介导的免疫反应, 通过杀伤感染的肝细胞和释放抗病毒的细胞因子来清除HBV. 尽管血中存在高浓度的病毒抗原, 慢性乙肝患者没有启动有效的免疫反应. 作为起核心作用的DC细胞可能与慢性乙肝患者对病毒抗原的这种弱反应有关. 现已有研究表明包括HBV在内的多种病毒感染中, 均存在抗原递呈功能缺陷[21-23]. Wong et al[24]还发现在乙肝相关性肝癌患者体内, 树突状细胞也存在缺陷, 这种减弱的抗原呈递功能可通过肿瘤抗原致敏增强. Akbar et al[25]通过用HBV转基因鼠模型研究HBV感染后机体免疫耐受状态与DC等免疫细胞功能的关系, 发现这种状态并不是因为淋巴细胞功能缺陷, 而是由于抗原递呈功能缺陷, 特别是DC功能缺陷引起. Yan et al[26]研究经过干扰素治疗的慢性乙肝患者体内树突状细胞亚类数量变化, 发现对干扰素治疗有效果的患者体内树突状细胞特别是髓系树突状细胞明显升高, 也间接证明了树突状细胞在乙肝病毒清除中的关键作用. 因此, 诱导成熟的DC细胞进行免疫过继治疗, 可能会取得对慢性乙肝患者重建细胞免疫的作用. DC用于抗病毒的免疫治疗的基本方法是: 体外用细胞因子诱导扩增DC, 并用病毒抗原冲击致敏, 再将致敏的DC回输到体内, 诱导出特异性的CTL, 从而发挥抗病毒作用. 为了能保持高水平而持久的抗病毒免疫应答, 可用病毒抗原多肽基因修饰DC, 使之持续表达基因产物. 因此, 寻找更有效的基因载体, 转染DC就成为目前的主要研究方向. 目前用重组腺病毒以及腺相关病毒作为载体, 转染细胞因子如GM-CSF, IL-12, IL-7以及乙肝抗原(S, C, E)等基因入DC, 诱导出的特异性CTL, 据初步研究[27-29], 杀伤作用提高显著. 据初步临床实验[30], 树突状细胞疫苗应用于人体是安全有效的. Gao et al[31]研究树突状细胞和血清HBV-DNA水平和肝脏炎症程度关系, 发现DC2数量和病毒数正相关, 而DC细胞数量和肝脏炎症积分无明显相关性, 这表明树突状细胞可能通过激活CTL, 针对的是乙肝病毒, 因而不会加重肝脏细胞损伤. Chen et al[32]用表面抗原致敏的树突状细胞治疗19例慢性乙肝患者, 10 名(52.6%)患者E抗原转为阴性; 2例联合拉米夫定的患者获得完全应答. 初步疗效表明与干扰素相当, 并发现合用拉米夫定效果更佳. Furukawa et al[33]发现用表面抗原致敏的树突状细胞疫苗, 防止慢性乙肝患者肝移植术后复发, 取得较好效果. 现已取得一些进展, 但抗乙肝病毒治疗方面没有开展大范围的研究, 能否用于清除HBV, 尚待进一步研究.
CIK细胞全称为多种细胞因子诱导的杀伤细胞, 1991年美国斯坦福大学医学院骨髓移植中心首先报道了这种高增殖力和高细胞毒性的细胞因子激活的杀伤细胞的培养方法. 1994年Lu et al[34]报道了体外大量增值CIK细胞的方法后, 在全世界范围内引起了普遍的关注. 国内外很多学者对其细胞来源, 免疫学特性, 抗病毒抗肿瘤的杀伤效能都作了深入的研究和阐述. Tong et al[35]在体外试验中比较了CIK细胞和LAK细胞的杀伤作用: CIK细胞最强毒力在培养第10-28 d, 可杀伤2.5-3.5个对数级的肿瘤细胞, 而LAK细胞仅杀伤0.5-1.5个对数级细胞. 由于CIK细胞具有非MHC限制性, 高增殖活性, 高细胞毒力, 细胞来源丰富等优点, 目前已经开始试用于治疗慢性乙型肝炎. 体外试验发现, 加入纯化HBsAg共培养后, 可以诱导CIK细胞产生特异性杀伤作用. 已有研究表明[36], 慢性乙肝患者CIK细胞同样存在缺陷. 因此怎样加强其杀伤活性为目前研究重点. 目前通过转染CIK细胞以及与树突状细胞共培养, 实验证明能够大大增强其杀伤活性[37,38]. Gao et al[39]对16名慢性乙肝患者用CIK治疗52 wk, 取得较好效果, 完成治疗的14名患者中, DNA转阴, HBeAg/anti-HBe血清转换, 及肝功能恢复正常的各占42.86%(6/14). 但CIK细胞用于临床治疗慢性乙型肝炎的经验和报道仍然很少, 其清除病毒的机制和效果尚需更多的研究来阐明. 其他淋巴细胞, 如自然杀伤细胞即NK细胞[40], 趋化因子活化的杀伤细胞即CHAK细胞, 初步研究表现出了较好的应用前景. Maghazachi et al[41]通过研究CHAK细胞体外常规生物学活性发现: CHAK细胞是一类不同于PBMC细胞及LAK细胞的新型免疫杀伤细胞, 虽然其在诱生初期并不比LAK细胞强, 但随着培养时间延长, CHAK细胞逐渐显示出更强的杀伤活性, 且杀伤功能维持时间较LAK细胞久.
