The Effectiveness of Paternal Lymphocyte Immunotherapy for Recurrent Miscarriage in Couples with Human Leukocyte Antigen Sharing: A Novel Approach

Main Article Content

Devika Gunasheela Aparna Nagaraj Akhila MV Sachin Shetty Swathi Shetty

Abstract

Background: The aetiology of recurrent pregnancy loss (RPL) is varied and ranges from genetic abnormalities, autoimmune, uterine structural abnormalities, thrombophilic disorders, endocrinologic dysfunction, infective to idiopathic factors. Reproductive immunology may provide an area of opportunity in treatment of idiopathic cases. Research has indicated that any amount of HLA compatibility among spouses leads to immunological perturbations leading to higher RPL rates. These disturbances in alloimmune parameters are found to be significantly reduced after a successful immunotherapy with paternal lymphocytes immunotherapy (LIT) among couples who share HLA.


Aim: To analyze the role of alloimmune factors in couples who are considered unexplained RPL by testing HLA sharing between the partners and to determine the effect of lymphocyte immunotherapy (LIT) on live birth rate in couples with HLA sharing.


Methods: This retrospective observational study was conducted in a single tertiary center in Bangalore for a duration of three years. Couples who satisfied the inclusion and exclusion criteria were selected and HLA sharing between the partners was tested. Couples with HLA sharing received LIT before and during pregnancy. The pregnancy and live birth rates were calculated and compared with couples with HLA sharing who did not receive LIT.


Results: Out of the 199 couples who were screened for HLA sharing among partners, 146 couples had different degrees of HLA sharing. 81 couples received LIT and 32 did not opt for LIT and were taken as control group. The pregnancy and live birth rates were significantly higher in the LIT group compared to control group (77.7% vs 40.6%, p-0.0001, OR 5.1, 95% CI 2.10-11.4 and 56.7% vs 21.8%, p-0.0002, OR 4.6, 95% CI 2.13-13.8 respectively). Miscarriage rates were similar between the two groups.


Conclusion:  Partner lymphocyte immunotherapy is a novel treatment option in improving the pregnancy outcomes among women with unexplained RPL and HLA sharing among partners.


Institutional ethical committee registration number- EC/22/000115


Ethical committee approval number for study-EC/OA/46/2023

Article Details

How to Cite
GUNASHEELA, Devika et al. The Effectiveness of Paternal Lymphocyte Immunotherapy for Recurrent Miscarriage in Couples with Human Leukocyte Antigen Sharing: A Novel Approach. Medical Research Archives, [S.l.], v. 11, n. 7.1, july 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4061>. Date accessed: 03 dec. 2024. doi: https://doi.org/10.18103/mra.v11i7.1.4061.
Section
Research Articles

