Иммунотерапия при привычном выкидыше, обусловленном аллоиммунными причинами

1. Левкович М.А., Линде В.А., Андреева В.О. и др. Иммуно-гормональные взаимодействия в генезе невынашивания беременности ранних сроков. Акушерство и гинекология. 2012; 8 (1): 10–4. / Levkovich M.A., Linde V.A., Andreeva V.O. i dr. Immuno-gormonal'nye vzaimodeistviia v geneze nevynashivaniia beremennosti rannikh srokov. Akusherstvo i ginekologiia. 2012; 8 (1): 10–4. [in Russian]
2. Hannan. N.J. Effects of Pravastatin on Human Placenta, Endothelium, and Women With Severe Preeclampsia. 2011. http://www.ncbi.nlm.nih.gov/pubmed 
3. Winger EE and Jane L. Reed Reccurent Pregnancy Loss, 2nd Edition (CRС Press, 2015) Should Immunotherapy Be Used? Lymphocyte Immunization Therapy.Yes 249. 
4. Early Pregnancy. Edited by RG Farquharson, Stephenson MD. Cambridge University Press, 2012. Cambridge Books Online http://ebooks.cambridge.org/ Book DOI: http://dx.doi.org/10.1017/CBO9780511777851
5. Lee SK, Kim JY, Lee M et al. Th17 and regulatory T cells in women with recurrent pregnancy loss. Am J Reprod Immunol 2012; 67: 311–5.
6. Li J, Chen Y, Liu C et al. Intravenous immunoglobulin treatment for repeated IVF/ICSI failure and unexplained infertility: A systematic review and a meta-analysis. Am J Reprod Immunol 2013; 704: 34–7.
7. Reznikoff-Etievant MF, Durieux I, Lobet R et al. Immunologic abortion and its treatment by immunotherapy. Rev Fr Transfus Immunohematol 1986; 29 (3): 135–48.
8. Сухих Г.Т., Ванько Л.В. Иммунология беременности. М.: Издательство РАМН, 2003: 339–92. / Sukhikh G.T., Van'ko L.V. Immunologiia beremennosti. M.: Izdatel'stvo RAMN, 2003: 339–92. [in Russian]
9. Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Editorial Group: Cochrane Pregnancy and Childbirth Group.
10. Schleussner E. Impact of the antiphospholipid syndrome on complications during pregnancy Transfus Med Hemother 2006; 33 (6): 486–92.
11. Ralph SG, Rutherford AJ, Wilson JD. Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study. BMJ 1999; 319 (7204): 220–3.
12. Szekeres-Bartho J, Barakonyi A, Polgar B et al. The Role of g/d Cells in Progesterone‐Mediated Immunomodulation During Pregnancy: A Review. Am J Reprod Immunol 1999; 42 (1): 44–8.
13. Посиссева Л.В., Малышкина А.И., Бойко Е.Л. и др. Реабилитация репродуктивного здоровья супружеских пар с невынашиванием беременности. Иваново: Иваново, 2008. / Posisseva L.V., Malyshkina A.I., Boiko E.L. i dr. Reabilitatsiia reproduktivnogo zdorov'ia supruzheskikh par s nevynashivaniem beremennosti. Ivanovo: Ivanovo, 2008. [in Russian]
14. Beer A et al. New horizons in the diagnosis, evaluation and therapy of recurrent spontaneous abortion. Clin Obstet Gynaecol 1986; 13 (1): 115–24.
15. Robertson SA, Sharkey D.J. The Male Role in Pregnancy Loss and Embryo Implantation Failure. 2001.
16. Карп Г. Систематический обзор применения дидрогестерона для лечения угрозы прерывания беременности. Здоровье женщины. 2013; 1: 46–56. / Karp G. Sistematicheskii obzor primeneniia didrogesterona dlia lecheniia ugrozy preryvaniia beremennosti. Zdorov'e zhenshchiny. 2013; 1: 46–56. [in Russian]
17. Saccone G, Schoen C, Franasiak JM et al. Supplementation with progestogens in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent miscarriage: a systematic review and meta-analysis of randomized, controlled trials. Fertil Steril 2017; 107 (2): 430–8.
