Low-dose lymphocyte immunotherapy rebalances the peripheral blood Th1/Th2/Treg paradigm in patients with unexplained recurrent miscarriage

Mengyuan Liu, Xin Zhen, Hongyan Song, Junhao Chen, Xiaoling Sun, Xiaoqin Li, Jianjun Zhou, Guijun Yan, Lijun Ding, Haixiang Sun, Mengyuan Liu, Xin Zhen, Hongyan Song, Junhao Chen, Xiaoling Sun, Xiaoqin Li, Jianjun Zhou, Guijun Yan, Lijun Ding, Haixiang Sun

Abstract

Background: The published results regarding lymphocytes immunotherapy for unexplained recurrent miscarriage (uRM) patients are conflicting due to different screening criteria and therapeutic protocols. The objective of the present study is to evaluate the effectiveness of immunotherapy using low-dose lymphocytes in patients with uRM and Th1/Th2/Treg paradigm disorders.

Methods: Sixty-four uRM patients who received low-dose lymphocytes immunotherapy served as the immunotherapy group, while the other 35 women who did not receive the treatment served as the control group. The proportions of peripheral blood Th1 cells, Th2 cells and Treg cells; and the concentration of TGF-β1 in serum were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively, before and after the immunotherapy.

Results: The proportion of Th1 cells was significantly decreased while the proportions of Th2 cells and Treg cells were significantly increased in immunotherapy group patients after treatment. In addition, the concentration of TGF-β1 in serum was significantly higher after immunotherapy than before. Forty-three uRM patients achieved pregnancy after receiving immunotherapy and 5 patients underwent miscarriages in the immunotherapy group (11.6%, 5/43), while 8 of the 23 pregnant patients experienced a miscarriage in the control group (34.8%, 8/23; p < 0.05).

Conclusions: Low-dose lymphocyte immunotherapy is beneficial for restoring balance in the Th1/Th2/Treg paradigm and improving pregnancy outcome in uRM patients.

Trial registration: NCT03081325 . ClinicalTrials.gov . Retrospectively registered July 2015.

Keywords: Lymphocyte immunotherapy; Recurrent miscarriage; Regulatory T cells; Th1 cells; Th2 cells.

Conflict of interest statement

Ethics approval and consent to participate

This study received approval from the Nanjing Drum Tower Hospital Research Ethics Committee (IRB#SZ201–502), and the therapeutic protocol for this study has been registered in Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
The treatment effect of low-dose lymphocyte immunotherapy on Th1/Th2/Treg paradigm disorder. *,P < 0.05;**,P < 0.01;***,<0.001
Fig. 2
Fig. 2
TGF-β1 concentrations and mRNA expression for IFN-γ, IL-4, and FOXP3 of uRM patients before and after low-dose lymphocyte immunotherapy

