Immunology Today, voL 5, No. 11, 1984
318
Leucocyte therapy for recurrent spontaneous abortion The first requirement of many clinicians when faced with a new concept in physiology or pathology is to know its relevance to their clinical practice. Laudable as that may be in some instances, it is inherently dangerous when used as a spurious criterion of the scientific merit of the work. Reproductive immunology has not been exempt from such pressures, and over the years an immune aetiology has been attributed to a whole series of pregnancy disorders. Although reasonable hypotheses have usually been proposed, the claims for clinical relevance have almost without exception been greater than any available data allowed. Currently the most topical pregnancy disorder for which an immune aetiology is proposed is recurrent spontaneous abortion. Although it was Rocklin and his colleagues' who proposed the absence of an 'immunologic blocking factor' from the serum of women suffering from recurrent idiopathic abortions, the subject was raised to prominence by Taylor and Faulk 2 when they reported that 4 women with a history of multiple primary recurrent spontaneous abortion had had successful pregnancies after treatment with mukiple buffy-coat infusions from donor blood before and during the first two trimesters of pregnancy. In addition the wife and husband of each couple were found to share M H C antigens far more frequently than expected. Faulk suggested that this sharing of M H C antigens was not important in itself, but was a marker for sharing of the trophoblast-lymphocyte cross-reactive (TLX) antigens. He speculated that, if excessive T L X antigen sharing occurred, protective 'blocking antibodies' would not be produced, laying the trophoblast open to immune attack. This would result in abortion. If, however, an antibody response could be engendered by infusing donor leucocytes, then it was, he reasoned, possible that any subsequent pregnancies might be successful. Beer and his colleagues 3'4reported on the successful treatment of a series of women suffering from recurrent abortion using two intradermal injections of leucocytes from the husband before pregnancy. Not only did they find excessive sharing of class I and II M H C antigens between husband and wife, but also unresponsiveness by a proportion of the affected women to paternal M H C antigens. They speculated that this interfered with imrnunoregulation and resulted in abortion. One of the infants whose mother was treated with paternal leucocytes has been reported as failing to thrive: the nature of the problem is unknown, although a 'graft versus host' reaction is a theoretical possibility. Mowbray et al. 5 have not confirmed H L A sharing between husband and wife in association with recurrent abortion, but do suggest strongly that maternal failure to produce 'blocking' antibody is the missing element in these patients. Patients are randomly allocated to treatment with their own or their husband's lymphocytes. Despite the seeming clinical benefit arising from this approach the fundamental basis of the problem, let alone the therapy, is still unknown. Before real progress can be
© 1984,ElsevierSciencePublishersB.V., Amsterdam 0167- 491918~:/$02.00
made an experimental model system is required which can be rigorously tested scientifically. For 'blocking antibodies' or any other factors to be considered seriously it must be possible to properly characterize, isolate and purify them. The recent work from Chavez and McIntyre 6 may, therefore, be a pointer in the right direction. They have demonstrated that heat-treated sera from 10 women who had experienced between 3 and 11 consecutive pregnancy losses consistently prevented the attachment or outgrowth of trophoblast in murine perimplantation blastocysts. This effect was not seen in sera from 10 age-matched normal individuals (3 men, 3 nulliparous and 4 multiparous women). The development of the inner cell mass was hardly affected in either cases or controls. The serum of one woman who had experienced 11 consecutive spontaneous abortions and which contained anti-paternal cytotoxic antibodies was studied further. The toxic effect on trophoblast demonstrated by whole heat-inactivated serum was abolished after passage through protein A-'sepharose', and by absorption with a human trophoblast membrane preparation and platelets (but not by mouse tissues). The effect of whole serum disappeared at concentrations of less than 10%. The authors suggest that the sera from the women with reproductive failure contain an antibody which is toxic to trophoblast in the absence of complement and which is a cause of the pregnancy losses. Although this may be so, the toxic factor may be an effect rather than a cause of the problem and it has not been conclusively proved to be antibody. Even if it is, its specificity has not been rigorously tested. One of the puzzling findings is that although the whole serum from the woman who had had 13 consecutive losses affected trophoblast but not the inner cell masses, the addition of the 'serum IgG' extracted on protein A-sepharose destroyed both, as did whole serum diluted 1:5 and 1:10. It is, therefore, too early to say whether this phenomenon is relevant biologically. However, this work not only raises interesting questions but also makes it theoretically possible to fully define the factors mediating these effects and relate them to the problem in vivo. ~] G O R D O N M. S T I R R A T
Department of Obstetrics and Gynaecology, University of Bristol, Bristol BS2
BEG. References 1 gocklin, R. E., Kitzmuller, J., Carpenter, B., Garvoney, M. and David, J. R. (1976)N. Engl. J. Med. 295, 1209 2 Taylor, C. and Fanlk, W. P. (1981) Lancet, ii. 68-9 3 Beer, A. E., Quebbeman, J. F., Ayers, J. W. T. and Haines, R. F. (1981) Am. J. Obstet. Gynecol. 141,987-999 4 Beer, A. E., Quebbeman, J. F., Semprini, A. E., Smouse, P. E. and Haines, R. F. (1983) in Reproductive Immunology 1983 (Isojuria, S. and Billington, W. D., eds.), pp. 185-195, Elsevier, Amsterdam 5 Mowbray, J. F., Gibbings, C. R., Sidgwiek, A.J., Ruzkiewicz, M. and Beard, R. W. (1983) Transpl. Proc. 15, 896-99 6 Chavez, D. J. and McIntyre, J. A. (1984)J. Reprod. Immunol. 6, 273-281
