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慢性移植物抗宿主病相关性干眼的研究进展

Research progress on dry eye associated with chronic graft-versus-host disease

来源期刊： 眼科学报 | 2023年1月 第38卷 第1期： 36-44 发布时间： 收稿时间：2023/1/16 17:04:46 阅读量：4439
作者：
陈海燕,
郑刚,
关键词：
移植物抗宿主病干眼造血干细胞移植治疗发病机制
graft-versus-host disease dry eye hematopoietic stem cell transplantation treatment pathogenesis
DOI：
10.3978/j.issn.1000-4432.2023.01.03
收稿时间：
 
修订日期：
 
接收日期：
 
慢性移植物抗宿主病(chronic graft-versus-host disease，cGVHD)是骨髓移植后最具有破坏性并发症之一。移植物抗宿主病(graft-versus-host disease，GVHD)发生在10%~80%的造血干细胞移植(hematopoietic stem cell transplantation)受者中，而眼睛是人身体最脆弱的器官之一，有40%~60%接受HSCT的患者发生眼部GVHD，它主要影响泪腺、睑板腺、角膜和结膜等。cGVHD相关性干眼(dry eye associated with chronic graft-versus-host disease，cGVHD-DE)是眼部GVHD最多见的表现形式。cGVHD-DE的长期治疗因涉及多学科、多重结合治疗，至今仍然具有挑战性，其除了全身免疫抑制和眼部润滑剂外，通常还使用局部类固醇、环孢霉素和他克莫司滴眼液。针对中度和重度cGVHD-DE的治疗干预包括使用自体血清滴眼液和佩戴巩膜镜等，新兴起的治疗方案包括重链透明质酸 (heavy chain-hvaluronan/穿透素(pentraxin 3)结膜下注射、间充质基质细胞静脉注射、抑制纤维化药物等。
Chronic graft-versus-host disease (cGVHD) is one of the most devastating complications following bone marrow transplantation. GVHD develops in 10–80% of patients after hematopoietic stem cell transplantation (HSCT). The eye is one of the most vulnerable organs of the human body. Ocular GVHD occurs in 40–60% of patients with GVHD undergoing HSCT, and it mostly affects the lacrimal glands, meibomian glands, cornea, and conjunctiva. The most common form of ocular GVHD is dry eye disease (DED). The long-term treatment of cGVHD-related dry eye syndrome remains challenging and involves a multidisciplinary approach. Besides systemic immunosuppression and ocular lubricants, topical steroids, topical cyclosporine, and topical tacrolimus are commonly prescribed. Newer therapeutic interventions for moderate and severe cGVHD-related DED include using serum eye drops and scleral contact lenses. Emerging treatment options include subconjunctival injection of heavy chain-hyaluronan (HC-HA)/ pentraxin 3 (PTX3), intravenous injection of mesenchymal stromal cells, antifibrotic drugs, etc. This article reviews the mechanisms, clinical findings, and treatment of cGVHD-related dry eye syndrome.
目前同种异体造血干细胞移植(allogeneic hematopoietic stem cell transplantation，allo-HSCT)是针对多种血液系统恶性肿瘤和其他严重血液疾病的一线治疗方法之一。然而随着allo-HSCT本身成功率的大大提高[1-2]，需要更多的医疗措施来对抗其引起的并发症。全球每年约进行25 000次allo-HSCT，并且移植数量持续增加[3-4]，与其相伴的移植物抗宿主病(graft-versus-host disease，GVHD)则是移植术后最主要的并发症，发病率高达10%~80%[3]。allo-HSCT术后GVHD是一种多器官疾病，源于供体同种异体反应性T细胞的免疫攻击，导致肝、皮肤、胃肠道、造血组织和其他脏器受损的慢性疾病，其中包括眼表[4]。40%~60%接受allo-HSCT的患者发生眼部GVHD[5-6]，而慢性移植物抗宿主病相关性干眼(dry eye associated with chronic graf t-versus -host disease，cGVHD-DE)是眼部GVHD最常见的表现，并且是慢性移植物抗宿主病(chronic graft-versus-host disease，cGVHD)的标志性发现[7-8]。研究[9]发现大部分allo-HSCT患者一旦出现干眼症状，干眼的病情发展迅速，虽不危及生命却严重影响生活质量。目前国内关于该病的报道很少，眼科医生对其认识不多且治疗棘手，本文就该病的发病机制、诊断及治疗研究的进展作一综述。