18. Brogin Moreli J. Interleukin 10 and Tumor Necrosis Factor-Alpha in Pregnancy: Aspects of Interest in Clinical Obstetrics. ISRN Obstet Gynecol 2012; 230–42. http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3302063/ 
19. Kheshtchin N, Gharagozloo M, Andalib A et al. The expression of Th1- and Th2-related chemokine receptors in women with recurrent miscarriage: the impact of lymphocyte immunotherapy. Am J Reprod Immunol 2010; 64 (2): 104–12.
20. Park DW, Lee HJ, Park CW et al. Peripheral blood NK cells reflect changes in decidual NK cells in women with recurrent miscarriages. Am J Reprod Immunol 2010; 63 (2): 173–80.
21. Wang WJ, Hao CF, Lin QD. Dysregulation of macrophage activation by decidual regulatory T cells in unexplained recurrent miscarriage patients. J Hyperlink 2011; 92 (1–2): 97–102.
22. Katano K, Suzuki S, Ozaki Y et al. Peripheral natural killer cell activity as a predictor of recurrent pregnancy loss: A large cohort study. Fertil Steril 2013; 100: 1629–34.
23. Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: The release of damage-associated molecular patterns and its physiological relevance. Immunity 2013; 38: 209–23.
24. Малышкина А.И., Можаева А.И., Воронин Д.Н. Особенности реакций врожденного иммунитета у женщин с угрозой прерывания беременности на ранних сроках. Рос. иммунол. журн. 2010; 4: 407–8. / Malyshkina A.I., Mozhaeva A.I., Voronin D.N. Osobennosti reaktsii vrozhdennogo immuniteta u zhenshchin s ugrozoi preryvaniia beremennosti na rannikh srokakh. Ros. immunol. zhurn. 2010; 4: 407–8. [in Russian]
25. Liang P, Mo M, Li GG et al. Comprehensive analysis of peripheral blood lymphocytes in 76 women with recurrent miscarriage before and after lymphocyte immunotherapy. Am J Reprod Immunol 2012; 68: 164–74.
26. Li J, Chen Y, Liu C et al. Intravenous immunoglobulin treatment for repeated IVF/ICSI failure and unexplained infertility: A systematic review and a meta-analysis. Am J Reprod Immunol 2013; 704: 34–7.
27. Reccurent pregnancy loss: causes, controversies and treatment. Ed. by Carp Howard J.A. Informa UK ltd, 2007.
28. Vacca P, Cantoni C, Vitale M et al. Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression. Proc Natl Acad Sci USA 2010; 107 (26): 11918–23.
29. Raj Rai. Debate: Should immunotherapy be used? No. In: Carp H.J.A., ed. Recurrent pregnancy loss: сauses, controversies, and treatment. 2nd ed. CRС Press; 2014: 265.
30. Trabanelli S, Ocadlikova D, Evangelisti C et al. Induction of Regulatory T Cells by Dendritic Cells through Indoleamine 2,3-dioxygenase: A Potent Mechanism of Acquired Peripheral Tolerance. Curr Med Chem 2011; 18 (15): 2234–9.
31. Крошкина Н.В., Малышкина А.И., Можаева Т.А. Особенности функционального состояния клеток макрофагального ряда у женщин с невынашиванием беременности ранних сроков. Вестн. уральской медицинской академической науки. 2010; 2 (1): 154–5. / Kroshkina N.V., Malyshkina A.I., Mozhaeva T.A. Osobennosti funktsional'nogo sostoianiia kletok makrofagal'nogo riada u zhenshchin s nevynashivaniem beremennosti rannikh srokov. Vestn. ural'skoi meditsinskoi akademicheskoi nauki. 2010; 2 (1): 154–5. [in Russian]
32. Hayakawa S, Karasaki-Suzuki M, Itoh T et al. Effects of paternal lymphocyte immunization on peripheral Th1:Th2 balance and TCR Vb and Vg repertoire usage of patients with recurrent spontaneous abortions. AJRI 2000; 43: 107–14.
