Evaluation of the effectiveness of cytotherapy in women with early pregnancy loss
- Authors: Shengeliia M.O.1, Bespalova O.N.1, Zhernakova T.S.1, Kornyushina E.A.1, Pachuliia O.V.1, Semenov V.A.1
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Affiliations:
- The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott
- Issue: Vol 73, No 6 (2024)
- Pages: 182-193
- Section: Original study articles
- Submitted: 31.03.2024
- Accepted: 06.09.2024
- Published: 06.12.2024
- URL: https://journals.eco-vector.com/jowd/article/view/629708
- DOI: https://doi.org/10.17816/JOWD629708
- ID: 629708
Cite item
Abstract
Background: Cytotherapy, or alloimmunization, with partner lymphocytes is a method of active immunocorrection through artificial immunization with allogeneic paternal or donor leukocytes or their fragments before and in the early stages of pregnancy, as an effective method for correcting immunoregulation, which will increase the effectiveness of assisted reproductive technologies protocols and the number of successful pregnancies ending in live birth in couples with recurrent pregnancy loss.
Aim: The aim of this study was to evaluate the clinical and laboratory effectiveness of cytotherapy in married couples with a history of reproductive disorders.
Materials and methods: The study included 77 married couples with recurrent miscarriage, primary infertility, and repeated implantation failure during in vitro fertilization. Inclusion criteria were age 20–44 years, 2 implantation failures during in vitro fertilization and more and/or 2 spontaneous abortions before 20 weeks of gestation and more, normal karyotypes of the abortus and partners, HLA (human leukocyte antigen, major histocompatibility complex) class II gene typing at three loci (DQA1, DQB1, DRB1) in the married couple. All women received cytotherapy as monotherapy before a planned pregnancy. To study the immune status, the patients’ blood was examined and the natural killer (NK) cell (CD3−CD16+CD56+) and natural T-killer (NKT) cell (CD3+CD16+CD56+) counts, as well as NK cell activity, were determined by spontaneous or activated expression of CD107a.
Results: Of the 77 women included in the study, 32 individuals did not have 12 months to register their pregnancy, therefore, of the remaining 48 married couples, 32 (66.7%) ones had pregnancy registered within 12 months after immunization. Among patients with recurrent miscarriage, pregnancy occurred in 87.0% of cases, in which in 45.2% of cases it ended in the birth of a healthy full-term newborn, and in 29% of cases, pregnancy is currently developing. Among patients with primary infertility and repeated implantation failure during in vitro fertilization, pregnancy occurred in 35.3% of cases. When comparing the functional activities of NK cells in peripheral blood before and two weeks after the second cytotherapy, we found a decrease in the total NK cell count by 5.1% (p = 0.015).
Conclusions: Cytotherapy is an effective therapy in patients with recurrent early miscarriage and leads to pregnancy in 87% of cases and its prolongation after 13 weeks in 74% of cases. The effect of the procedure is justified by its immunoregulatory functions, which is manifested by a decrease in the total NK cell count.
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About the authors
Margarita O. Shengeliia
The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott
Author for correspondence.