1 cGVHD-DE 的发病机制

组织萎缩和过度纤维化是 allo-HSCT术后cGVHD 的组织学特征，但其潜在机制尚不清楚 。cGVHD是一种全身性、多器官的免疫性疾病，主要是供体与受体之间次要组织相容性位点不同所致。基于临床前小鼠模型[10]， 将cGVHD的病理生理过程分为以下3个阶段：第一个阶段是组织损伤引起的早期炎症反应，化疗、预处理方案、急性GVHD等均可导致组织损伤，组织损伤使得抗原提呈细胞与T细胞接触时被激活，上调共刺激分子来防止相关的组织损伤，也可触发可溶性炎症介质释放到循环和细胞外液中，在cGVHD早期诱导自身免疫或免疫耐受。第二个阶段是慢性炎症引起的胸腺损伤及B细胞和T细胞免疫失调。cGVHD长期慢性的炎症反应以及对其的治疗会导致胸腺功能损害，T细胞的阴性选择受损，导致同种反应性T细胞的产生、调节性T细胞(regulatory cells)减少、B细胞免疫的分化和成熟，最终引起T细胞和B细胞的免疫失调。最后一个阶段是组织纤维化。异基因抗体与巨噬细胞相互作用，从而促进巨噬细胞的激活和异常分化，活化的巨噬细胞产生多种细胞因子来诱导纤维母细胞活化及增殖，导致细胞外基质和成纤维细胞过度积聚，引起组织纤维化。
    基于cGVHD的病理生理，关于cGVHD-DE的发病机制，许多学者[11]认为是以眼表的泪腺上皮组织和角结膜上皮组织的广泛纤维化和淋巴细胞浸润，T细胞和成纤维细胞相互免疫介导或免疫活性T细胞直接攻击结膜、泪腺上皮，导致泪液分泌减少，角膜、结膜上皮细胞反复脱落所致。

2 cGVHD-DE 的临床症状及体征

干眼是眼表的多因素疾病，以泪膜稳态丧失为特征表现，并伴有眼部症状，发病机制包括泪膜不稳定、泪液高渗透压、眼表炎症与损伤和神经感觉异常[12]。cGVHD-DE临床上主要表现为allo-HSCT术后发作的眼部干燥感、异物感或眼部刺痛，导致明显眼部不适、视力下降、甚至失明。专科检查可发现患者泪液分泌量减少、泪膜破裂时间缩短、睑缘异常、瘢痕性结膜炎、角膜敏感性降低、角膜上皮弥漫点状荧光着色或剥脱、角膜丝状物等。有研究[13]使用泪液蒸发测定法、睑板腺检查、印迹细胞学和角膜敏感性等方法评估cGVHD-DE患者、无干眼症的allo-HSCT术后患者和健康人的眼表和泪液功能改变的基线谱。他们发现所有cGVHD-DE患者的角膜敏感性降低、睑板腺阻塞率增加、杯状细胞密度显著降低。结膜瘢痕形成或上皮下纤维化(conjunctival scarring or subepithelial fibrosis，CSEF)可能是cGVHD对眼表影响的重要标志，可能与眼部GVHD严重程度评估有关，具体还待进一步研究[14]。