33. Kwiatek M , Gęca T, Krzyżanowski A et al. Public Peripheral dendritic cells and CD4+CD25+Foxp3+ regulatory T cells in the first trimester of normal pregnancy and in women with recurrent miscarriage. PLoS One 2015; 10 (5): e0124747.
34. Wegmann TG, Lin H, Guilbert L, Mosmann TR: Bidirectional cytokine interactions in the maternal-fetal relachionship: is successful pregnancy a Th2 phenomen. Immunol Today 1993; 14: 353–6.
35. Romero R, Gotsch F, Pineles B, Kuzanovic JP. Inflamation in pregnancy its role in reproductive physiology, obstetrical complications, and fetal injury. Nutr Rev 2007; (II): 194–202.
36. Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci 2011; 1221: 80–7.
37. Saito S, Shima T, Nakashima A et al. What is the role of regulatory T cells in the success of implantation and early pregnancy? Assist Reprod Genet 2007; 24: 379–86.
38. Clark DA. Cell surface CD200 may predict efficacy of paternal mononuclear leukocyte immunotherapy in treatment of human reccurent pregnancy loss. Am J Reprod Immunol 2009; 61: 75–84.
39. Clark DA, Wong K, Banwatt D et al. CD200-dependent and nonCD200-dependent pathways of NK cell suppression by human IVIG. J Assist Reprod Genet 2008; 25 (2–3): 67–72.
40. Gharesi-Fard B, Zolghadri J, Foroughinia L et al. Effectiveness of leukocyte immunotherapy in primary recurrent spontaneous abortion (RSA). Iran J Immunol 2007; 4 (3): 173–8.
41. 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: 289–98.
42. Kheshtchin N, Gharagozloo M, Andalib A et al.The expression of Th1- and Th2-related chemokine receptors in women with recurrent miscarriage: the impact of lymphocyte immunotherapy. Am J Reprod Immunol 2010; 64 (2): 104–12.
43. Beaman KD, Ntrivalas E, Mallers TM et al. Immune Etiology of Recurrent Pregnancy Loss and Its Diagnosis. North Chicago, IL, USA, 2015. 
44. Сидельникова В.М. Подготовка и ведение беременности у женщин с привычным невынашиванием: метод. пособия и клин. рекомендации. М: МЕДпресс-информ, 2011. / Sidel'nikova V.M. Podgotovka i vedenie beremennosti u zhenshchin s privychnym nevynashivaniem: metod. posobiia i klin. rekomendatsii. M: MEDpress-inform, 2011. [in Russian]
45. Check JH. A practical approach to the prevention of miscarriage: part 2-active immunotherapy. Clin Exp Obstet Gynecol 2010; 37 (1): 5–9.
46. Yang H, Qiu L, Di W et al. Proportional change of CD4+CD25+ regulatory T cells after lymphocyte therapy in unexplained recurrent spontaneous abortion patients. Fertil Steril 2009; 92 (1): 301–5.
47. Khonina NA, Broitman EV, Shevela EY et al. Mixed lymphocyte reaction blocking factors (MLR-Bf) as potential biomarker for indication and efficacy of paternal lymphocyte immunization in recurrent spontaneous abortion. Arch Gynecol Obstet 2013; 288 (4): 933–7.
48. Nonaka T, Takakuwa K, Ooki I et al. Results of immunotherapy for patients with unexplained primary recurrent abortions--prospective non-randomized cohort study. Am J Reprod Immunol 2007; 58 (6): 530–6.
49. Wilczyński JR, Radwan P, Tchórzewski H, Banasik M. Immunotherapy of patients with recurrent spontaneous miscarriage and idiopathic infertility: does the immunization-dependent Th2 cytokine overbalance really matter? Arch Immunol Ther Exp (Warsz) 2012; 60 (2): 151–60.
