淋巴免疫活疗治疗复发性流产理论不清

在最近浙江省中医院违规操作引发多人感染艾滋病毒的热点事件中，流传出的多条相关信息暗示，这起事件牵涉一种名为“封闭抗体免疫疗法”的治疗手段。这种疗法的有效性随即引起了医疗界人士的激烈争论。

这是一种什么疗法，它的疗效到底如何呢?封闭抗体免疫疗法是干什么的?

这里的“封闭抗体免疫疗法”，又叫“主动免疫疗法”或者“淋巴细胞免疫疗法”。如果你上网检索，会看到对它原理和操作的大致描述是这样的：“……这些患者的流产次数越多，体内免疫系统紊乱越严重，若没有针对性有效的免疫干预，她们很难有机会成为母亲。自1981年Taytor和Beer等创立了淋巴细胞主动免疫疗法，国内外不同学者对原因不明性反复自然流产患者进行淋巴细胞免疫治疗后，妊娠成功率达72.73%~86.2%。…………治疗时医务人员抽取丈夫体内一定量外周血进行离心沉淀机淋巴细胞分离、培养，再回输到妻子的前臂皮内。每4周一个循环，一直做到怀孕四五个月以后，确保妻子正常怀孕!”​[1]

在中国，不少医院都在开展这种治疗。它的疗效到底如何呢?

答案很简单：目前科学证据表明，这种疗法无效，早在2002年就在美国被FDA彻底叫停。

不明原因的反复流产就是指进行了染色体、感染、内分泌、代谢、凝血相关和解剖等一系列检查之后，仍无法发现病因的情况。由于这种不确定性，医生对于检查和相应治疗的意义也有不同理解。同样由于这个原因，也给一些鱼目混珠的骗子提供了发挥空间。这对患者来说确实很难。

最近一篇国际权威性综述文章比较准确的描述了淋巴免疫活疗治疗反复自然流产的状况 – 理论不清，治疗效果不明确, 副作用大，需谨慎使用。

Recurrent Pregnancy Losses and the Role of Immunotherapy. Review Article, Arch Gynecol Obstet (2000) 264:3-12

Charles A. Omwandho, Hans R. Tinneberg, Aloys G. Tumbo-Oeri, Timothy K. Roberts, John Falconer,) C.A. Omwandho · A.G. Tumbo-Oeri Department of Biochemistry, University of Nairobi, Kenya H.R. Tinneberg (.) Department of Obstetrics and Gynecology, Institute of Reproductive Medicine, Rosenh?he Hospital, An der Rosenh?he 27, D-33647 Bielefeld, Germany T.K. Roberts Biological Sciences Department, The University of Newcastle, Australia J. Falconer Discipline of Reproductive Medicine, The University of Newcastle, Australia

要点如下：

免疫活疗仍然充满矛盾和问题。

Abstract Post implantation pregnancy losses are psychologically and economically stressful to the childbearing population. The etiology in the vast majority of cases is unknown but is partly thought to result from a breakdown of the maternal tolerance to the fetoplacental unit. Immunologically based therapy remains controversial but no alternative therapy is available at the moment. This article reviews the conceived immunological basis of recurrent pregnancy losses, discussing the controversies arising, and recommending the use of intravenous immunoglobulin, IVIg, in well controlled experiments for further clinical trials.

RSA发病率在孕妇中为 1-2%，绝大部分病案病因不清，几种理论并存。

Recurrent pregnancy loss occurs in 1—2% of the childbearing population [19]. In the vast majority of the cases, the etiology is unknown and several hypotheses have been made on the basis of available data.

基于患者承受巨大的心理和经济压力，迫切需要搞清发病机理，推动临床治疗的发展。

However, given the psychological and economic stresses suffered by the affected couples, there is need to focus a lot more effort into finding out the mechanisms involved immunological or otherwise with the view to enhancing the development of therapy.

父源淋巴细胞免疫疗法可实现高治愈率是不可靠的。

Immunotherapy for management of recurrent spontaneous abortions In about half of the couples suffering recurrent spontaneous abortions, no specific cause (chromosomal, anatomical, endocrine, or microbial) can be found. It was claimed that these couples could be treated with a high success rate by immunisation with paternal lymphocytes[3]. The model for active immunotherapy was also based on the finding that pre-transplant blood transfusion significantly increased renal allograft survival [58] and that successful pregnancies resulted in the production of blocking antibodies, suppressor cells, and auto antiidiotypic

antibodies [10].

