复发性流产（recurrent spontaneous abortion，RSA）定义为与同一性伴侣发生连续2次或2次以上的自然流产，其病因十分复杂，除遗传性、内分泌性、感染和解剖性等原因外，免疫因素也是其重要的病因。大约50%的RSA根本原因仍然未知，80%原因不明的流产与免疫因素密切相关[1]。随着生殖免疫学研究的不断深入，学者们对妊娠免疫、免疫性不孕及RSA等的许多疑难问题有了新的认识，逐渐确定免疫因素在生殖过程中的重要作用。有研究表明，免疫疗法和细胞疗法在改善妊娠结局和活产率方面具有良好的效果[2]。淋巴细胞免疫治疗（lymphocytes immunotherapy， LIT）是一种主动形式的免疫疗法，已在多项试验中被证明可显著增强母体免疫平衡和妊娠结局。LIT的主要目标是调节免疫系统，以便为胚胎植入创造有利的耐受性免疫环境，从而改善RSA患者的妊娠结局[3]。现对近年LIT的研究进展，对淋巴细胞免疫的作用机制、LIT的有效性和安全性进行综述。
1 LIT的概念
LIT是妊娠前将丈夫或无关第三者的淋巴细胞注入患者皮下，刺激母体的免疫耐受机制，促进封闭抗体（blocking antibody）的产生，有效阻止胚胎父系抗原被母体免疫系统杀伤，从而有效保护胚胎，在进行反复注射刺激后，可提高免疫记忆，从而提高再次妊娠成功率[4]。许多研究人员认为，免疫疗法是提高RSA患者活产率的有用策略[5]。大多数不明原因复发性流产（unexplained recurrent spontaneous abortion，URSA）患者免疫系统失衡，母体与胚胎存在免疫冲突，该疗法缓解患者免疫失衡状态，减轻母体对胚胎的排斥，使胎儿存活率显著上升[6]。有研究显示，在对RSA患者进行主动免疫治疗时，患者体内的淋巴细胞、自然杀伤细胞（natural killer cell，NK细胞）具有调节作用，能明显提高封闭抗体及混合淋巴细胞反应封闭因子水平，同时，通过调节患者T淋巴细胞水平能够促进抗体的分泌[7]。自20世纪80年代给RSA患者注射淋巴细胞进行免疫治疗开始，陆续有很多学者对此方法进行了研究，对其临床效果褒贬不一。目前对于LIT治疗RSA仍有很大的争议。2012年美国生殖医学会（American Society for Reproductive Medicine，ASRM）指南认为LIT治疗没有有益效果[8]。Wong等[9]的回顾性研究发现LIT在改善RSA妇女的活产率或降低未来流产风险方面均未表现出比安慰剂显著的有益效果。2018年欧洲生殖和胚胎医学会（European Society of Human Reproductive and Embryonic Medicine，ESHRE）指南认为LIT不应用于不明原因的反复妊娠丢失（recurrent pregnant loss，RPL）的治疗，因为其没有显著的效果，并且可能存在严重的不良反应[10]。但是Cavalcante等[11]检索了6项已发表的荟萃分析说明，尽管有2项研究发现在RSA治疗中使用LIT后活产率没有改善，但仍有4项研究发现在RSA病例中使用LIT的有益效果，活产率显著改善。Sarno等[12]报告的数据显示，相对于无LIT治疗组而言，LIT组的妊娠成功率显著提高（60.1% vs. 33.1%，P<0.001）。2022年刘小立[13]的研究也发现，LIT能显著提高RSA患者的封闭抗体转阳率、妊娠成功率以及成功转阳患者的T细胞封闭效率。
2 LIT的作用机制
2.1 封闭抗体转阳
正常妊娠其实是一种半同种移植，胎儿之所以不被母体免疫系统所排斥，与母胎界面生理性抑制反应增强有关。这种免疫状态又称为母胎免疫耐受，有学者认为这种免疫耐受主要与封闭抗体相关[14]。正常孕妇血清中的封闭抗体可以与胚胎滋养细胞抗原或母体淋巴细胞结合，防止胚胎携带的父系抗原被母体免疫系统识别和杀死。如果没有封闭抗体产生，母体将无法对胚胎半抗原形成免疫耐受，这可能导致母体排斥胚胎，将其当作异物，导致妊娠失败[13]。LIT能有效促进封闭抗体的产生，从而抵抗母体对胎儿的排斥，成功妊娠。史晓艳等[15]研究表明，用LIT治疗封闭抗体阴性RSA患者，封闭抗体阳性率明显增加，相对封闭抗体阴性患者，封闭抗体阳性患者的妊娠成功率明显较高（90.0% vs. 57.14%）。丁桂春等[16]给予112例RSA患者LIT后，83例封闭抗体阳性，转阳率为74.1%；101例（90.1%）成功受孕；封闭抗体阳性组妊娠79例（95.2%），60例孕足月分娩，表明LIT确实可以提高封闭抗体阴性RSA患者的封闭抗体转阳率，封闭抗体有助于母体对胎儿形成免疫耐受，从而提高妊娠率。
2.2 改善T淋巴细胞亚群比例
2.2.1 Th1/Th2细胞