References

1. Sarno M, Cavalcante MB, Niag M, et al. Gestational and perinatal outcomes in recurrent miscarriages couples treated with lymphocyte immunotherapy. European Journal of Obstetrics & Gynecology and Reproductive Biology: X. 2019;3:100036.
2. Bender Atik R, Christiansen OB, Elson J, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2):hoy004.
3. Ajmal L, Ajmal S, Ajmal M, et al. HLA System and its Participation in Recurrent Pregnancy Loss. PJZ. 2022;54(4): 1905-1916
4. Cavalcante MB, Sarno M, Barini R. Lymphocyte immunotherapy in recurrent miscarriage and recurrent implantation failure. Am J Reprod Immunol. 2021;85(4):e13408.
5. Singh M, Rajak J, Kadam S, B. Rajadhyaksha S. Alloimmunization and Role of HLA in Pregnancy. Complications of Pregnancy. 2019.
6. Christiansen OB. Reproductive immunology. Molecular Immunology. 2013;55(1):8-15.
7. van der Zwan A, Bi K, Norwitz ER, et al. Mixed signature of activation and dysfunction allows human decidual CD8 + T cells to provide both tolerance and immunity. Proc Natl Acad Sci USA. 2018;115(2):385-90.
8. Hviid T, Hylenius S, Lindhard A, Christiansen O. Association between human leukocyte antigen-G genotype and success of in vitro fertilization and pregnancy outcome. Tissue Antigens. 2004;64(1):66-9.
9. Persson G, Jørgensen N, Nilsson LL, Andersen LHJ, Hviid TVF. A role for both HLA-F and HLA G in reproduction and during pregnancy? Human Immunology. 2020;81(4):127-33.
10. Strauss-Albee DM, Horowitz A, Parham P, Blish CA. Coordinated Regulation of NK Receptor Expression in the Maturing Human Immune System. The Journal of Immunology. 2014;193(10):4871-9.
11. Le Gars M, Seiler C, Kay AW, et al. Pregnancy-Induced Alterations in NK Cell Phenotype and Function. Front Immunol. 2019;10:2469
12. Tersigni C, Redman C, Dragovic R, et al. HLA-DR is aberrantly expressed at feto-maternal interface in pre-eclampsia. Journal of Reproductive Immunology. 2018;129:48-52.
13. Omu AE, Al-Qattan F, Bukhadour N. Human leucocyte antigens in pregnant women with pre-eclampsia associated with intrauterine growth retardation and in normal controls. Archives of Gynecology and Obstetrics. 1998;261(3):129-37.
14. Cecati M, Giannubilo SR, Emanuelli M, Tranquilli AL, Saccucci F. HLA-G and pregnancy adverse outcomes. Medical Hypotheses. 2011;76(6):782-4.
15. Aruna M, Nagaraja T, Andal Bhaskar S, et al. Novel alleles of HLA-DQ and -DR loci show association with recurrent miscarriages among South Indian women. Human Reproduction. 2011;26(4):765-74.
16. Gharesi-Fard B, Askarinejad-Behbahani R, Behdin S. The effect of HLA-DRB1 sharing between the couples with recurrent pregnancy loss on the pregnancy outcome after leukocyte therapy. Iran J Immunol. 2014;11(1):13-20.
17. Takakuwa K, Hataya I, Arakawa M, et al. Possible Susceptibility of the HLA-DPB1*0402 and HLA-DPB1*04 Alleles to Unexplained Recurrent Abortion: Analysis by means of Polymerase Chain Reaction-Restricted Fragment Length Polymorphism Method. American Journal of Reproductive Immunology. 1999;42(4):233-9.
18. D'Ippolito S, Gasbarrini A, Castellani R, et al. Human leukocyte antigen (HLA) DQ2/DQ8 prevalence in recurrent pregnancy loss women. Autoimmunity Reviews. 2016;15(7):638-43.
19. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685-711.
20. Mekinian A, Cohen J, Alijotas-Reig J, et al. Unexplained Recurrent Miscarriage and Recurrent Implantation Failure: Is There a Place for Immunomodulation. Am J Reprod Immunol. 2016;76(1):8-28.
21. Taylor C, Faulk WP. Prevention of recurrent abortion with leucocyte transfusions. Lancet. 1981;2(8237):68-70.
22. Beer AE, Semprini AE, Zhu XY, Quebbeman JF. Pregnancy outcome in human couples with recurrent spontaneous abortions: HLA antigen profiles; HLA antigen sharing; female serum MLR blocking factors; and paternal leukocyte immunization. Exp Clin Immunogenet. 1985;2(3):137-53.
23. Szpakowski A, Malinowski A, Cieślak J, et al. [Influence of paternal lymphocyte immunization on the selected subpopulations of peripheral blood lymphocytes in women with recurrent spontaneous abortions of unknown etiology]. Ginekol Pol. 2003;74(4):288-96.
24. Matsubayashi H, Maruyama T, Ozawa N, et al. Anti-paternal antibodies by flow cytometry in the management of alloimmunization on recurrent miscarriages. Am J Reprod Immunol. 2000;44(5):284-8.
25. Ito K, Tanaka T, Tsutsumi N, Obata F, Kashiwagi N. Possible mechanisms of immunotherapy for maintaining pregnancy in recurrent spontaneous aborters: analysis of anti-idiotypic antibodies directed against autologous T-cell receptors. Hum Reprod. 1999;14(3):650-5.
26. Pandey MK, Saxena V, Agrawal S. Characterization of mixed lymphocyte reaction blocking antibodies (MLR-Bf) in human pregnancy. BMC Pregnancy Childbirth. 2003;3(1):2.
27. Masuko-Hongo K, Hayashi K, Yonamine K, Tokuyama M, Nishioka K, Kato T. Disappearance of clonally expanded T cells after allogeneic leukocyte immunotherapy in peripheral blood of patients with habitual abortion. Hum Immunol. 2001;62(10):1111-21.
28. Hayakawa S, Karasaki-Suzuki M, Itoh T, et al. Effects of paternal lymphocyte immunization on peripheral Th1/Th2 balance and TCR V beta and V gamma repertoire usage of patients with recurrent spontaneous abortions. Am J Reprod Immunol. 2000;43(2):107-15.
29. Ober C, Karrison T, Odem RR, et al. Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial. Lancet. 1999;354(9176):365-9.
30. i D, Li C, Zhu Y. [Comparative study of the third party and paternal leukocyte immunization in recurrent spontaneous abortion of lowered maternal-fetal immuno-recognition]. Zhonghua Fu Chan Ke Za Zhi. 1998;33(10):597-600.
31. Wong LF, Porter TF, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev. 2014;2014(10):CD000112.
32. Clark DA. The end of evidence-based medicine. Inflammopharmacology. 2012;20(4):187-93.
33. 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(5):308-13.
34. Liu Z, Xu H, Kang X, Wang T, He L, Zhao A. Allogenic Lymphocyte Immunotherapy for Unexplained Recurrent Spontaneous Abortion: A Meta-Analysis. Am J Reprod Immunol. 2016;76(6):443-53.
35. Cavalcante MB, Sarno M, Araujo Júnior E, Da Silva Costa F, Barini R. Lymphocyte immunotherapy in the treatment of recurrent miscarriage: systematic review and meta-analysis. Arch Gynecol Obstet. 2017;295(2):511-8.
36. Günther V, Alkatout I, Meyerholz L, et al. Live Birth Rates after Active Immunization with Partner Lymphocytes. Biomedicines. 2021;9(10):1350.
37. 21. Cui Y.P, Zhong X.Y, Ban Q.M, Hu K, Xiao S.J. Study of immunotherapy with lymphocytes in women with recurrent spontaneous abortion. Mod. Prev. Med. 2011;38:1626–27.
38. Lin S, Yan S, Shan E. Analysis the efficacy of immunotherapy with lymphocytes for recurrent spontaneous abortion. Jilin Med. 2012;33:1822-23.
39. 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;28:876–78.
40. Yu HL, Deng XH, Chao L, Chen C, Han YL. [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(12):903-6.