Natural killer cells, miscarriage, and infertility
http://www.100md.com
《英国医生杂志》
1 Department of Pathology, University of Cambridge, Cambridge CB2 1QP, 2 Recurrent Miscarriage Clinic, Academic Department of Obstetrics and Gynaecology, St Mary's Hospital, Imperial College School of Medicine, London W2 1NY, 3 Assisted Conception Unit, Academic Department of Women's Health Guy's, King's and St Thomas' School of Medicine, London SE1 7EH
Correspondence: A Moffett am485@cam.ac.uk
Enthusiasm for new treatments aimed at natural killer cells in women with reproductive failure is unfortunately not backed up by the science
Introduction
Based on the assumed similarities between NK cells in blood and uterine NK cells, it has become increasingly common to examine peripheral blood NK cells in women with infertility and recurrent miscarriage. These tests are based on the speculation that women with recurrent miscarriage and infertility have abnormalities in uterine NK cell function, and it has been implied that these are discernible from analysis of NK cells in blood.6 7 This approach has several problems. Firstly, as mentioned above, uterine NK cells are different from those in peripheral blood. Examination of peripheral blood NK cells will not tell us what is happening in the uterus. This is akin to estimating the number and activity of black cabs in Trafalgar Square by analysing red mini-cabs circulating on the M25.
Secondly, the percentage of CD56+ NK cells in peripheral blood in normal healthy individuals varies from 5% to 29%.8 Despite this, a finding of more than 12% NK cells in women with infertility or miscarriage has been arbitrarily defined as abnormally raised and used as an indication for treatment.9 The percentage of NK cells in blood can be affected by many factors including sex, ethnicity, stress, and age, but there is no indication that concentrations in the upper end of the normal range are ever harmful.
Thirdly, NK activity is measured by a range of assays and the results will vary in different laboratories. The most commonly used in vitro assay is cytotoxicity, which may not have much relevance to NK function in vivo.10 Certainly, in viral infection, NK cells function mainly by producing cytokines. Furthermore, uterine NK cells have much lower cytolytic activity than blood NK cells. Thus, no clinically relevant information is gained from studying either the percentage or cytotoxicity of blood NK cells in women with pregnancy failure.
Uterine NK cells in pregnancy failure
Infertile women and those with recurrent miscarriages are being given treatments such as steroids, intravenous immunoglobulin, and tumour necrosis factor- blocking drugs with the questionable aim of suppressing NK cells. Recent high profile radio and press reports have featured a UK trial of steroids in recurrent miscarriage that has not been published but claims a success rate of about 85% (Woman's Hour, 29 Jan 2004).14 How this study was controlled is uncertain, but it is important to bear in mind the placebo effect and the well documented success achieved with such patients simply using care and reassurance.15 Neither steroids nor the other treatments being offered to women with "raised" levels of NK cells in blood are licensed for use in reproductive medicine, and all these treatments are associated with known risks to mother and fetus. The treatments are offered despite recent guidelines from the Royal College of Obstetricians and Gynaecologists, a Cochrane review, and a meta-analysis all concluding that there is no evidence to show they are beneficial.16-18 The situation is reminiscent of the publicity and controversy surrounding paternal leucocyte immunisation as a treatment for recurrent miscarriage in the 1980s. After much flurry and expense, this treatment has now been banned by the US Food and Drug Administration. 19
Understanding the function of uterine NK cells is certainly a major challenge in human reproduction. However, until more is known about their role in normal pregnancy, there is no evidence of any benefit in offering NK cell testing to women with recurrent miscarriage or infertility. Of course, women with these distressing conditions will be disappointed. In the technological medicine of today, patient expectations are high and a lack of a diagnosis and treatment is hard to accept. The danger posed by internet sources, the popular press, and radio highlighting idiosyncratic personal practices of a few physicians should not be underestimated. This unfortunate group of women are particularly vulnerable to financial exploitation, and of being exposed to powerful treatments that have, as yet, no rational scientific basis.
Contributors and sources: AM is a leading international authority on the role of uterine natural killer cells in reproduction, PB is on the Human Fertilisation and Embryology Authority and is a leading fertility expert, and LR is an expert on recurrent miscarriage and runs the largest miscarriage clinic in Europe. AM provided the scientific basis and wrote the paper. LR and PB provided clinical and ethical advice. AM is the guarantor.
Competing interests: None declared.
References
Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immuol 2002;2: 656-63.
King A. Uterine leukocytes and decidualisation. Hum Reprod Update 2000;6: 28-36.
Pijnenborg R, Vercruysse L, Hanssens M, Van Assche A. Incomplete trophoblast invasion: the evidence. In: Critchley H, MacLean A, Poston L, Walker J, eds. Pre-eclampsia. London: RCOG Press, 2003: 15-26.
Parham P. NK cells and trophoblasts: partners in pregnancy. J Exp Med 2004;200: 951-5.
Hiby SE, Walker JJ, O'Shaughnessy KM, Redman CWG, Carrington M, Trowsdale J, et al. Combinations of maternal and paternal innate immune genes influence the risk of pre-eclampsia. J Exp Med 2004;200: 957-65.