免疫活疗与非治疗自主治愈率无显著差别。按同样分类，非免疫治疗对照组(心理支持，关爱)与免疫活疗组临床治愈率相同(见下表)。

Active immmunotherapy vs. spontaneous cure rates

Table 1 shows the results of subsequent reproductive performance of recurrent aborters following active immunotherapy.

Table 1 Results of immunotherapy on subsequent reproduction in women with recurrent abortion

Study

Number of Patients

Type of Therapy

% Success

Additional Observation

Gafter et al. [27]

9

paternal mononuclear

77.7

Increase in IL-10, TNFa secretion +

cells decreae in IL-1, IL-2, IL-6, IL-12,

TNF á, TGF ?, NK and LAK

cells post immunisation

Malinowski et al. [60]

117

paternal lymphocytes

87.2

non pregnant aborters have high

CD4/CD8 ratio & high incidence of anticardiolipin, ACA. Lower success rates in women with medium to high ACA levels

Maejima et al. [59]

10

lymphocyte immunotherapy

80.0

Tamura et al. [96]

55

paternal lymphocytes

70.0

(1) MLR was +ve in 15/17 (82.4%) of successful patients tested and only in 1/10 (10%) unsuccessful patients tested

(2) blocking of MLR significantly

increased with prenatal course in

patients who succeeded

Tanaka et al. [97]

63

paternal lymphocytes

74.6

Pena et al. [75]

33

lymphocytes

80.0

(1) 50% successful cases produced MLR blocking abs, 5 subsequent losers had but 2 did not have MLR blocking

abs

(2) 4/5 (80%) of patients who tested +ve for cytotoxic antibodies aborted but 11/12 (91.7%) who tested –ve succeeded

Dupont et al. [24]

56

leukocytes

74.0

Katano et al. [43]

23

killed streptococcal

73.9

low NK activity in peripheral blood preparations seen in most successful cases

205

paternal lymphocytes

75.1

Pfeiffer et al. [77]

22

hemolysed and UV

irradiated autologous

blood

86.0

Stray Pedersen and

Stray Pedersen [94]

37

心理支持，关爱

psychological support, bed rest, tender lovingcare

86.5

24

无治疗

no care

33.3

l 表一的数据表面看上去有说服力，但是淋巴活疗引起了巨大的争论。反面意见认为林巴活疗并不提高反复流产孕妇的成功率。一些专家认真的评估了现有的治疗方法，结论是现有的治疗方法没有效果，并认为不同报道中所提到的成功率应归功于这类病情的自然治愈率。

Although the data provided in Table 1 look convincing, leukocyte immunotherapy has attracted substancial controversies. Of interest was the claim that immunotherapy with leukocytes and trophoblast membranes does not significantly improve the reproductive performance of

aborting women [26]. The authors critically evaluated the then existing methods employed and concluded that this form of therapy was of no consequence. Similarly, it was suggested that the subsequent pregnancy success rates claimed from various therapies could be accounted for by

spontaneous cure rates typical of this order [103].

The authors reported that the probability of a subsequent abortion after three consecutive abortions was only 20% thus giving an 80% spontaneous cure rate. These figures are similar to those presented elsewhere by Stray-Pederson and Stray-Pederson [94] claiming that tender loving care alone was as effective a therapy in achieving a subsequent live birth for the couple as any reported in the literature. In these studies, successful healthy deliveries were reported in 32 of 37 couples (86.5%) of habitual aborters following psychological support, bed rest, and tender loving care alone and in another 8 of 24 (33%) couples without special care. More studies have shown that dedication to supportive care with and without pharmacological or surgical intervention facilitates successful pregnancies[13].

l 这些矛盾重重的研究提示免疫活疗也许不具备临床效果。

Paradoxically, these observations, suggested that leukocyte immunotherapy per se may be of no clinical consequence. Interestingly, however, those authors who discounted immunotherapy and supported spontaneous cure rates and or tender loving care alone did not invite the participation of immunology into play. Thus without taking sides, one would argue that the spontaneous cure rates achieved after three or more consecutive abortions may result from a slow but consistent build up of immunological factors such as blocking antibodies with every pregnancy lost. Thus, given that each of the lost fetuses would have had a unique set of paternal genes, it may be speculated that the mother may have attempted immunological responses at the gene products there to but was inadequate

each time. However, the cumulative effect of three or more aborted fetuses may have exposed the mother to a larger repertoire of paternal antigens leading to an adequate build up of blocking antibodies that sustained the subsequent pregnancies hence the apparent spontaneous cure rates. This speculation may not necessarily hold true in every case of spontaneous cure following recurrent abortion, in as much as it would make immunological sense but should not be downplayed.