Email: bakleicheva@gmail.com
ORCID iD: 0000-0002-0103-8583
SPIN-code: 7831-2698
MD, Cand. Sci. (Medicine)
Russian Federation, Saint PetersburgOlesya N. Bespalova
The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott
Email: shiggerra@mail.ru
ORCID iD: 0000-0002-6542-5953
SPIN-code: 4732-8089
MD, Dr. Sci. (Medicine)
Russian Federation, Saint PetersburgTatiana S. Zhernakova
The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott
Email: tatazhernakova@gmail.com
ORCID iD: 0000-0002-5131-4363
SPIN-code: 3913-7697
MD
Russian Federation, Saint PetersburgEkaterina A. Kornyushina
The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott
Email: hapacheva@yandex.ru
ORCID iD: 0009-0003-5918-2697
SPIN-code: 5844-1975
MD, Cand. Sci. (Medicine)
Russian Federation, Saint PetersburgOlga V. Pachuliia
The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott
Email: for.olga.kosyakova@gmail.com
ORCID iD: 0000-0003-4116-0222
SPIN-code: 1204-3160
Scopus Author ID: 57299197900
MD, Cand. Sci. (Medicine)
Russian Federation, Saint PetersburgVyacheslav A. Semenov
The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott
Email: semenov.v.a@gmail.com
ORCID iD: 0009-0001-1777-9650
Russian Federation, Saint Petersburg
References
- Saribegova VA, Tetruashvili NK, Vtorushina VV, et al. The influence of immunocytotherapy on the course and outcomes of pregnancies in women with recurrent miscarriage, depending on the timing of pregnancy. Journal of Obstetrics and Women’s Diseases. 2017;66(S):36–37. (In Russ.) EDN: YLAOIG
- Francisco PD, Tan-Lim CSC, Agcaoili-De Jesus MSL. Efficacy of lymphocyte immunotherapy in the treatment of recurrent pregnancy loss from alloimmunity: a systematic review and meta-analysis. Am J Reprode Immunol. 2022;88(4):e13605. doi: 10.1111/aji.13605
- Ramhorst R., Agriello E., Zittermann S., et al. Is the paternal mononuclear cells’ immunization a successful treatment for recurrent spontaneous abortion? Am J Reprod Immunol. 2000;44(3):129–135. doi: 10.1111/j.8755-8920.2000.440301.x
- Pandey MK, Agrawal S. Prevalence of anti-idiotypic antibodies in pregnancy v/s recurrent spontaneous abortion (RSA) women. Obstet Gynaecol Today. 2002;10:574–578.
- Hajipour H, Nejabati HR, Latifi Z, et al. Lymphocytes immunotherapy for preserving pregnancy: mechanisms and challenges. Am J Reprod Immunol. 2018;80(3):12853. doi: 10.1111/aji.12853
- Günther V, Alkatout I, Meyerholz L, et al. Live birth rates after active immunization with partner lymphocytes. Biomedicines. 2021;29;9(10):1350. doi: 10.3390/biomedicines9101350
- Meng L, Tan J, Du T, et al. The effects of LIT and MLR-Bf on immune biomarkers and pregnancy outcomes in women with previous early recurrent miscarriage: a retrospective study. Front Immunol. 2021;4(12):642120. doi: 10.3389/fimmu.2021.642120
- Arefieva A, Nikolaeva M, Stepanova E, et al. Association of CD200 expression in paternal lymphocytes with female Th1/Th2 balance and pregnancy establishment at immunotherapy of recurrent spontaneous abortion. Am J Reprod Immunol. 2021;85(3):13355. doi: 10.1111/aji.13355
- Sarkesh A, Sorkhabi AD, Ahmadi H, et al. Allogeneic lymphocytes immunotherapy in female infertility: lessons learned and the road ahead. Life Sci. 2022;15(299):120503. doi: 10.1016/j.lfs.2022.120503
- Moffett A, Chazara O, Colucci F. Maternal allo-recognition of the fetus. Fertil Steril. 2017;107(6):1269–1272. doi: 10.1016/j.fertnstert.2017.05.001
- Krechetova LV, Vanko LV, Vtorushina VV, et al. Lymphocyte activation in the development of immune tolerance in women with recurrent pregnancy loss. Biochemistry (Mosc). 2020;85(5):583–593. doi: 10.1134/S0006297920050077
- Govallo VI, Sidelnikova VM. Immunization of pregnant women with allogeneic lymphocytes of the husband as a method of preventing spontaneous miscarriages. Obstetrics and Gynecology. 1983;12:25–27. (In Russ.)