50. Duckitt K, Qureshi A. Recurrent miscarriage. Clin Evid (Online) 2011; 2011. pii: 1409. 
51. Check JH, Arwitz M, Gross J et al. Lymphocyte immunotherapy (LI) increases serum levels of progesterone induced blocking factor (PIBF). Am J Reprod Immunol 1997; 37 (1): 17–20.

________________________________________________

1. Levkovich M.A., Linde V.A., Andreeva V.O. i dr. Immuno-gormonal'nye vzaimodeistviia v geneze nevynashivaniia beremennosti rannikh srokov. Akusherstvo i ginekologiia. 2012; 8 (1): 10–4. [in Russian]
2. Hannan. N.J. Effects of Pravastatin on Human Placenta, Endothelium, and Women With Severe Preeclampsia. 2011. http://www.ncbi.nlm.nih.gov/pubmed 
3. Winger EE and Jane L. Reed Reccurent Pregnancy Loss, 2nd Edition (CRС Press, 2015) Should Immunotherapy Be Used? Lymphocyte Immunization Therapy.Yes 249. 
4. Early Pregnancy. Edited by RG Farquharson, Stephenson MD. Cambridge University Press, 2012. Cambridge Books Online http://ebooks.cambridge.org/ Book DOI: http://dx.doi.org/10.1017/CBO9780511777851
5. Lee SK, Kim JY, Lee M et al. Th17 and regulatory T cells in women with recurrent pregnancy loss. Am J Reprod Immunol 2012; 67: 311–5.
6. Li J, Chen Y, Liu C et al. Intravenous immunoglobulin treatment for repeated IVF/ICSI failure and unexplained infertility: A systematic review and a meta-analysis. Am J Reprod Immunol 2013; 704: 34–7.
7. Reznikoff-Etievant MF, Durieux I, Lobet R et al. Immunologic abortion and its treatment by immunotherapy. Rev Fr Transfus Immunohematol 1986; 29 (3): 135–48.
8. Sukhikh G.T., Van'ko L.V. Immunologiia beremennosti. M.: Izdatel'stvo RAMN, 2003: 339–92. [in Russian]
9. Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Editorial Group: Cochrane Pregnancy and Childbirth Group.
10. Schleussner E. Impact of the antiphospholipid syndrome on complications during pregnancy Transfus Med Hemother 2006; 33 (6): 486–92.
11. Ralph SG, Rutherford AJ, Wilson JD. Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study. BMJ 1999; 319 (7204): 220–3.
12. Szekeres-Bartho J, Barakonyi A, Polgar B et al. The Role of g/d Cells in Progesterone‐Mediated Immunomodulation During Pregnancy: A Review. Am J Reprod Immunol 1999; 42 (1): 44–8.
13. Posisseva L.V., Malyshkina A.I., Boiko E.L. i dr. Reabilitatsiia reproduktivnogo zdorov'ia supruzheskikh par s nevynashivaniem beremennosti. Ivanovo: Ivanovo, 2008. [in Russian]
14. Beer A et al. New horizons in the diagnosis, evaluation and therapy of recurrent spontaneous abortion. Clin Obstet Gynaecol 1986; 13 (1): 115–24.
15. Robertson SA, Sharkey D.J. The Male Role in Pregnancy Loss and Embryo Implantation Failure. 2001.
16. Karp G. Sistematicheskii obzor primeneniia didrogesterona dlia lecheniia ugrozy preryvaniia beremennosti. Zdorov'e zhenshchiny. 2013; 1: 46–56. [in Russian]
17. Saccone G, Schoen C, Franasiak JM et al. Supplementation with progestogens in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent miscarriage: a systematic review and meta-analysis of randomized, controlled trials. Fertil Steril 2017; 107 (2): 430–8.