Th1细胞产生促炎细胞因子，如肿瘤坏死因子α（tumor necrosis factor-α，TNF-α）、TNF-β、γ干扰素（interferon-γ，IFN-γ）、白细胞介素-1（interleukin-1，IL-1）、IL-2等，参与细胞免疫和排斥过程。Th2细胞产生抗炎细胞因子，如IL-4、IL-5、IL-6、IL-10、IL-12等，其刺激B细胞产生抗体并对抗Th1型细胞因子[17]。因此，对于正常妊娠来说，Th1细胞是有害的，而Th2细胞有益于妊娠过程的维持。王红宇等[18]对150例URSA患者给予主动免疫治疗，治疗组治疗后血清IFN-γ水平较治疗前显著下降、IL-4水平明显升高，表明LIT可明显提高Th2型细胞因子并下调Th1型细胞因子，纠正母体免疫紊乱状态，使得妊娠成功。Liu等[19]的研究发现，免疫治疗组64例RSA患者中有33例（51.56%）Th1细胞异常增加，14例（21.88%）Th2细胞异常减少；免疫治疗后RSA患者异常Th1细胞的比例较治疗前显著降低，Th2细胞的比例显著增加，说明主动免疫改善了T淋巴细胞的比例。2021年的一项研究对RSA患者、正常分娩者的Th1型细胞因子、Th2型细胞因子进行分析，结果显示，RSA组IL-2、IFN-α、IFN-γ高于正常分娩组（P<0.05），IL-4、IL-10低于正常分娩组（P<0.05）[20]。表明RSA患者的Th1细胞增多，Th2细胞减少，导致母胎免疫失衡，妊娠失败。而LIT治疗确实可以通过上调Th2型细胞因子、下调Th1型细胞因子来改善RSA患者的Th1细胞与Th2细胞的平衡，使其朝向更有利于妊娠的方向发展。
2.2.2 Th17/调节性T细胞（regulatory T cell，Treg细胞）
目前有许多研究认为，由于Th17细胞过多或Treg细胞缺乏而导致的Th17和Treg细胞失衡可导致RPL和许多其他妊娠期疾病[21]。Th17在妊娠过程中发挥负性调控作用，对妊娠不利，Treg细胞则有利于减轻母体对胎儿的排斥[22-23]。Li等[24]发现与正常妊娠小鼠相比，流产小鼠中Treg细胞的百分比显著降低（4.29% vs. 8.28%，P<0.05），相反，流产组Th17细胞水平高于正常妊娠组（4.38% vs. 2.52%，P<0.05）。Wu等[25]的一项研究发现，与LIT前的细胞因子浓度相比，免疫治疗后Th17型细胞因子IL-17A的浓度显著降低，Treg型细胞因子TGF-β显著高于免疫治疗前的浓度，与免疫治疗前相比，免疫治疗后Th17/Treg细胞因子的比例显著降低。张小玲等[26]发现，对患者实施主动免疫治疗可升高Treg型细胞因子叉头框蛋白p3（forkhead box p3，Foxp3）以及细胞因子IL-35水平，并且还可降低Th17型细胞因子IL-17A以及转录因子视黄酸相关孤儿受体γt（retinoid-related orphan nuclear receptor-γt，ROR-γt）水平。张维平等[27]的一项回顾性研究发现，妊娠12周，主动免疫组Treg细胞比率、Treg/Th17比值高于非免疫组，Th17细胞比例低于非免疫组（P<0.05），主动免疫组妊娠率高达98.04%，保胎成功率为92.16%，表明LIT可显著改善URSA妊娠结局。这些研究充分表明了LIT治疗是通过给予外来淋巴细胞使母体免疫功能激活和强化，增加保护性淋巴细胞和细胞因子的分泌，抑制对妊娠有害的细胞和细胞因子。
2.3 降低NK细胞活性
研究表明，NK细胞直接参与胚胎植入，外周血和子宫内膜层NK细胞的毒性增高与生殖失败有关[4]。当母胎界面中的细胞间对话被破坏时，蜕膜自然杀伤细胞（decidual natural killer cell，dNK细胞）的成熟不足会导致免疫耐受性的下调和细胞毒性的上调。免疫失衡会诱发一系列妊娠并发症，如滋养层侵袭不足和蜕膜血管重塑缺陷，最终可能引发URSA[28]。王和坤等[29]给患者使用其丈夫或健康者外周血进行LIT，抽取患者外周血2 mL，用流式细胞仪测定细胞中的CD3/CD16+CD56，结果发现，CD3/CD16+CD56明显下降，表明主动免疫治疗能够减轻患者的免疫紊乱，减少对胚胎的免疫排斥，最终达到较高的妊娠率。赵花等[30]发现RSA患者进行LIT后外周血淋巴细胞免疫表型发生了明显的改变，CD3-CD56+NK细胞和CD4+T细胞比例降低，表明LIT能明显降低NK细胞的比例，减弱NK细胞的毒性，有利于妊娠。以上研究均表明了LIT能通过降低NK细胞的毒性改善妊娠环境，提高妊娠率。
3 LIT的安全性和风险