3 cGVHD-DE 的诊断和严重程度的评分

美国国立卫生研究院(National Institutes of Health，NIH)于2005年首次提出了眼部GVHD的诊断标准[6]：患者allo-HSCT术后发作的眼表临床症状，如干涩感、异物感等；无表面麻醉的泪液分泌实验(Schirmer I test)≤5 mm或6~10 mm伴角膜荧光色阳性，至少伴有1个其他器官受累，并且必须排除感染或其他原因则可诊断。2014年NIH共识对cGVHD-DE的评分标准[6]见表1，与2005年版NIH共识相比，由眼科医生确诊的无症状干燥性角结膜炎被纳入诊断。更新了关于使用滴眼液要求的评分，评分仅包括润滑剂滴眼液。Schirmer I test不作为评估严重性的标准，已从评分表中移除，因Schirmer I test可能对cGVHD-DE的诊断有用，但由于其与症状改变相关性较差，不能作为随访时评估病情有无好转的标准，所以这些数值对于随访cGVHD-DE无意义。NIH对cGVHD-DE严重程度的分级是基于润滑剂眼药水的使用频率和视功能的损害，它的局限在于既不包括炎症活动，也不包括眼表疾病的程度(眼睑、结膜、角膜的累及)，对指导疾病的治疗及真正评估病情的严重性并没有实质性作用。
    关于cGVHD-DE的诊断及严重性评分，以下介绍另一种更为实用的国际慢性眼移植物抗宿主病共识组(International Chronic Ocular Graft-Versus-Host-Disease Consensus Group，ICCGVHD)对cGVHD-DE的诊断及评分标准[15](表2，3)。
     ICCGVHD评分包括眼表疾病指数(ocular surface disease index，OSDI)、无表面麻醉的Schirmer I test、角膜荧光素染色评分及结膜充血程度。建议的分级系统如表2所示。角膜荧光素染色评分为0~3：0级为无染色，1级为较少染色，2级为轻度/中度染色，3级为严重染色。结膜的结膜充血评分为0~2：0级为无，1级为轻度/中度，2级为严重。每一项高于1分即被视为异常。根据各项参数的总分，疾病严重程度将分为正常(0~4)、轻度/中度(5~8)和严重(9~11，表2)。

表1 2014年NIH共识对慢性眼部GVHD评分标准
Table 1 NIH proposed the severity score criteria for chronic ocular GVHD in 2014

20230117090022_4441.png

表2 慢性眼部GVHD的严重程度评分(ICCGVHD诊断标准)
Table 2 ICCGVHD proposed the severity score criteria for chronic ocular GVHD

20230117090110_7086.png

表3 慢性眼部GVHD的诊断(ICCGVHD诊断标准)
Table 3 ICCGVHD proposed the diagnosis of chronic ocular GVHD

20230117090157_2456.png
基于系统性GVHD的存在或不存在以及评估的总分诊断眼部GVHD(表3)。存在全身性GVHD时，0~3分为没有眼部GVHD；4~5分表示“可能的”眼部GVHD，得分≥6表示“明确的”眼部GVHD。在没有系统性GVHD的情况下，评分0~5表示不存在眼GVHD，评分6~7表示“可能的”眼GVHD，评分≥8表示“明确的”眼GVHD。
     研究[16]表明新提出的ICCGVHD诊断标准可以重复使用于诊断和确定cGVHD-DE的严重程度。
     近年来随着对干眼诊疗的不断重视与进步，许多辅助诊断方法不断在更新。有研究[17-19]显示泪液中IL-8/CXCL8、IFN-γ、IL-12AP70、IL-17A、MMP-9、IL-1Ra表达水平升高被认为是cGVHD-DE发生的危险因素。cGVHD-DE患者在allo-HSCT术前，测得泪液中IL-6、IL-1Ra、fractalkine等细胞因子表达水平升高，表明这些细胞因子可能预测cGVHD-DE的发生[20]。这些泪液细胞因子的变化为cGVHD-DE的预防、早期发现、早期诊断和早期治疗提供了依据。

