Aktive Immunisierung mit Partnerlymphozyten bei Kinderwunschpatientinnen – der aktuelle Stand

Zusammenfassung

Etwa 1 – 3% aller Kinderwunschpaare sind von einem habituellen Abortgeschehen betroffen. Dies ist laut WHO definiert als das Auftreten von 3 oder mehr aufeinanderfolgenden Aborten bis zur 20. SSW. Die Ursachen hierfür sind vielfältig, bleiben in einer Vielzahl der Fälle sogar unklar, sodass unter anderem immunologische Faktoren diskutiert werden können. Der Embryo stellt für das Immunsystem der Mutter ein semiallogenes Transplantat dar, da die Hälfte der Gene des Embryos paternaler Herkunft sind. Anstelle einer üblichen Immunantwort induziert der Embryo einen sekundären Schutzmechanismus, welcher zur erfolgreichen Implantation beiträgt. Bei der Immunisierung mit Partnerlymphozyten werden der Patientin aufbereitete Lymphozyten ihres Partners in die volare Seite des Unterarms intrakutan injiziert, um so eine Immunmodulation mit konsekutiv erhöhter Schwangerschafts- und Lebendgeburtenrate zu induzieren. Voraussetzung für dieses Verfahren ist, dass zuvor alle anderen infrage kommenden Sterilitätsursachen ausgeschlossen wurden. Aufgrund der äußerst heterogenen Datenlage kann ein signifikanter Nutzen durch die Immunisierung immer noch nicht eindeutig belegt werden. Es gibt jedoch Hinweise, dass die Therapie bei Verwendung möglichst frisch entnommener Lymphozyten wirksam sein könnte. Die Behandlung stellt insgesamt ein sicheres und risikoarmes Verfahren dar. Nach ausführlicher Aufklärung des Paares über die Erfolgsaussichten und genauer Überprüfung von Indikation und Kontraindikationen kann individuell mit dem Paar eine Immunisierung mit Partnerlymphozyten diskutiert werden – vorausgesetzt, zuvor wurden alle anderen infrage kommenden Sterilitätsursachen ausgeschlossen.