318
Leucocyte therapy for recurrent spontaneous abortion The first requirement of many clinicians when faced with a new concept in physiology or pathology is to know its relevance to their clinical practice. Laudable as that may be in some instances, it is inherently dangerous when used as a spurious criterion of the scientific merit of the work. Reproductive immunology has not been exempt from such pressures, and over the years an immune aetiology has been attributed to a whole series of pregnancy disorders. Although reasonable hypotheses have usually been proposed, the claims for clinical relevance have almost without exception been greater than any available data allowed. Currently the most topical pregnancy disorder for which an immune aetiology is proposed is recurrent spontaneous abortion. Although it was Rocklin and his colleagues' who proposed the absence of an 'immunologic blocking factor' from the serum of women suffering from recurrent idiopathic abortions, the subject was raised to prominence by Taylor and Faulk 2 when they reported that 4 women with a history of multiple primary recurrent spontaneous abortion had had successful pregnancies after treatment with mukiple buffy-coat infusions from donor blood before and during the first two trimesters of pregnancy. In addition the wife and husband of each couple were found to share M H C antigens far more frequently than expected. Faulk suggested that this sharing of M H C antigens was not important in itself, but was a marker for sharing of the trophoblast-lymphocyte cross-reactive (TLX) antigens. He speculated that, if excessive T L X antigen sharing occurred, protective 'blocking antibodies' would not be produced, laying the trophoblast open to immune attack. This would result in abortion. If, however, an antibody response could be engendered by infusing donor leucocytes, then it was, he reasoned, possible that any subsequent pregnancies might be successful. Beer and his colleagues 3'4reported on the successful treatment of a series of women suffering from recurrent abortion using two intradermal injections of leucocytes from the husband before pregnancy. Not only did they find excessive sharing of class I and II M H C antigens between husband and wife, but also unresponsiveness by a proportion of the affected women to paternal M H C antigens. They speculated that this interfered with imrnunoregulation and resulted in abortion. One of the infants whose mother was treated with paternal leucocytes has been reported as failing to thrive: the nature of the problem is unknown, although a 'graft versus host' reaction is a theoretical possibility. Mowbray et al. 5 have not confirmed H L A sharing between husband and wife in association with recurrent abortion, but do suggest strongly that maternal failure to produce 'blocking' antibody is the missing element in these patients. Patients are randomly allocated to treatment with their own or their husband's lymphocytes. Despite the seeming clinical benefit arising from this approach the fundamental basis of the problem, let alone the therapy, is still unknown. Before real progress can be
© 1984,ElsevierSciencePublishersB.V., Amsterdam 0167- 491918~:/$02.00
made an experimental model system is required which can be rigorously tested scientifically. For 'blocking antibodies' or any other factors to be considered seriously it must be possible to properly characterize, isolate and purify them. The recent work from Chavez and McIntyre 6 may, therefore, be a pointer in the right direction. They have demonstrated that heat-treated sera from 10 women who had experienced between 3 and 11 consecutive pregnancy losses consistently prevented the attachment or outgrowth of trophoblast in murine perimplantation blastocysts. This effect was not seen in sera from 10 age-matched normal individuals (3 men, 3 nulliparous and 4 multiparous women). The development of the inner cell mass was hardly affected in either cases or controls. The serum of one woman who had experienced 11 consecutive spontaneous abortions and which contained anti-paternal cytotoxic antibodies was studied further. The toxic effect on trophoblast demonstrated by whole heat-inactivated serum was abolished after passage through protein A-'sepharose', and by absorption with a human trophoblast membrane preparation and platelets (but not by mouse tissues). The effect of whole serum disappeared at concentrations of less than 10%. The authors suggest that the sera from the women with reproductive failure contain an antibody which is toxic to trophoblast in the absence of complement and which is a cause of the pregnancy losses. Although this may be so, the toxic factor may be an effect rather than a cause of the problem and it has not been conclusively proved to be antibody. Even if it is, its specificity has not been rigorously tested. One of the puzzling findings is that although the whole serum from the woman who had had 13 consecutive losses affected trophoblast but not the inner cell masses, the addition of the 'serum IgG' extracted on protein A-sepharose destroyed both, as did whole serum diluted 1:5 and 1:10. It is, therefore, too early to say whether this phenomenon is relevant biologically. However, this work not only raises interesting questions but also makes it theoretically possible to fully define the factors mediating these effects and relate them to the problem in vivo. ~] G O R D O N M. S T I R R A T
Department of Obstetrics and Gynaecology, University of Bristol, Bristol BS2
BEG. References 1 gocklin, R. E., Kitzmuller, J., Carpenter, B., Garvoney, M. and David, J. R. (1976)N. Engl. J. Med. 295, 1209 2 Taylor, C. and Fanlk, W. P. (1981) Lancet, ii. 68-9 3 Beer, A. E., Quebbeman, J. F., Ayers, J. W. T. and Haines, R. F. (1981) Am. J. Obstet. Gynecol. 141,987-999 4 Beer, A. E., Quebbeman, J. F., Semprini, A. E., Smouse, P. E. and Haines, R. F. (1983) in Reproductive Immunology 1983 (Isojuria, S. and Billington, W. D., eds.), pp. 185-195, Elsevier, Amsterdam 5 Mowbray, J. F., Gibbings, C. R., Sidgwiek, A.J., Ruzkiewicz, M. and Beard, R. W. (1983) Transpl. Proc. 15, 896-99 6 Chavez, D. J. and McIntyre, J. A. (1984)J. Reprod. Immunol. 6, 273-281