4 cGVHD-DE 的治疗

4.1 一般治疗

4.1.1 润滑剂治疗
对于各种类型的干眼，特别是蒸发过强型，使用人工泪液可以有效地缓解眼部症状，让患者的眼睛表面重新形成一种人工泪液保护膜。对于轻度cGVHD-DE的患者，可选用不含或含弱毒性防腐剂的人工泪液，当使用频率超过每天3~4次时，则推荐使用不含防腐剂的人工泪液。但由于鼻泪管的引流作用，大部分人工泪液将在点眼后的15~30 s流失，导致作用时间缩短，生物利用度降低[21]。对于中度、重度cGVHD-DE患者，则应选用黏度较高的眼膏、凝胶或含有脂质成分的人工泪液。
4.1.2 抗炎治疗
采用局部糖皮质激素、环孢霉素A(c yclosprine A，CyA)、他克莫司(FK506)和全身免疫抑制剂治疗。
根据2014年NIH专家共识[6]，凡是符合中至重度cGVHD的患者(3个及以上器官累及，或累及任何单一器官且评分≥2，或任何的肺累及)均应接受全身系统性治疗。全身使用糖皮质激素是中至重度cGVHD患者的一线用药，原则是采用泼尼松(起始剂量1 mg/kg/d)，联合钙调神经磷酸酶抑制剂一起，可以达到全身抗炎及免疫抑制的作用，但不良反应较多。
眼表糖皮质激素滴眼液一直用于中重度干眼症的治疗，也用于cGVHD-DE的治疗[22-23]。近期有研究表明即使具有相似的疾病严重程度，与没有眼部GVHD的患者相比，cGVHD-DE患者对低剂量局部类固醇方案的反应较差[24]。而且长期使用局部糖皮质激素药物还有其副作用，如高眼压、青光眼、白内障形成、角膜变薄和感染性角膜炎等。
CyA是由11个氨基酸组成的环状多肽，是土壤中一种真菌的活性代谢物，自2000年以来已被FDA批准用于治疗干眼症[25]。CyA滴眼液已显示可减少眼表中活化T细胞的数量、增加结膜杯状细胞密度、减少上皮细胞凋亡并减少促炎性细胞因子。在一项针对cGVHD-DE患者的小型研究中，受试者使用0.05%的CyA滴眼液每天2次点眼治疗，使用3个月后，受试者的Schirmer I test评分平均值增加，泪液破裂时间改善和主观症状改善[26]。在另一项仅有16例cGVHD-DE患者(32只眼)的研究中，62.5%的患者眼表症状得到改善，平均随访90天后，所有眼睛的角膜荧光素染色评分都有降低[27]。Malta等[28]报道了一项对105名HSCT患者进行的回顾性研究，证明cGVHD-DE患者早期开始使用局部0.05%的CyA可缓解患者的眼部干燥症状以及可能会减少泪腺中的炎症反应。
FK506是一种免疫调节剂，通过抑制钙调神经磷酸酶来损害T细胞活性。据报道，FK506较0.05%的CyA强效10~100倍，Abud等[29-30]对比了局部用使用0.05%FK506及0.5%甲基强的松龙的效果，受试者每天使用0.05%FK506或0.5%甲基强的松龙点眼2次，持续10周，发现FK506和甲基强的松龙一样可以有效减少这些患者的干眼临床体征和症状，并且有更高的耐受性及安全性。这可能与它具有抑制T细胞分裂的进行、增强T调节细胞增殖、调节炎症反应并促进伤口愈合有关[31-34]。
4.1.3 自体血清治疗
自体血清(autologous serum，AS)滴眼液是第一种用于治疗角膜疾病的外周血衍生产品，AS中有表皮生长因子(endothelial growth factor，EGF)、血小板衍生因子(platelet-derived growth factor，PDGF)和成纤维细胞生长因子(fibroblast growth factor，FGF)等8种生长因子，介导角膜组织修复过程。因而已被多项病例对照研究证实，AS对cGVHD-DE具有良好的治疗效果，且安全性高[35]。然而也有研究[36]表明A S可能含有白细胞脱颗粒的促炎剂，这可能会妨碍眼组织的再生，加重病情。
4.1.4 抗菌药物滴眼液治疗
局部使用抗菌药物可以预防角膜上皮糜烂或者角膜溃疡的患者感染，也因为 MGD 是导致cGVHD-DE的原因之一，局部应用抗菌药物可有效抑制MGD患眼病原菌的生长、减轻酯酶分解、甚至可有部分抗炎作用。
4.1.5 巩膜镜
巩膜镜可以治疗多种眼表疾病，包括GVHD、Sjogren综合征、Stevens-Johnson综合征和暴露性角膜炎等[37-39]，它可以减少泪液蒸发，为眼表提供恰当的湿度，对改善眼表环境有重要作用。巩膜镜一直被证明对患者的舒适度和视觉功能有益，而且使用巩膜镜的并发症被认为是罕见且轻微的。一篇关于300余例巩膜镜佩戴者并发症的综述[40]描述到，佩戴巩膜镜最常见的并发症是角膜新生血管(13.3%)、角膜水肿(7.4%)、角膜磨损(3.1%)和巨乳头状突起、结膜炎(1.7%)等。除了这些相对发病率较高的并发症外，还有关于巩膜镜片佩戴者感染的病例报道，包括棘阿米巴角膜炎[41]和多种微生物和微孢子虫感染[42]，虽然是少数病例，但是仍然值得引起眼科医师注意。