目前，临床上仍对给RSA患者注射异体淋巴细胞存在争议。虽然目前对主动免疫治疗的有效性比较确定，该疗法能明显提高RSA患者的妊娠率和活产率，但对其安全性的系统研究相对较少，所以有一些学者不推荐将LIT作为URSA患者的常规治疗方案，除非在取得患者知情同意的情况下进行规范化的临床试验[31]。LIT的常见局部不良反应主要是轻度疲劳，头痛或头晕，注射部位有红斑、瘙痒、肿胀和水疱等，但这些都是比较轻微的症状，持续时间一般不超过一个月[32]。除此之外，LIT的常见全身不良反应有流感样症状，输血反应（包括发热）和病毒传播（乙型肝炎病毒和巨细胞病毒）[4]，但这些不良反应都是可以预防的，一般来说这些局部不良反应不会对母体和胎儿造成生命影响。一项长期随访调查表明皮内LIT的急性不良反应对免疫功能正常的育龄妇女并不严重，LIT的不良反应类似于注射疫苗，没有直接证据表明过敏反应、移植物抗宿主反应或自身免疫是由皮内LIT引发的[33]。LIT与输注血制品类似，存在传播感染因子的风险，2000—2003年，随访调查3 246例接受LIT治疗的RSA患者，7例患者报告感染性疾病，分别为治疗后1个月内出现唇疱疹（5例）和3.5个月、4个月出现感染性单核细胞增多症（2例），还没有胎儿感染病毒的报告[34]。但2016年12月30日浙江杭州某医院进行LIT期间发生了潜在的人类免疫缺陷病毒（human immunodeficiency virus，HIV）疫情，这次事件导致34例接受LIT治疗的患者处于HIV暴露风险中，5例患者诊断为急性HIV感染[35]。在此次事件中，造成HIV感染的主要原因是未充分检查淋巴细胞供体的身体状况、收集完样本之后未做到专管专用，以及工作人员没有及时记录。
鉴于由主动免疫治疗产生的不良反应，研究者们采取了严格的纳入和排除标准。一般能够接受LIT的女性包括：有2次及2次以上自然流产史、封闭抗体阴性、无子宫畸形、无多囊卵巢综合征等解剖结构异常因素、内分泌正常、夫妇外周血染色体核型正常、并且排除了其他原因导致的RSA患者，免疫功能异常的患者不能接受LIT[13,15]。对于父方或者提供淋巴细胞的第三方也有严格的要求，伴有乙型病毒性肝炎、梅毒、丙型病毒性肝炎及艾滋病等感染性疾病者不能提供淋巴细胞[36]。目前来看主动免疫治疗的局部不良反应都是注射当时造成的短期影响，并未对患者和胎儿造成伤害。作为一种类似输血的治疗方式，LIT存在的制剂污染、病毒传播以及过敏反应等均可以在治疗过程中预防和积极处理。对于主动免疫治疗本身来讲，LIT治疗利大于弊，应优化RSA患者的治疗方案，严格把控淋巴细胞的制备流程，积极探索LIT的潜在价值。
4 结语
回顾封闭抗体与LIT的相互关系、LIT治疗的有效性和安全性发现，对封闭抗体阴性的RSA患者，LIT确实能改善其妊娠率。但是，目前对LIT的作用机制还没有完全研究清楚，仍处于探索阶段，且在治疗过程中主动免疫治疗的方式、淋巴细胞的输注量、淋巴细胞的保存期限、免疫接种的频率均没有统一的规定，所以不同研究中的结果也各不相同。因此，对于URSA患者，在排除其他可能的致病因素后，可根据患者的情况和意愿，综合考虑利弊，制定个体化的LIT治疗方案，以期获得最大的益处。
参考文献
Recent Advances in Treatment of Recurrent Spontaneous Abortion
[J].
DOI:10.1097/OGX.0000000000001033
PMID:35672876
[本文引用: 1]
Recurrent spontaneous abortion (RSA) is a distressing condition experienced by approximately 1% of women trying to conceive. However, the treatment of RSA is a challenge both for clinicians and patients.The aim of this review is to discuss the medical and surgical approach to the management of RSA, including those caused by anatomical, genetic, male, infectious, endocrine, and immune factors.A literature search using MeSH terms for each topic was undertaken using PubMed, supplemented by hand searching for additional references. Retrieved articles were reviewed, synthesized, and summarized.Available treatments target hypothetical risk factors for RSA, although the effectiveness of many treatment options is controversial. Intervention should depend on the benefit-to-risk ratio of the proposed treatment.The etiology of RSA is heterogeneous, and patients