由于HBV不仅能感染患者的骨髓基质细胞, 而且还感染患者的外周血淋巴细胞, 且骨髓移植风险较高; 因此, 有研究者将目光投向了造血干细胞. Ilan et al[42]观察了12例接受HBsAg阳性供者的造血干细胞移植的患者, 其中HBsAg阳性8例, 阴性4例. 随访13.2 mo(中位数), 8例HBsAg阳性患者中有1例死于肝衰竭, 1例ALT升高; 4例阴性患者无一例发生HBV感染. 因此认为, 造血干细胞移植可能会减少HBV感染, 且HBsAg阳性并不是造血干细胞移植的反指征, 除非HBV处于高复制水平. Chiba et al[43]报告一例慢性乙肝患者因急性淋巴细胞白血病而接受外周血干细胞移植, 供体为单纯乙肝表面抗体阳性. 结果获得彻底痊愈. 因患者应用拉米夫定, 并认为拉米夫定可能起协同作用.
其在动物实验中也显示出了良好的前景: Li et al[44]对28只小鼠实施原位肝移植, 对21只小鼠实施骨髓移植作为对照. 供体小鼠均为乙肝表面抗原疫苗注射后并出现抗-HBs, 阳性, 结果接受肝移植的小鼠有23只(82%)出现了抗-HBs, 并持续了2-9 wk. 而接受骨髓移植的21只小鼠有19只(90%)出现了抗-HBs, 并持续了2-12 wk. Dahmen et al[45]亦有类似报道: 对34只小鼠实施原位肝移植, 供体为抗-HBs小鼠. 结果29只(85%)出现了抗-HBs并持续了2-10 wk, 且受体和供体最大滴度无明显差异. 上述研究显示出了肝移植可能作为过继免疫的一个手段, 其机制及能否临床应用有待进一步研究.
随着对乙型肝炎慢性化和免疫耐受机制的揭示, 免疫调节疗法在慢性乙肝治疗中将发挥越来越重要的作用. 骨髓移植是一种彻底的免疫重建, 最有希望达到完全清除HBV的目的. 但骨髓移植死亡率高, 花费大, 限制了其在临床上的应用. 因此, 深入探讨其过继免疫的作用机制, 改进移植方法, 有望使这一方法应用到慢性乙肝的治疗中. 外周淋巴细胞输注疗法, 是比较安全, 操作较为方便,已经应用于临床[46], 并取得较好效果的免疫过继疗法. 因为慢性乙肝免疫耐受机制可能与多种淋巴细胞功能缺陷相关, 从多方面不同角度着手, 如: 积极改善培养方法[47], 混合淋巴细胞(LAK, CIK, DC等)培养及输注[48-50], 以及联合抗病毒药物, 导入某些免疫佐剂[51-53]及抗原片段等[54-56], 理论上能增加过继免疫疗效, 上述体外试验也表明能取得更好效果. 但应用于人体的有效性尚需进一步较大规模临床试验加以证明. 怎样增强外周血淋巴细胞活性, 如导入某种基因片段等, 联合应用生物反应及免疫调节剂, 可能为今后研究方向. 因慢性乙肝患者个体免疫缺陷不尽相同, 针对个体免疫缺陷的病因有针对性的辨证应用, 能否指导临床应用有待进一步研究.
电编: 张敏 编辑: 菅鑫妍 审读: 张海宁
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