Schlüsselwörter

Abort - Immunologie - Implantation - Immunisierung - Partnerlymphozyten

• References/Literatur

• 1 Rai R, Regan L. Recurrent miscarriage. Lancet 2006; 368: 601-611
• 2 Practice Committee of American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril 2013; 99: 63
• 3 Garrido-Gimenez C, Alijotas-Reig J. Recurrent miscarriage: causes, evaluation and management. Postgrad Med J 2015; 91: 151-162
• 4 Steck T. Immuntherapie zur Abortprophylaxe und zur Verbesserung der Implantation bei der extrakorporalen Befruchtung. Zentralbl Gynäkol 2001; 123: 357-360
• 5 Banchereau J, Briere F, Caux C. et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18: 767-811
• 6 Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol 2003; 21: 685-711
• 7 Hempstock J, Cindrova-Davies T, Jauniaux E. et al. Endometrial glands as a source of nutrients, growth factors and cytokines during the first trimester of human pregnancy: a morphological and immunohistochemical study. Reprod Biol Endocrinol 2004; 2: 58
• 8 Bischof P, Aplin JD, Bentin-Ley U. et al. Implantation of the human embryo: research lines and models. From the implantation research network ‘Fruitful’. Gynecol Obstet Invest 2006; 62: 206-216
• 9 Billington WD. The immunological problem of pregnancy: 50 years with the hope of progress. A tribute to Peter Medawar. J Reprod Immunol 2003; 60: 1-11
• 10 Medawar P. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symposium of the Society for Experimental Biology 1953; 320
• 11 Maejima M, Fujii T, Kozuma S. et al. Presence of HLA-G-expressing cells modulates the ability of peripheral blood mononuclear cells to release cytokines. Am J Reprod Immunol 1997; 38: 79-82
• 12 Krikun G, Lockwood CJ, Abrahams VM. et al. Expression of Toll-like receptors in the human decidua. Histol Histopathol 2007; 22: 847-854
• 13 Christiansen OB, Nielsen HS, Kolte AM. Future directions of failed implantation and recurrent miscarriage research. Reprod Biomed Online 2006; 13: 71-83
• 14 Clark DA. Immunological factors in pregnancy wastage: fact or fiction. Am J Reprod Immunol 2008; 59: 277-300
• 15 Li TC, Makris M, Tomsu M. et al. Recurrent miscarriage: aetiology, management and prognosis. Hum Reprod Update 2002; 8: 463-481
• 16 Santoni A, Carlino C, Gismondi A. Uterine NK cell development, migration and function. Reprod Biomed Online 2008; 16: 202-210
• 17 Moffett A, Loke C. Immunology of placentation in eutherian mammals. Nat Rev Immunol 2006; 6: 584-594
• 18 Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 2006; 27: 939-958
• 19 Bulmer JN, Lash GE. Human uterine natural killer cells: a reappraisal. Mol Immunol 2005; 42: 511-521
• 20 Quenby S, Nik H, Innes B. et al. Uterine natural killer cells and angiogenesis in recurrent reproductive failure. Hum Reprod 2009; 24: 45-54
• 21 Wegmann TG, Lin H, Guilbert L. et al. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?. Immunol Today 1993; 14: 353-356
• 22 Raghupathy R, Makhseed M, Azizieh F. et al. Cytokine production by maternal lymphocytes during normal human pregnancy and in unexplained recurrent spontaneous abortion. Hum Reprod 2000; 15: 713-718
• 23 Lim KJ, Odukoya OA, Ajjan RA. et al. The role of T-helper cytokines in human reproduction. Fertil Steril 2000; 73: 136-142
• 24 Whitcomb BW, Schisterman EF, Klebanoff MA. et al. Circulating levels of cytokines during pregnancy: thrombopoietin is elevated in miscarriage. Fertil Steril 2008; 89: 1795-1802
• 25 Edmonds DK, Lindsay KS, Miller JF. et al. Early embryonic mortality in women. Fertil Steril 1982; 38: 447-453
• 26 Rogenhofer N, Mittenzwei S, Thaler CJ. et al. Stellenwert der aktiven Immuntherapie bei Kinderwunschpatientinnen. Gyn Endokrinologie 2011; 9: 215-218
• 27 Kwak JY, Kwak FM, Gilman-Sachs A. et al. Immunoglobulin G infusion treatment for women with recurrent spontaneous abortions and elevated CD56+ natural killer cells. Early Pregnancy 2000; 4: 154-164
• 28 Wong LF, Porter TF, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2014; (10) CD000112
• 29 Takeshita T. Diagnosis and treatment of recurrent miscarriage associated with immunologic disorders: Is paternal lymphocyte immunization a relic of the past?. J Nippon Med Sch 2004; 71: 308-313
• 30 Wu L, Luo LH, Zhang YX. et al. Alteration of Th17 and Treg cells in patients with unexplained recurrent spontaneous abortion before and after lymphocyte immunization therapy. Reprod Biol Endocrinol 2014; 12: 74
• 31 Stray-Pedersen B, Stray-Pedersen S. Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion. Am J Obstet Gynecol 1984; 148: 140-146
• 32 Stray-Pedersen B, Stray-Pedersen S. Recurrent Abortion: the Role of Psychotherapy. In: Beard RW, Sharp F. eds. Early Pregnancy Loss, Mechanisms and Treatment. London, Berlin, Heidelberg: Springer; 1988: 433-440
• 33 Carp HJ, Toder V, Gazit E. et al. Immunization by paternal leukocytes for prevention of primary habitual abortion: results of a matched controlled trial. Gynecol Obstet Invest 1990; 29: 16-21
• 34 Mowbray JF. Autoantibodies, alloantibodies and reproductive success. Curr Opin Immunol 1989; 2: 761-764
• 35 Beer AE. Pregnancy Outcome in Couples with recurrent Abortion following immunological Evaluation and Therapy. In: Beard RW, Sharp F. eds. Early Pregnancy Loss, Mechanisms and Treatment. Ashton-under-Lyne: Peacock Press; 1988: 337-349
• 36 Kling C, Steinmann J, Westphal E. et al. Adverse effects of intradermal allogeneic lymphocyte immunotherapy: acute reactions and role of autoimmunity. Hum Reprod 2006; 21: 429-435