often lack specific clinical manifestations, which has hindered the progress in predicting and preventing RSA to some extent. Despite intensive workup, at least 50% of couples do not have a clear underlying pathology. In addition, an evidence-based treatment is not available in most patients even if abnormal test results are present. Many new treatment directions are also still actively exploring; empirical and combined multiple treatments are still the main methods.
The Impact of New Immunological Therapeutic Strategies on Recurrent Miscarriage and Recurrent Implantation Failure
[J].
DOI:10.1016/j.imlet.2021.05.008
PMID:34090942
[本文引用: 1]
Maternal-fetal immune dysregulation is one of the risk factors that increases the probability of embryo rejection and reproductive failure. The stimulation of immunological tolerance and suppression of immunological rejection are prerequisites for protecting embryos and preventing immunological attacks. Hence, it appears that immunomodulatory and immunosuppressive therapies can manage reproductive failures by controlling immune cells. The current medical literature has shown that immunotherapy approaches and cell therapy have promising results in improving pregnancy outcomes and live birth rates. These outcomes are obtained by regulating maternal immune responses, and exerting positive effects on human reproductive processes.Copyright © 2021 Elsevier Ltd. All rights reserved.
Allogeneic lymphocytes immunotherapy in female infertility: Lessons learned and the road ahead
[J].DOI:10.1016/j.lfs.2022.120503 URL [本文引用: 1]
Lymphocyte immunotherapy in recurrent miscarriage and recurrent implantation failure
[J].DOI:10.1111/aji.13408 [本文引用: 3]
Clinical effect of lymphocyte immunotherapy on patients with unexplained recurrent spontaneous abortion
[J].DOI:10.1002/iid3.474 URL [本文引用: 1]
主动免疫治疗对不明原因早期复发性自然流产患者妊娠结局的影响
[J].DOI:10.14164/j.cnki.cn11-5581/r.2021.24.026 [本文引用: 1]
血清维生素D、sPD-L1及HCG与复发性流产主动免疫治疗预后的关系研究
[J].DOI:10.3969/j.issn.1673-4130.2020.18.022 [本文引用: 1]
Evaluation and treatment of recurrent pregnancy loss: a committee opinion
[J].