4.2 手术治疗

4.2.1 泪点塞
泪点塞是一种先进的干眼治疗方法，它们通过阻塞上眼睑和下眼睑的泪点来起作用，以帮助保持眼表面上泪液量。北京协和医院眼科医院阳雪等[43]纳入28例56眼严重干眼患者，进行泪点塞治疗效果自身前后的对比实验。这28例严重干眼患者接受弹性硅泪点塞治疗，发现与治疗前基线对比，治疗3个月后患者症状及体征得到极大改善，而且这种治疗可以部分缓解患者的焦虑和抑郁。泪点塞使用安全，除局部不适外，没有发现溢泪，局部炎症反应，小管性化脓性肉芽肿等并发症[44]。但Ervin等[45]的研究却有相反的结果，他们搜索了2016年之前发表的来自各个国家关于泪点塞的所有文献，发现泪点塞无法最终改善干眼症状，也没有明确证据证明泪点塞优于口服毛果芸香碱或局部滴用眼药水如CyA、人工泪液等。该研究还得出泪点塞可能与溢泪有关，有时伴有更严重的情况，如泪囊内的感染或肿胀等。目前关于泪点塞使用的有效性及安全性仍不明确，需要更多研究来证明。
4.2.2 眼睑缝合术
对于角膜溃疡经久不愈、经常穿孔的cGVHD-DE的患者，可以采用眼睑缝合术。它是一种减少泪液蒸发的方法，并能有效保护角膜及结膜。
4.2.3 多层羊膜移植术和穿透性角膜移植术
因为其可能发生复杂的免疫过程，所以allo-HSCT患者角膜和羊膜移植相关的风险可能高于非造血干细胞移植的患者。而且羊膜移植对cGVHD角膜穿孔患者只有短期疗效，大多数患者要进行再次的穿透性角膜移植术。