Aoki K, Kajiura S, Matsumoto Y, Ogasawara M, Okada S, Yagami Y, et al. Preconceptional natural-killer-cell activity as a predictor of miscarriage. Lancet 1995;345: 1340-2.
Ntrivalas EI, Kwak-Kim JY, Gilman-Sacchs A, Chung-Bang H, Ng SC, Beaman KD, et al. Status of peripheral blood natural killer cells in women with recurrent spontaneous abortions and infertility of unknown aetiology. Hum Reprod 2001;16: 855-61.
Bisset LR, Lung TL, Kaelin M, Ludwig E, Dubs RW. Reference values for peripheral blood lymphocyte phenotypes applicable to the healthy adult population in Switzerland. Eur J Haematol 2004;72: 203-12.
Kwak JY, Kwak FM, Gilman-Sachs A, Beaman KD, Cho DD, Beer AE, et al. Immunoglobulin G infusion treatment for women with recurrent spontaneous abortions and elevated CD56+ natural killer cells. Early Preg 2000;4: 154-64.
Biron CA, Nguyen KB, Pien GC. Innate immune responses to LCMV infections: natural killer cells and cytokines. Curr Top Microbiol Immunol 2002;263: 7-27.
Shimada S, Kato EH, Morikawa M, Iqwabuchi K, Nishida R, Kishi R, et al. No difference in natural killer or natural killer T-cell population, but aberrant T-helper cell population in the endometrium of women with repeated miscarriage. Hum Reprod 2004;19: 1018-24.
Quenby S, Bates M, Doig T, Brewster J, Lewis-Jones DI, Johnson PM, et al. Pre-implantation endometrial leukocytes in women with recurrent miscarriage. Hum Reprod 1999;14: 2386-91.
Quenby S, Farquharson R, Young M, Vince G. Successful pregnancy outcome following 19 consecutive miscarriages: case report. Hum Reprod 2003;18: 2562-4.
Parenting: the simple ￡15 `cure' for miscarriage. Sunday Times 2004 Mar 21.
Clifford K, Rai R, Regan L Future pregnancy outcome in unexplained recurrent first trimester miscarriage. Hum Reprod 1997;12: 387-9.
RCOG Scientific Advisory Committee. Immunological testing and interventions for reproductive failure. London: RCOG, 2003. (Opinion paper 5.)
Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2003;(1): CD000112.
Daya S, Gunby J, Clark DA. Intravenous immunoglobulin therapy for recurrent spontaneous abortion: a meta-analysis. Am J Reprod Immunol 1998;39: 69-76.
Center for Biologics Evaluation and Research. Lymphocyte immune therapy. www.fda.gov/cber/ltr/lit013002.htm (accessed 8 Sep 2003).(Ashley Moffett, King's Co)
Correspondence: A Moffett am485@cam.ac.uk
Enthusiasm for new treatments aimed at natural killer cells in women with reproductive failure is unfortunately not backed up by the science
Introduction
Based on the assumed similarities between NK cells in blood and uterine NK cells, it has become increasingly common to examine peripheral blood NK cells in women with infertility and recurrent miscarriage. These tests are based on the speculation that women with recurrent miscarriage and infertility have abnormalities in uterine NK cell function, and it has been implied that these are discernible from analysis of NK cells in blood.6 7 This approach has several problems. Firstly, as mentioned above, uterine NK cells are different from those in peripheral blood. Examination of peripheral blood NK cells will not tell us what is happening in the uterus. This is akin to estimating the number and activity of black cabs in Trafalgar Square by analysing red mini-cabs circulating on the M25.
Secondly, the percentage of CD56+ NK cells in peripheral blood in normal healthy individuals varies from 5% to 29%.8 Despite this, a finding of more than 12% NK cells in women with infertility or miscarriage has been arbitrarily defined as abnormally raised and used as an indication for treatment.9 The percentage of NK cells in blood can be affected by many factors including sex, ethnicity, stress, and age, but there is no indication that concentrations in the upper end of the normal range are ever harmful.
Thirdly, NK activity is measured by a range of assays and the results will vary in different laboratories. The most commonly used in vitro assay is cytotoxicity, which may not have much relevance to NK function in vivo.10 Certainly, in viral infection, NK cells function mainly by producing cytokines. Furthermore, uterine NK cells have much lower cytolytic activity than blood NK cells. Thus, no clinically relevant information is gained from studying either the percentage or cytotoxicity of blood NK cells in women with pregnancy failure.