18. Brogin Moreli J. Interleukin 10 and Tumor Necrosis Factor-Alpha in Pregnancy: Aspects of Interest in Clinical Obstetrics. ISRN Obstet Gynecol 2012; 230–42. http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3302063/ 
19. Kheshtchin N, Gharagozloo M, Andalib A et al. The expression of Th1- and Th2-related chemokine receptors in women with recurrent miscarriage: the impact of lymphocyte immunotherapy. Am J Reprod Immunol 2010; 64 (2): 104–12.
20. Park DW, Lee HJ, Park CW et al. Peripheral blood NK cells reflect changes in decidual NK cells in women with recurrent miscarriages. Am J Reprod Immunol 2010; 63 (2): 173–80.
21. Wang WJ, Hao CF, Lin QD. Dysregulation of macrophage activation by decidual regulatory T cells in unexplained recurrent miscarriage patients. J Hyperlink 2011; 92 (1–2): 97–102.
22. Katano K, Suzuki S, Ozaki Y et al. Peripheral natural killer cell activity as a predictor of recurrent pregnancy loss: A large cohort study. Fertil Steril 2013; 100: 1629–34.
23. Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: The release of damage-associated molecular patterns and its physiological relevance. Immunity 2013; 38: 209–23.
24. Malyshkina A.I., Mozhaeva A.I., Voronin D.N. Osobennosti reaktsii vrozhdennogo immuniteta u zhenshchin s ugrozoi preryvaniia beremennosti na rannikh srokakh. Ros. immunol. zhurn. 2010; 4: 407–8. [in Russian]
25. Liang P, Mo M, Li GG et al. Comprehensive analysis of peripheral blood lymphocytes in 76 women with recurrent miscarriage before and after lymphocyte immunotherapy. Am J Reprod Immunol 2012; 68: 164–74.
26. Li J, Chen Y, Liu C et al. Intravenous immunoglobulin treatment for repeated IVF/ICSI failure and unexplained infertility: A systematic review and a meta-analysis. Am J Reprod Immunol 2013; 704: 34–7.
27. Reccurent pregnancy loss: causes, controversies and treatment. Ed. by Carp Howard J.A. Informa UK ltd, 2007.
28. Vacca P, Cantoni C, Vitale M et al. Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression. Proc Natl Acad Sci USA 2010; 107 (26): 11918–23.
29. Raj Rai. Debate: Should immunotherapy be used? No. In: Carp H.J.A., ed. Recurrent pregnancy loss: сauses, controversies, and treatment. 2nd ed. CRС Press; 2014: 265.
30. Trabanelli S, Ocadlikova D, Evangelisti C et al. Induction of Regulatory T Cells by Dendritic Cells through Indoleamine 2,3-dioxygenase: A Potent Mechanism of Acquired Peripheral Tolerance. Curr Med Chem 2011; 18 (15): 2234–9.
31. Kroshkina N.V., Malyshkina A.I., Mozhaeva T.A. Osobennosti funktsional'nogo sostoianiia kletok makrofagal'nogo riada u zhenshchin s nevynashivaniem beremennosti rannikh srokov. Vestn. ural'skoi meditsinskoi akademicheskoi nauki. 2010; 2 (1): 154–5. [in Russian]
32. Hayakawa S, Karasaki-Suzuki M, Itoh T et al. Effects of paternal lymphocyte immunization on peripheral Th1:Th2 balance and TCR Vb and Vg repertoire usage of patients with recurrent spontaneous abortions. AJRI 2000; 43: 107–14.
33. Kwiatek M , Gęca T, Krzyżanowski A et al. Public Peripheral dendritic cells and CD4+CD25+Foxp3+ regulatory T cells in the first trimester of normal pregnancy and in women with recurrent miscarriage. PLoS One 2015; 10 (5): e0124747.
34. Wegmann TG, Lin H, Guilbert L, Mosmann TR: Bidirectional cytokine interactions in the maternal-fetal relachionship: is successful pregnancy a Th2 phenomen. Immunol Today 1993; 14: 353–6.
35. Romero R, Gotsch F, Pineles B, Kuzanovic JP. Inflamation in pregnancy its role in reproductive physiology, obstetrical complications, and fetal injury. Nutr Rev 2007; (II): 194–202.
36. Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci 2011; 1221: 80–7.
37. Saito S, Shima T, Nakashima A et al. What is the role of regulatory T cells in the success of implantation and early pregnancy? Assist Reprod Genet 2007; 24: 379–86.
38. Clark DA. Cell surface CD200 may predict efficacy of paternal mononuclear leukocyte immunotherapy in treatment of human reccurent pregnancy loss. Am J Reprod Immunol 2009; 61: 75–84.
39. Clark DA, Wong K, Banwatt D et al. CD200-dependent and nonCD200-dependent pathways of NK cell suppression by human IVIG. J Assist Reprod Genet 2008; 25 (2–3): 67–72.
40. Gharesi-Fard B, Zolghadri J, Foroughinia L et al. Effectiveness of leukocyte immunotherapy in primary recurrent spontaneous abortion (RSA). Iran J Immunol 2007; 4 (3): 173–8.
41. 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: 289–98.
42. Kheshtchin N, Gharagozloo M, Andalib A et al.The expression of Th1- and Th2-related chemokine receptors in women with recurrent miscarriage: the impact of lymphocyte immunotherapy. Am J Reprod Immunol 2010; 64 (2): 104–12.
43. Beaman KD, Ntrivalas E, Mallers TM et al. Immune Etiology of Recurrent Pregnancy Loss and Its Diagnosis. North Chicago, IL, USA, 2015. 
44. Sidel'nikova V.M. Podgotovka i vedenie beremennosti u zhenshchin s privychnym nevynashivaniem: metod. posobiia i klin. rekomendatsii. M: MEDpress-inform, 2011. [in Russian]
45. Check JH. A practical approach to the prevention of miscarriage: part 2-active immunotherapy. Clin Exp Obstet Gynecol 2010; 37 (1): 5–9.
46. Yang H, Qiu L, Di W et al. Proportional change of CD4+CD25+ regulatory T cells after lymphocyte therapy in unexplained recurrent spontaneous abortion patients. Fertil Steril 2009; 92 (1): 301–5.
47. Khonina NA, Broitman EV, Shevela EY et al. Mixed lymphocyte reaction blocking factors (MLR-Bf) as potential biomarker for indication and efficacy of paternal lymphocyte immunization in recurrent spontaneous abortion. Arch Gynecol Obstet 2013; 288 (4): 933–7.
48. Nonaka T, Takakuwa K, Ooki I et al. Results of immunotherapy for patients with unexplained primary recurrent abortions--prospective non-randomized cohort study. Am J Reprod Immunol 2007; 58 (6): 530–6.
49. Wilczyński JR, Radwan P, Tchórzewski H, Banasik M. Immunotherapy of patients with recurrent spontaneous miscarriage and idiopathic infertility: does the immunization-dependent Th2 cytokine overbalance really matter? Arch Immunol Ther Exp (Warsz) 2012; 60 (2): 151–60.
50. Duckitt K, Qureshi A. Recurrent miscarriage. Clin Evid (Online) 2011; 2011. pii: 1409. 
51. Check JH, Arwitz M, Gross J et al. Lymphocyte immunotherapy (LI) increases serum levels of progesterone induced blocking factor (PIBF). Am J Reprod Immunol 1997; 37 (1): 17–20.

В.А.Сарибегова*, Н.К.Тетруашвили, Л.В.Кречетова, А.А.Агаджанова 

ФГБУ «Научный центр акушерства, гинекологии и перинатологии им. В.И.Кулакова» Минздрава России. 117997, Россия, Москва, ул. Академика Опарина, д. 4
*saribegova_v@rambler.ru

________________________________________________

V.A.Saribegova*, N.K.Tetruashvili, L.V.Krechetova, A.A.Agadzhanova

V.I.Kulakov Research Center for Obstetrics, Gynecology and Perinatology of the Ministry of Health of the Russian Federation. 117997, Russian Federation, Moscow, ul. Akademika Oparina, d. 4
*saribegova_v@rambler.ru