DOI:10.1016/j.fertnstert.2012.06.048
PMID:22835448
[本文引用: 1]
The majority of miscarriages are sporadic and most result from genetic causes that are greatly influenced by maternal age. Recurrent pregnancy loss (RPL) is defined by two or more failed clinical pregnancies, and up to 50% of cases of RPL will not have a clearly defined etiology.Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
Immunotherapy for recurrent miscarriage
[J].DOI:10.1002/14651858.CD000112.pub3 [本文引用: 1]
ESHRE guideline: recurrent pregnancy loss
[J].DOI:10.1093/hropen/hoy004 [本文引用: 1]
Lymphocyte immunotherapy in the treatment of recurrent miscarriage: systematic review and meta-analysis
[J].
DOI:10.1007/s00404-016-4270-z
PMID:28004193
[本文引用: 1]
Recurrent miscarriage (RM) affects up to 2-3% of couples of reproductive age. There are several causes for this condition, including immunologic. The embryo is considered an allograft, subject to the rejection mechanisms of the maternal immune system. Immunotherapy involving immunization with lymphocytes is considered in cases of idiopathic RM. However, there is still no consensus regarding the efficacy and safety of this therapy.This systematic review and meta-analysis evaluated the data available in the literature regarding the efficacy and safety of the use of immunotherapy with lymphocytes in couples with history of RM. Searches in PubMed/Medline, SCOPUS, and Cochrane Library databases were conducted, using the following keywords: "recurrent miscarriage," "lymphocyte immunotherapy," and "meta-analysis." Statistical analyses were performed using Review Manager 5.3 (RevMan), version 5.3.Six published meta-analysis were retrieved; two found no improvements in the rate of live births after the use of immunization with lymphocytes in the treatment of RM, and four found a beneficial effect of the use of immunotherapy with lymphocytes in cases of RM, with significant improvements in the rate of live births.Data available in the literature supports the efficacy and safety of immunotherapy with lymphocytes in cases of RM without an identified cause.
Gestational and perinatal outcomes in recurrent miscarriages couples treated with lymphocyte immunotherapy
[J].DOI:10.1016/j.eurox.2019.100036 URL [本文引用: 1]
淋巴细胞主动免疫疗法治疗封闭抗体阴性复发性流产患者的效果
[J].DOI:10.3969/j.issn.1672-0369.2022.10.018 [本文引用: 3]
淋巴细胞主动免疫治疗对封闭抗体阴性复发性流产后患者外周血Th1/Th2/Th17细胞因子表达水平变化
[J].DOI:10.3969/j.issn.1000-7377.2017.10.036 [本文引用: 2]
主动免疫治疗封闭抗体阴性复发性流产的临床观察
[J].DOI:10.3969/j.issn.1004-8189.2018.08.026 [本文引用: 1]
Characterization of the subsets of human NKT-like cells and the expression of Th1/Th2 cytokines in patients with unexplained recurrent spontaneous abortion
[J].
DOI:10.1016/j.jri.2015.05.001
PMID:26057526
[本文引用: 1]
The objective was to investigate the subsets of natural killer T (NKT)-like cells and the expression of Th1/Th2 cytokines in the peripheral blood (PB) and/or decidual tissue of patients with unexplained recurrent spontaneous abortion (URSA). The percentages of NKT-like cells in the PB and deciduas of URSA patients in early pregnancy and in the PB of nonpregnant women were analyzed by flow cytometry. The expression of interferon (IFN)-γ (Th1 cytokine) and Th2 cytokines, interleukin (IL)-4 and IL-10, in the PB and decidual tissue was measured by quantitative RT-PCR and enzyme-linked immunosorbent assay (ELISA). Most percentages of subsets of NKT-like cells (CD3(+)CD56(+), CD3(+)CD56(+)CD16(+)) in the PB and deciduas were significantly greater in URSA patients than in normal pregnant and nonpregnant women. A cut-off value of 3.75% for the increased percentage of CD3(+)CD56(+)CD16(+) NKT-like cells in the PB appeared to be predictive of pregnancy failure. Moreover, we found that in the decidua, IFN-γ expression was significantly higher, while IL-4 and IL-10 expression was significantly lower in URSA patients compared with those with a normal pregnancy. The ratio of decidual Th1/Th2 cytokines in URSA patients was significantly increased compared with that in normal pregnant women. Decidual IL-4 expression correlated negatively with the percentages of blood CD3(+)CD56(+)CD16(+) NKT-like cells and the decidual CD3(+)CD56(+) and CD3(+)CD56(+)CD16(+) NKT-like cells. NKT-like cells may play an important role in maintaining normal pregnancy. Measurement of CD3(+)CD56(+)CD16(+) NKT-like cells in the PB may provide a potential tool for assessing patients' risk of spontaneous abortion. Copyright © 2015. Published by Elsevier Ireland Ltd.