4.3 有研究前景的治疗方案

4.3.1 维生素 A
有研究[46]发现血清维生素A水平与cGVHD-DE患者眼部表现的严重程度有关。血清维生素A浓度越低，cGVHD-DE的眼部评分就会越高，而眼局部使用维生素A软膏治疗后，眼部评分就会下降，这些结果表明维生素A参与了与cGVHD-DE相关的眼部表现的发病机制。也增加了一种治疗的可能性，全身补充维生素A或者局部维生素A眼药水眼膏的使用可能会改善cGVHD-DE的症状及体征。
4.3.2 自体血小板裂解液
自体血小板裂解液(platelet lysate，PL)滴剂的长期治疗对于cGVHD-DE是安全有效的，并且从cGVHD-DE的初始阶段开始可以是有效的治疗选择，可以防止永久性眼部损伤和改善患者的生活质量[47]。与A S滴剂相比，PL滴剂有更高水平的生长因子，因为其从生长因子更丰富的血小板中获得，浓度通过诱导PL的冻融方案进一步增加。特别是较高水平的EGF能增强角膜上皮细胞的增殖和迁移、加速伤口愈合。此外，与AS滴剂相比，在PL滴剂中检测到更高水平的FGF、转化生长因子-β(transforming growth factor-β，TGF-β)和PDGF，可以促进成纤维细胞的增殖和迁移活性。使用时从患者中抽取40 mL抗凝外周血并以900 r/min离心以获得富含血小板的血浆。然后，将其用无菌盐水溶液稀释使终浓度为30%(v/v)，并等分于1.5 mL无菌小瓶中，在?80 ℃下冷冻至少60 min后在4 ℃解冻，以诱导血小板溶解和PDGF释放。然后将最终产物在?20 ℃下再次冷冻并储存在患者自己的冰箱中最多45 d。将每个小瓶解冻后最多使用24 h，每天滴眼4次[48]。
4.3.3 细胞疗法
细胞疗法是治疗难治性眼病的有前景的方法。间充质基质细胞(mesenchymal stromal cells，MSCs)具有不影响宿主保护性免疫应答的免疫调节特性。它们具有多向分化能力，并且正在成为一种有希望的增强移植耐受性的治疗方式[49-51]。研究表明通过静脉注射MSCs能改善cGVHD-DE患者的临床症状、干眼评分、眼表疾病指数评分和Schirmer I test的结果[52]。MSCs可能通过触发CD8+ CD28? T细胞的产生来调节Th1和Th2之间的平衡发挥其作用。cGVHD-DE是一种炎症和纤维化过程，MSCs通过调节局部和全身性炎症反应来发挥潜在的治疗作用，并且可能导致与cGVHD-DE的完全消退。
4.3.4 重链透明质酸/穿透素
重链透明质酸(heavy chain-hvaluronan，HC-HA)/穿透素(pentraxin 3，PTX3)是一种从人羊膜中提纯的复合物，具有抗炎及抑制瘢痕形成的作用。有研究[53]利用cGVHD-DE的小鼠模型实验来验证HC-HA/PTX3是否对cGVHD-DE小鼠有改善眼部相关体征及抑制炎症和结膜瘢痕形成的作用。结果表明其皮下或结膜下注射或可提高cGVHD-DE鼠的泪液分泌量和结膜杯状细胞密度，还可以抑制炎症反应及抑制结膜瘢痕形成。
4.3.5 抑制纤维化相关药物
Ogawa等[54]发现泪腺区活化的成纤维细胞高表达HSP47；Yamak awa等[55]观察到cGVHD小鼠滴用HSP47拮抗剂后，成纤维细胞中HSP47表达受到抑制，泪腺纤维化和干眼症状均减轻。对细胞因子的研究[56-57]发现TGF-β及IL-6在cGVHD患者皮肤、肺和肝纤维化中起重要作用；国外学者实验[58]证明cGVHD-DE患者局部滴用TGF-β抑制剂曲尼司特后症状较对照组显著改善；cGVHD模型小鼠在使用 IL-6 拮抗剂 MR16-1 后泪腺纤维化减轻[59]，推测IL-6、TGF- β拮抗剂在抑制cGVHD-DE纤维化中具有应用前景。

5 总结

综上所述，虽然allo-HSCT的适应证在逐渐扩大，拯救了很多血液病患者，但是cGVHD仍是导致术后预后不良的主要原因，因此如何减少cGVHD所带来的负面效果成了当今的研究热点。尽管allo-HSCT术后cGVHD-DE的发生率已有很多研究报道，但对其长期眼部并发症和预后的研究报道较少。此外，目前虽然有了一些针对cGVHD-DE的治疗方法，但效果不佳，没有非常理想的治疗方案。尽管很多研究表明诸如FK506等药物可改善患者预后，但该治疗均是在泪腺和结膜组织发生永久性损害之后才开始实施的，预防性治疗措施尚少。因此还需要收集更多cGVHD-DE的长期预后资料，以便对其治疗性和预防性方案进行疗效评价。

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1、海南省重点研发计划 (ZDYF2020151)；海南省临床医学中心。
This work was supported by the Hainan Key Research and Development Plan (ZDYF2020151) and Hainan Province Clinical Medical Center, China.()
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发布于: 2022-12-01
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