- Chen J, Liu B, Zhang Y, et al. Effect of immunotherapy on patients with unexplained recurrent spontaneous abortion. Ann Palliat Med. 2020;9(5):2545–2550. doi: 10.21037/apm-19-440b
- Sarno M, Cavalcante MB, Niag M, et al. Gestational and perinatal outcomes in recurrent miscarriages couples treated with lymphocyte immunotherapy. Eur J Obstet Gynecol Reprod Biol. 2019;7(3):100036. doi: 10.1016/j.eurox.2019.100036
- Eidizadeh A, Papert S, Valk J, et al. Adverse drug reactions following lymphocyte immunotherapy for the treatment of infertility: a retrospective study. J Obstet Gynaecol Res. 2022;48(10):2571–2582. doi: 10.1111/jog.15348
- Li J, Gu Y, Zhang S, et al. Effect of prepregnancy lymphocyte active immunotherapy on unexplained recurrent miscarriage, pregnancy success rate, and maternal-infant outcome. BioMed Res Int. 2021;2021:7878752. doi: 10.1155/2021/7878752
- Liu S, Gu X, Weng R. Clinical effect of lymphocyte immunotherapy on patients with unexplained recurrent spontaneous abortion. Immun Inflamm Dis. 2021;9(4):1272–1278. doi: 10.1002/iid3.474
- Rezayat F, Esmaeil N, Rezaei A, et al. Contradictory effect of lymphocyte therapy and prednisolone therapy on CD3+CD8+CD56+ Natural Killer T Population in Women with Recurrent Spontaneous Abortion. J Hum Reprod Sci. 2023;16(3):246–256. doi: 10.4103/jhrs.jhrs_8_23
- Aslanian-Kalkhoran L, Kamrani A, Alipourfard I, et al. The effect of lymphocyte immunotherapy (LIT) in modulating immune responses in patients with recurrent pregnancy loss (RPL). Int Immunopharmacology. 2023;121:110326. doi: 10.1016/j.intimp.2023.110326
- Gharesi-Fard B, Zolghadri J, Kamali-Sarvestani E. Effect of leukocyte therapy on tumor necrosis factor-alpha and interferon-gamma production in patients with recurrent spontaneous abortion. Am J Reprod Immunol. 2008;59(3):242–250. doi: 10.1111/j.1600-0897.2007.00569.x
- Díaz-Hernández I, Alecsandru D, García-Velasco JA, et al. Uterine natural killer cells: from foe to friend in reproduction. Hum Reprod Update. 2021;27(4):720–746. doi: 10.1093/humupd/dmaa062
- Günther V, Alkatout I, Junkers W, et al. Active immunisation with partner lymphocytes in female patients who want to become pregnant – current status. Geburtshilfe und Frauenheilkunde, 2018;78(3):260–273. doi: 10.1055/s-0044-101609
- Liang X, Qiu T, Qiu L, et al. Female third party lymphocytes are effective for immunotherapy of patients with unexplained primary recurrent spontaneous abortion: a retrospective analysis of outcomes. Eur J Contracept Reprod Health Care. 2015;20(6):428–437. doi: 10.3109/13625187.2015.1046593
- Sarkesh A, Sorkhabi AD, Ahmadi H, et al. Allogeneic lymphocytes immunotherapy in female infertility: lessons learned and the road ahead. Life Sci. 2022;15(299):120503. doi: 10.1016/j.lfs.2022.120503
- Parhizkar F, Motavalli-Khiavi R, Aghebati-Maleki L, et al. The impact of new immunological therapeutic strategies on recurrent miscarriage and recurrent implantation failure. Immunol Letters. 2021;236:20–30. doi: 10.1016/j.imlet.2021.05.008
- Bespalova ON. Genetic risk factors for miscarriage [dissertation abstract]: Saint-Petersburg; 2009. Available from: https://www.dissercat.com/content/geneticheskie-faktory-riska-nevynashivaniya-beremennosti/read. (In Russ.)