References

    1. Toth B, Wuerfel W, Bohlmann MK, Gillessen-Kaesbach G, Nawroth F, Rogenhofer N, Tempfer C, Wischmann T, von Wolff M. Recurrent miscarriage: diagnostic and therapeutic procedures. Guideline of the DGGG (S1-level, AWMF registry no. 015/050) Geburtshilfe Frauenheilkd. 2013;75(11):1117–1128.
    1. Larsen EC, Christiansen OB, Kolte AM, Macklon N. New insights into mechanisms behind miscarriage. BMC Med. 2013;11:154. doi: 10.1186/1741-7015-11-154.
    1. Kwak-Kim J, Park JC, Ahn HK, Kim JW, Gilman-Sachs A. Immunological modes of pregnancy loss. Am J Reprod Immunol. 2010;63(6):611–623. doi: 10.1111/j.1600-0897.2010.00847.x.
    1. Chaouat G. Innately moving away from the Th1/Th2 paradigm in pregnancy. Clin Exp Immunol. 2003;131(3):393–395. doi: 10.1046/j.1365-2249.2003.02100.x.
    1. Piccinni MP, Beloni L, Livi C, Maggi E, Scarselli G, Romagnani S. Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nat Med. 1998;4(9):1020–1024. doi: 10.1038/2006.
    1. Li XC, Zand MS, Li Y, Zheng XX, Strom TB. On histocompatibility barriers, Th1 to Th2 immune deviation, and the nature of the allograft responses. J Immunol. 1998;161(5):2241–2247.
    1. Raghupathy R. Th1-type immunity is incompatible with successful pregnancy. Immunol Today. 1997;18(10):478–482. doi: 10.1016/S0167-5699(97)01127-4.
    1. Raghupathy R, Makhseed M, Azizieh F, Omu A, Gupta M, Farhat R. Cytokine production by maternal lymphocytes during normal human pregnancy and in unexplained recurrent spontaneous abortion. Hum Reprod. 2000;15(3):713–718. doi: 10.1093/humrep/15.3.713.
    1. Alijotas-Reig J, Llurba E, Gris JM. Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells. Placenta. 2014;35(4):241–248. doi: 10.1016/j.placenta.2014.02.004.
    1. Mei S, Tan J, Chen H, Chen Y, Zhang J. Changes of CD4+CD25high regulatory T cells and FOXP3 expression in unexplained recurrent spontaneous abortion patients. Fertil Steril. 2010;94(6):2244–2247. doi: 10.1016/j.fertnstert.2009.11.020.
    1. Wang WJ, Hao CF, Qu QL, Wang X, Qiu LH, Lin QD. The deregulation of regulatory T cells on interleukin-17-producing T helper cells in patients with unexplained early recurrent miscarriage. Hum Reprod. 2010;25(10):2591–2596. doi: 10.1093/humrep/deq198.
    1. Winger EE, Reed JL. Low circulating CD4(+) CD25(+) Foxp3(+) T regulatory cell levels predict miscarriage risk in newly pregnant women with a history of failure. Am J Reprod Immunol. 2011;66(4):320–328. doi: 10.1111/j.1600-0897.2011.00992.x.
    1. Li X, Wang B, Li Y, Wang L, Zhao X, Zhou X, Guo Y, Jiang G, Yao C. The Th1/Th2/Th17/Treg paradigm induced by stachydrine hydrochloride reduces uterine bleeding in RU486-induced abortion mice. J Ethnopharmacol. 2013;145(1):241–253. doi: 10.1016/j.jep.2012.10.059.
    1. Mowbray JF, Gibbings C, Liddell H, Reginald PW, Underwood JL, Beard RW. Controlled trial of treatment of recurrent spontaneous abortion by immunisation with paternal cells. Lancet. 1985;1(8435):941–943. doi: 10.1016/S0140-6736(85)91723-4.
    1. Gatenby PA, Cameron K, Simes RJ, Adelstein S, Bennett MJ, Jansen RP, Shearman RP, Stewart GJ, Whittle M, Doran TJ. Treatment of recurrent spontaneous abortion by immunization with paternal lymphocytes: results of a controlled trial. Am J Reprod Immunol. 1993;29(2):88–94. doi: 10.1111/j.1600-0897.1993.tb00571.x.
    1. Liang P, Mo M, Li G, Yin B, Cai J, Wu T, He X, Zhang X, Zeng Y. Comprehensive analysis of peripheral blood lymphocytes in 76 women with recurrent miscarriage before and after lymphocyte immunotherapy. Am J Reprod Immunol. 2012;68(2):164–174. doi: 10.1111/j.1600-0897.2012.01141.x.
    1. Wu L, Luo LH, Zhang YX, Li Q, Xu B, Zhou GX, Luan HB, Liu YS. 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. doi: 10.1186/1477-7827-12-74.
    1. Beer AE, Quebbeman JF, Ayers JW, Haines RF. 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.
    1. Ober C, Karrison T, Odem RR, Barnes RB, Branch DW, Stephenson MD, Baron B, Walker MA, Scott JR, Schreiber JR. Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial. Lancet. 1999;354(9176):365–369. doi: 10.1016/S0140-6736(98)12055-X.
    1. Wong LF, Porter TF, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev. 2014;10:D112.
    1. Cavalcante MB, Sarno M, Araujo Júnior E, Da Silva CF, Barini R. Lymphocyte immunotherapy in the treatment of recurrent miscarriage: systematic review and meta-analysis. Arch Gynecol Obstet. 2016;
    1. Deligiannidis A, Parapanissiou E, Mavridis P, Tabakoudis G, Mavroudi A, Papastavrou T, Tabakoudis P. Thrombophilia and antithrombotic therapy in women with recurrent spontaneous abortions. J Reprod Med. 2007;52(6):499–502.
    1. Pandey MK, Rani R, Agrawal S. An update in recurrent spontaneous abortion. Arch Gynecol Obstet. 2005;272(2):95–108. doi: 10.1007/s00404-004-0706-y.
    1. 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):443–453. doi: 10.1111/aji.12511.
    1. Prins JR, Kieffer TEC, Scherjon SA. Immunomodulators to treat recurrent miscarriage. Eur J Obstet Gynecol Reprod Biol. 2014;181:334–337. doi: 10.1016/j.ejogrb.2014.07.038.
    1. Lee SK, Kim JY, Hur SE, Kim CJ, Na BJ, Lee M, Gilman-Sachs A, Kwak-Kim J. An imbalance in interleukin-17-producing T and Foxp3(+) regulatory T cells in women with idiopathic recurrent pregnancy loss. Hum Reprod. 2011;26(11):2964–2971. doi: 10.1093/humrep/der301.
    1. Clark DA. Immunological factors in pregnancy wastage: fact or fiction. Am J Reprod Immunol. 2008;59(4):277–300. doi: 10.1111/j.1600-0897.2008.00580.x.
    1. Mjosberg J, Berg G, Jenmalm MC, Ernerudh J. FOXP3+ regulatory T cells and T helper 1, T helper 2, and T helper 17 cells in human early pregnancy decidua. Biol Reprod. 2010;82(4):698–705. doi: 10.1095/biolreprod.109.081208.
    1. Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology. 2004;112(1):38–43. doi: 10.1111/j.1365-2567.2004.01869.x.
    1. Guerin LR, Prins JR, Robertson SA. Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment? Hum Reprod Update. 2009;15(5):517–535. doi: 10.1093/humupd/dmp004.
    1. Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA. Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25- precursors. J Immunol. 2002;169(8):4183–4189. doi: 10.4049/jimmunol.169.8.4183.

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