l 新的研究进一步挑战淋巴免疫活疗的有效性。用失活的细菌或融血后UV照射的自身血液进行免疫治疗，产生同样高的治愈率。这些观察置疑淋巴免疫活疗的机理。

A new dimension of study has further put to test the merits of immunotherapy with leukocytes. In this study[43] recurrent aborters were immunised with killed streptococcal preparations before and during pregnancy, and the authors reported success in 17 of 23 (73.9%) women which compared very well with 154 of 205 (75.1%) success rates recorded in women that were immunized with paternal lymphocytes. Elsewhere, 36 recurrent aborters were treated with intramuscular injections of extracorporally hemolysed and ultra violet (UV) irradiated autologous blood [77]. Again 19 of 22 (86%) women gave birth to live newborns compared with a 64% live births in the control group. These observations question the concept that immunisation with leukocytes evoked maternal immune responses to specific leukocyte antigens that are necessary for success of pregnancy. According to a review using a 95% confidence intervals in a large meta analysis [82], only as few as 4 to as many as 167 women would need to receive leukocyte immunization to achieve one additional live birth [49].

l 进一步研究，淋巴活疗还产生一些严重的副作用，例如红细胞超敏，。因此，选择这种治疗必须非常小心，尤其是全球都认识到许多疾病，如AIDS，都可通过血液传染。

In addition, lymphocyte immunotherapy has been associated with some adverse side effects such as erythrocyte sensitization, thrombocytopenia and intrautering growth retardation among others [35, 45, 49]. Also, the fact that leukocyte immunotherapy uses whole cells with intact nuclear material works against its merits. This form of therapy must therefore be treated with caution especially after the global realisation that diseases such as the aquired immunodeficiency syndrome (AIDS) could be transferred from one individual to another by blood transfusions.

l 由于淋巴免疫疗法的众多问题，静脉注射γ免疫球蛋白作为新的疗法被提出。

Immunotherapy with intravenous ? immunoglobulin (IVIg)

Given the controversies that have surrounded leukocyte immunotherapy, Intravenous gamma immunoglobulin, IVIg has been used by some workers as a safer alternative method of treatment to recurrent spontaneous abortion.

l 免疫疗法的潜在副作用，必须极端谨慎使用免疫疗法。

Table 3 Potential side effects of immunotherapy

Form Therapy

Mode of Action

Potential Side Effects

Risk of Infection

Complicance

Rate

Leukocyte immunization

Induction of blocking antibodies

– transfusion reactions

– auto-immunity

– erythrocyte and platelet sensitization

– infections

– intra-uterine growth retardation,.

– graft versus host disease,、thrombocytopenia

– neonatal death

high

high

Intravenous immunoglobulin immunization IVIg

passive transfer of blocking antivbiodies

– hypotension

– intrauterine growth retardation

– mosaicism

– nausea

– headache

low

high

l 尽管在过去35年里，生殖医学取得了长足进展，RSA患者仍然承受着心理和经济上的重大压力。同样，畜牧业也遭受反复流产造成的巨大经济损失。

Conclusion – 结论

The post implantation immunology of pregnancy has registered commendable achievements in the last thirty five years with such great findings as the expression of HLAG on the human placenta, an observation that directly supports the concept that a well regulated maternal immune response may be critical in the success of pregnancies.This set of information together with the others discussed in the literature have improved our understanding of the immunology of pregnancy and guided the course of immunotherapy to date. However, despite the recent advances in reproductive medicine and the brilliant experimental data obtained in the last thirty five or more years, the affected couples have continued languishing in the psychological and financial stresses associated with this condition.

Similarly, huge losses have been experienced in the livestock Industry due to undetected preclinical pregnancy losses. This has also remained a nagging source of stress to the physicians who cannot answer such questions as what caused the loss and what are the chances that a subsequent pregnancy is at risk.

l 免疫治疗RSA仍然是个难题，其原因是诊断RSA的方法还没有令人信服的建立，完整设计的临床治疗测试还没有实现。

Therapy for alloimmune reproductive failures remain anecdotal partly because the diagnosis for alloimmune recurrent spontaneous abortion has not been convincingly developed and a well designed clinical trial has not been satisfactorily accomplished to date.

l 应该非常慎重的使用淋巴免疫疗法，因为此法会有许多副作用，尤其是使用含有完整核物质的完整活细胞的风险。