- Robertson SA, Care AS, Moldenhauer LM. Regulatory T cells in embryo implantation and the immune response to pregnance. J Clin Invest. 2018;128(10):4224–4235. doi: 10.1172/JCI122182
- Piccinni MP, Raghupathy R, Saito S, et al. Cytokines, hormones and cellular regulatory mechanisms favoring successful reproduction. Front Immunol. 2021;28(12):717808. doi: 10.3389/fimmu.2021.717808
- Yuan MM, Du MR, Wang MY, et al. Combination of CD4(+)CD25(+)CD127(-) regulatory T cells with MLC-BE and BE-Ab2: an efficient evaluation of the therapy of paternal lymphocyte induced immunization in unexplained recurrent spontaneous abortion patients. Int J Clin Exper Pathol. 2015;8(4):4022–4032.
- Agrawal S, Kishore R, Halder A, et al. Outcome of pregnancy in women with recurrent spontaneous abortion following immunotherapy with allogeneic lymphocytes. Hum Reprod. 1995;10(9):2280–2284. doi: 10.1093/oxfordjournals.humrep.a136285
- Aoki K, Kajiura S, Matsumoto Y, et al. Clinical evaluation of immunotherapy in early pregnancy with x-irradiated paternal mononuclear cells for primary recurrent aborters. Am J Obstet Gynecol. 1993;169(3):649–653. doi: 10.1016/0002-9378(93)90638-y
- Beer AE, Quebbeman JF, Ayers JW, et al. Major histocompatibility complex antigens, maternal and paternal immune responses, and chronic habitual abortions in humans. Am J Obstet Gynecol. 1981;141(8):987–999. doi: 10.1016/s0002-9378(16)32690-4
- Kishore R, Agarwal S, Halder A, et al. HLA sharing, anti-paternal cytotoxic antibodies and MLR blocking factors in women with recurrent spontaneous abortion. J Obstet Gynaecol Res. 1996;22(2):177–183. doi: 10.1111/j.1447-0756.1996.tb00962.x
- Smith JB, Cowchock FS. Immunological studies in recurrent spontaneous abortion: effects of immunization of women with paternal mononuclear cells on lymphocytotoxic and mixed lymphocyte reaction blocking antibodies and correlation with sharing of HLA and pregnancy outcome. J Reprod Immunol. 1988;14(2):99–113. doi: 10.1016/0165-0378(88)90062-9
- Agarwal S, Kishore R, Halder A, et al. Outcome of pregnancy in women with recurrent spontaneous abortion following immunotherapy with allogeneic lymphocyes. Hum Reprod. 1995;10(9):2280–2284. doi: 10.1093/oxfordjournals.humrep.a136285
- Motak-Pochrzest H, Malinowski A. Polish experiences with paternal lymphocyte immunization in women with recurrent miscarriages. Neuroendocrinol Lett. 2015;36(6):572–577.
- Fainboim L, Belén S, González V, et al. Evaluation of paternal lymphocyte immunotherapy and potential biomarker mixed lymphocyte reaction-blocking factor in an Argentinian cohort of women with unexplained recurrent spontaneous abortion and unexplained infertility. Am J Reprod Immunol. 2021;86(2):13422. doi: 10.1111/aji.13422
- Antukh EI, Smirnova IV. Method of immunization with husband’s lymphocytes in the treatment of recurrent miscarriage. Protection of motherhood and childhood. 2011;17(1):66–68. (In Russ.) EDN: ODCNCP
- Mamedli GH, Babaeva GI, Azizova ME, et al. Homology of class II HLA antigens as a cause of early reproductive losses. Biomedicine (Baku). 2021;19(2):18–23. (In Russ.) doi: 10.24412/1815-3917-2021-2-18-23
- Alexandrova M, Manchorova D, Dimova T. Immunity at maternal-fetal interface: KIR/HLA (Allo)recognition. Immunol Rev., 2022;308(1):55–76. doi: 10.1111/imr.13087
- Xu L, Li Y, Sang Y, et al. Crosstalk between trophoblasts and decidual immune cells: the cornerstone of maternal-fetal immunotolerance. Front Immunol. 2021;25(12):642392. doi: 10.3389/fimmu.2021.642392
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