• 37 Kling C, Schmutzler A, Wilke G. et al. Two-year outcome after recurrent implantation failure: prognostic factors and additional interventions. Arch Gynecol Obstet 2008; 278: 135-142
• 38 Liu Z, Xu H, Kang X. et al. Allogenic lymphocyte immunotherapy for unexplained recurrent spontaneous abortion: a meta-analysis. Am J Reprod Immunol 2016; 76: 443-453
• 39 Cavalcante MB, Sarno M, Araujo Júnior E. et al. Lymphocyte immunotherapy in the treatment of recurrent miscarriage: systematic review and meta-analysis. Arch Gynecol Obstet 2017; 295: 511-518
• 40 Mowbray JF, Gibbings C, Liddell H. et al. Controlled trial of treatment of recurrent spontaneous abortion by immunisation with paternal cells. Lancet 1985; 1: 941-943
• 41 Cauchi MN, Lim D, Young DE. et al. Treatment of recurrent aborters by immunization with paternal cells–controlled trial. Am J Reprod Immunol 1991; 25: 16-17
• 42 Ho HN, Gill 3rd TJ, Hsieh HJ. et al. Immunotherapy for recurrent spontaneous abortions in a Chinese population. Am J Reprod Immunol 1991; 25: 10-15
• 43 Gatenby PA, Cameron K, Simes RJ. et al. Treatment of recurrent spontaneous abortion by immunization with paternal lymphocytes: results of a controlled trial. Am J Reprod Immunol 1993; 29: 88-94
• 44 Carp HJ, Toder V, Torchinsky A. et al. Allogenic leukocyte immunization after five or more miscarriages. Recurrent Miscarriage Immunotherapy Trialists Group. Hum Reprod 1997; 12: 250-255
• 45 Kilpatrick DCL, Liston W. Abstracts of contributorsʼ individual data submitted to the worldwide prospective observation study on immunotherapy for treatment of recurrent spontaneous abortion. American Journal of Reproductive Immunology 1994; 32: 264
• 46 Clark DA, Daya S. Trials and tribulation in the treatment of recurrent spontaneous abortion. Am J Reprod Immunol 1991; 25: 18-24
• 47 Pandey M, Halder A, Agarwal S. Immuno therapy in recurrent spontaneous abortion: randomized and non-randomized trials. Internet J Gynecol Obstet 2003; 2: 13
• 48 Yanping C, Xiaoye Z, Qingmei B. Study of immunotherapy with lymphocytes in women with recurrent spontaneous abortion. Mod Prev Med 2011; 38: 1626-1627
• 49 Lin S, Yan S, Shan E. Analysis the efficacy of immunotherapy with lymphocytes for recurrent spontaneous abortion. Jilin Med 2012; 33: 1822-1823
• 50 Aiwu W, Mingzhu L, Runzhi W. Preventive treatment of unexplained recurrent spontaneous abortion and effect on pregnancy outcome by lymphocytes immunotherapy. China J Chin Med 2013; 28: 876-878
• 51 Bin T, Kaishu H, Wenquan Z. Analysis of lymphocytes immunotherapy for recurrent spontaneous abortion. Chin Med Treat Works 2013; 21: 171-172
• 52 Hong L, Huaixiu W, Jing W. The lymphocyte injects and treats the habitual abortion that the immune factor causes. Med Mag Shanxi 2003; 32: 308-309
• 53 Stray-Pederson S. unpublished data, nach Wong LF et al. 2014. 1994
• 54 Recurrent Miscarriage Immunotherapy Trialists Group. Worldwide collaborative observational study and meta-analysis on allogenic leukocyte immunotherapy for recurrent spontaneous abortion. Am J Reprod Immunol 1994; 32: 55-72
• 55 Illeni MT, Marelli G, Parazzini F. et al. Immunotherapy and recurrent abortion: a randomized clinical trial. Hum Reprod 1994; 9: 1247-1249
• 56 Collins J, Roberts R. Immunotherapy for recurrent spontaneous abortion: analysis 1. Am J Reprod Immunol 1994; 32: 275-280
• 57 Ober C, Karrison T, Odem RR. et al. Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial. Lancet 1999; 354: 365-369
• 58 Daya S, Gunby J. The effectiveness of allogeneic leukocyte immunization in unexplained primary recurrent spontaneous abortion. Recurrent Miscarriage Immunotherapy Trialists Group. Am J Reprod Immunol 1994; 32: 294-302
• 59 Scott JR, Branch WD, Dudley DJ, Hatasaka HH. Immunotherapy for recurrent pregnancy loss: the University of Utah perspective. Reproductive Immunology. Serono Symposium Publications, Raven Press; 1997: 255-257
• 60 Christiansen OB, Mathiesen O, Husth M. et al. Placebo-controlled trial of active immunization with third party leukocytes in recurrent miscarriage. Acta Obstet Gynecol Scand 1994; 73: 261-268
• 61 Reznikoff-Etievant MF. Abstracts of contributorsʼ individual data submitted to the worldwide prospective observation study on immunotherapy for treatment of recurrent spontaneous abortion. Am J Reprod Immunol 1994; unpublished data, nach Wong LF et al. 2014; 32: 266 – 267.
• 62 Pandey MK, Agrawal S. Induction of MLR-Bf and protection of fetal loss: a current double blind randomized trial of paternal lymphocyte immunization for women with recurrent spontaneous abortion. Int Immunopharmacol 2004; 4: 289-298
• 63 Fraser EJ, Grimes DA, Schulz KF. Immunization as therapy for recurrent spontaneous abortion: a review and meta-analysis. Obstet Gynecol 1993; 82: 854-859
• 64 Clark DA. The end of evidence-based medicine?. Inflammopharmacology 2012; 20: 187-193
• 65 Clark DA. Cell-surface CD200 may predict efficacy of paternal mononuclear leukocyte immunotherapy in treatment of human recurrent pregnancy loss. Am J Reprod Immunol 2009; 61: 75-84
• 66 Yu HL, Deng XH, Chao L. et al. [Study on positive rate of blocking antibody in women with recurrent spontaneous abortion administered by route and frequency of paternal lymphocyte immunotherapy]. Zhonghua Fu Chan Ke Za Zhi 2013; 48: 903-906
• 67 Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2006; (02) CD000112
• 68 Pandey MK, Thakur S, Agrawal S. Lymphocyte immunotherapy and its probable mechanism in the maintenance of pregnancy in women with recurrent spontaneous abortion. Arch Gynecol Obstet 2004; 269: 161-172