Th1/Th2型细胞因子与原因不明复发性流产的相关性研究
[J].DOI:10.14172/j.issn1671-4008.2017.03.008 [本文引用: 1]
Low-dose lymphocyte immunotherapy rebalances the peripheral blood Th1/Th2/Treg paradigm in patients with unexplained recurrent miscarriage
[J].DOI:10.1186/s12958-017-0315-9 URL [本文引用: 1]
复发性流产患者Th1/Th2型细胞因子的表达分析
[J].DOI:10.3969/j.issn.1004-4337.2021.01.018 [本文引用: 1]
The role and mechanism of vitamin D-mediated regulation of Treg/Th17 balance in recurrent pregnancy loss
[J].DOI:10.1111/aji.13112 URL [本文引用: 1]
CaMK4 promotes abortion-related Th17 cell imbalance by activating AKT/mTOR signaling pathway
[J].DOI:10.1111/aji.13315 [本文引用: 1]
辅助性T细胞17和调节性T细胞相关细胞因子在不明原因复发性流产中的变化及意义
[J].DOI:10.11655/zgywylc2019.08.023 [本文引用: 1]
The role of Th17/Treg-mediated immunoregulation in abortion mice
[J].DOI:10.1177/2058739218760354 [本文引用: 1]
Alteration of Th17 and Treg cells in patients with unexplained recurrent spontaneous abortion before and after lymphocyte immunization therapy
[J].DOI:10.1186/1477-7827-12-74 URL [本文引用: 1]
淋巴细胞主动免疫治疗对原因不明性复发性流产患者Treg及Th17细胞因子的影响
[J].DOI:10.3969/j.issn.1000-744X.2020.10.013 [本文引用: 1]
主动免疫治疗对原因不明性复发性流产患者Treg/Th17免疫平衡的影响
[J].DOI:10.13390/j.issn.1672-1861.2021.03.009 [本文引用: 1]
Polarization disorder of decidual NK cells in unexplained recurrent spontaneous abortion revealed by single-cell transcriptome analysis
[J].
DOI:10.1186/s12958-022-00980-9
[本文引用: 1]
Unexplained recurrent spontaneous abortion (URSA) is one of the most common diseases in pregnancy and is mainly caused by immune disorders. The foetus is similar to semiallogeneic maternal tissue, so the balance of immune tolerance must be dynamically maintained during pregnancy. Decidual natural killer (dNK) cells primarily mediate the immune tolerance microenvironment at the maternal–fetal interface. By using single-cell RNA sequencing (scRNA-seq) and high-throughput transcriptome sequencing analysis, we explored the characteristic distribution of dNK cells in URSA patients.
NK细胞在不明原因复发性流产诊治研究中的意义
[J].DOI:10.3969/j.issn.1004-5775.2015.06.003 [本文引用: 1]
复发性流产患者主动免疫治疗后淋巴细胞免疫表型的变化
[J].DOI:10.3969/j.issn.1004-3845.2014.06.005 [本文引用: 1]
自然流产诊治中国专家共识(2020年版)
[J].
DOI:10.19538/j.fk2020110113
[本文引用: 1]
自然流产（spontaneous abortion，SA）是妇产科最常见的妊娠并发症之一。育龄期女性发生1次SA的风险为10%左右［1］。复发性流产（recurrent spontaneous abortion，RSA）的发生率为1%～5%［2］，RSA的复发风险随着流产次数的增加而上升。曾有3次以上连续自然流产史的患者再次妊娠后胚胎丢失率为40%～80%［3］。如果不及时干预，不仅会给患者及其家庭带来严重的经济负担，而且还将对患者的身心健康造成极大的影响。浏览更多请关注本刊微信公众号及当期杂志。
Adverse drug reactions following lymphocyte immunotherapy for the treatment of infertility: A retrospective study
[J].DOI:10.1111/jog.15348 URL [本文引用: 1]
Adverse effects of intradermal allogeneic lymphocyte immunotherapy: acute reactions and role of autoimmunity
[J].