Uterine NK cells in pregnancy failure
Infertile women and those with recurrent miscarriages are being given treatments such as steroids, intravenous immunoglobulin, and tumour necrosis factor- blocking drugs with the questionable aim of suppressing NK cells. Recent high profile radio and press reports have featured a UK trial of steroids in recurrent miscarriage that has not been published but claims a success rate of about 85% (Woman's Hour, 29 Jan 2004).14 How this study was controlled is uncertain, but it is important to bear in mind the placebo effect and the well documented success achieved with such patients simply using care and reassurance.15 Neither steroids nor the other treatments being offered to women with "raised" levels of NK cells in blood are licensed for use in reproductive medicine, and all these treatments are associated with known risks to mother and fetus. The treatments are offered despite recent guidelines from the Royal College of Obstetricians and Gynaecologists, a Cochrane review, and a meta-analysis all concluding that there is no evidence to show they are beneficial.16-18 The situation is reminiscent of the publicity and controversy surrounding paternal leucocyte immunisation as a treatment for recurrent miscarriage in the 1980s. After much flurry and expense, this treatment has now been banned by the US Food and Drug Administration. 19
Understanding the function of uterine NK cells is certainly a major challenge in human reproduction. However, until more is known about their role in normal pregnancy, there is no evidence of any benefit in offering NK cell testing to women with recurrent miscarriage or infertility. Of course, women with these distressing conditions will be disappointed. In the technological medicine of today, patient expectations are high and a lack of a diagnosis and treatment is hard to accept. The danger posed by internet sources, the popular press, and radio highlighting idiosyncratic personal practices of a few physicians should not be underestimated. This unfortunate group of women are particularly vulnerable to financial exploitation, and of being exposed to powerful treatments that have, as yet, no rational scientific basis.
Contributors and sources: AM is a leading international authority on the role of uterine natural killer cells in reproduction, PB is on the Human Fertilisation and Embryology Authority and is a leading fertility expert, and LR is an expert on recurrent miscarriage and runs the largest miscarriage clinic in Europe. AM provided the scientific basis and wrote the paper. LR and PB provided clinical and ethical advice. AM is the guarantor.
Competing interests: None declared.
References
Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immuol 2002;2: 656-63.
King A. Uterine leukocytes and decidualisation. Hum Reprod Update 2000;6: 28-36.
Pijnenborg R, Vercruysse L, Hanssens M, Van Assche A. Incomplete trophoblast invasion: the evidence. In: Critchley H, MacLean A, Poston L, Walker J, eds. Pre-eclampsia. London: RCOG Press, 2003: 15-26.
Parham P. NK cells and trophoblasts: partners in pregnancy. J Exp Med 2004;200: 951-5.
Hiby SE, Walker JJ, O'Shaughnessy KM, Redman CWG, Carrington M, Trowsdale J, et al. Combinations of maternal and paternal innate immune genes influence the risk of pre-eclampsia. J Exp Med 2004;200: 957-65.
Aoki K, Kajiura S, Matsumoto Y, Ogasawara M, Okada S, Yagami Y, et al. Preconceptional natural-killer-cell activity as a predictor of miscarriage. Lancet 1995;345: 1340-2.
Ntrivalas EI, Kwak-Kim JY, Gilman-Sacchs A, Chung-Bang H, Ng SC, Beaman KD, et al. Status of peripheral blood natural killer cells in women with recurrent spontaneous abortions and infertility of unknown aetiology. Hum Reprod 2001;16: 855-61.
Bisset LR, Lung TL, Kaelin M, Ludwig E, Dubs RW. Reference values for peripheral blood lymphocyte phenotypes applicable to the healthy adult population in Switzerland. Eur J Haematol 2004;72: 203-12.
Kwak JY, Kwak FM, Gilman-Sachs A, Beaman KD, Cho DD, Beer AE, et al. Immunoglobulin G infusion treatment for women with recurrent spontaneous abortions and elevated CD56+ natural killer cells. Early Preg 2000;4: 154-64.
Biron CA, Nguyen KB, Pien GC. Innate immune responses to LCMV infections: natural killer cells and cytokines. Curr Top Microbiol Immunol 2002;263: 7-27.
Shimada S, Kato EH, Morikawa M, Iqwabuchi K, Nishida R, Kishi R, et al. No difference in natural killer or natural killer T-cell population, but aberrant T-helper cell population in the endometrium of women with repeated miscarriage. Hum Reprod 2004;19: 1018-24.
Quenby S, Bates M, Doig T, Brewster J, Lewis-Jones DI, Johnson PM, et al. Pre-implantation endometrial leukocytes in women with recurrent miscarriage. Hum Reprod 1999;14: 2386-91.
Quenby S, Farquharson R, Young M, Vince G. Successful pregnancy outcome following 19 consecutive miscarriages: case report. Hum Reprod 2003;18: 2562-4.
Parenting: the simple ￡15 `cure' for miscarriage. Sunday Times 2004 Mar 21.
Clifford K, Rai R, Regan L Future pregnancy outcome in unexplained recurrent first trimester miscarriage. Hum Reprod 1997;12: 387-9.
RCOG Scientific Advisory Committee. Immunological testing and interventions for reproductive failure. London: RCOG, 2003. (Opinion paper 5.)
Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2003;(1): CD000112.
Daya S, Gunby J, Clark DA. Intravenous immunoglobulin therapy for recurrent spontaneous abortion: a meta-analysis. Am J Reprod Immunol 1998;39: 69-76.
Center for Biologics Evaluation and Research. Lymphocyte immune therapy. www.fda.gov/cber/ltr/lit013002.htm (accessed 8 Sep 2003).(Ashley Moffett, King's Co)