DOI:10.1093/humrep/dei316
PMID:16210388
[本文引用: 1]
Immunotherapy with allogeneic lymphocytes was introduced as a therapeutic option for selected infertile couples in different centres worldwide 20 years ago. It has been suggested for other indications as well, e.g. for pregnant women at risk of a child with Rhesus-D haemolytic disease, or as a vaccine which might reduce the receptiveness for HIV-1 infection. Here we report on our experience on adverse side-effects of intradermal lymphocyte immunotherapy (LIT) for infertile couples using partner's lymphocytes.Prospective 4 week follow-up of all couples from 2000 to 2003 for acute reactions (feedback 2687/3246 [corrected] 83%). All couples treated between 1996 and 2002 received questionnaires after 2-3 years (feedback 1914/3041, 63%).Local reactions predominantly consisted of redness and itching for approximately 2 weeks. Systemic reactions could be attributed to LIT in 6-8%. Blisters at the injection sites were characteristic of LIT but not dependent on the HLA class I mismatch status between cell donor and host. The incidence of autoimmune disease was 0.1%. Four patients developed thromboembolism in pregnancy which was not ascribed to antiphospholipid syndrome.Acute side-effects are comparable to those reported after intradermal vaccination for infectious diseases. Specific risks for anaphylaxis, autoimmune or graft versus host disease were not detected.
Transfusion-related risks of intradermal allogeneic lymphocyte immunotherapy: single cases in a large cohort and review of the literature
[J].
DOI:10.1111/j.1600-0897.2006.00413.x
PMID:16911711
[本文引用: 1]
Lymphocyte immunotherapy (LIT) is applied in infertility treatment. Moreover, it has been suggested for prevention of rhesus D-hemolytic disease and as a vaccine for reduction of human immunodeficiency virus-1 susceptibility. Although transfusion-related problems have been rarely reported they were a matter of debate. Here we discuss extensive single-center experience with intradermal LIT for implantation failure and recurrent miscarriages.Retrospective 2- to 3-year follow-up of in vitro fertilization couples treated during 1996-2002 (feedback 2,848/3,041 = 93%), registering 930 deliveries. Prospective survey for acute reactions for 2000-2003 (feedback 2,687/3,246 = 83%). Review of the literature.Infections of the patient and transplant rejection later in life are minor residual risks. Post-transfusion purpura was suspected once but not verified. Anaphylaxis or malignancy were not promoted. Fetal/newborn alloimmune disease (severe hemolytic disease, thrombocytopenia, neutropenia) were not observed.Based on microbiological, immunological, and hematological testing the risks of intradermal LIT are low.
Outbreak of HIV Infection Linked to Nosocomial Transmission, China, 2016-2017
[J].
DOI:10.3201/eid2412.180117
PMID:30457542
[本文引用: 1]
On January 25, 2017, a physician from ZC Hospital in Hangzhou, China, reported to the Zhejiang Provincial Center for Disease Control and Prevention that a potential HIV outbreak might have occurred during lymphocyte immunotherapy (LIT) performed at the hospital on December 30, 2016. We immediately began investigating and identified the index case-patient as an LIT patient's husband who donated lymphocytes for his wife's LIT and later screened HIV-reactive. Subsequent contamination by a technician resulted in the potential exposure of 34 LIT patients. Acute HIV infection was diagnosed in 5 persons. Phylogenetic analysis confirmed that the HIV-1 gag, pol, and env gene sequences from the index and outbreak-related cases had >99.5% similarity. Rapid investigation and implementation of effective control measures successfully controlled the outbreak. This incident provides evidence of a lapse in infection control causing HIV transmission, highlighting the need for stronger measures to protect patients from infectious disease exposure.
早期免疫治疗对不明原因复发性流产患者IL-2和IL-10水平的影响
[J].DOI:10.19829/j.zgfybj.issn.1001-4411.2021.21.031 [本文引用: 1]
