Immunotherapy

Lymphocytes Immunotherapy for Preserving Pregnancy

A Ray of hope for Mothers –To-Be

Our conventional understanding of the immune system might suggest that the mother’s immune system would reject this foreign genetic material. However, during a healthy pregnancy, we see that the mother’s immune system becomes tolerant to the fetus paternally-determined proteins and this allows the pregnancy to continue to term.  When Peter Medawar, an early Nobel Prize winner for the immunology of transplantation, considered the problem of maternal tolerance, he thought that the maternal immune system must somehow be oblivious to the fetus, either because of physical separation created by the placenta or by some other means that would avoid alerting the maternal immune system to the presence of the foreign fetal tissues.  We understand that the maternal immune system actively makes a decision to tolerate rather than reject the fetus. Immunotherapy seen in the light of current science appears to enhance the friendly introduction of the immune system to paternal-gene programmed proteins, the same that the mother will encounter in placental tissues. The story that unfolds reveals new and important cells in the immune response. The numbers of these cells (T regulatory cells) in the blood have been shown to correlate with outcomes. Appropriate interaction with these cells is paramount for success. Deceptively, proper Immunotherapy technique is very important for making the proper introduction and ultimate success.
Immunotherapy is a procedure where by special types of white blood cells from the prospective father are injected into the skin of the prospective mother to prepare the maternal immune system for pregnancy. Because pregnancy tissues are the product of both the mothers as well as the fathers genes. Immunotherapy assists the mother’s immune system in the development of immunologic tolerance to the genetically foreign pregnancy tissues.

❖ Lymphocyte immunotherapy (LIT) is a cost-effective, safe, and useful approach, with a proper dose of fresh lymphocytes inducing intradermally before and during pregnancy.
❖ LIT induces the production of anti-paternal cytotoxic antibodies (APCAs), mixed lymphocyte reaction blocking antibodies (MLR- Babs or MLR-BF), and anti-idiotypic antibodies (Ab2) that can cover paternal human leukocyte antigen (HLA) in the surface of the fetus and thereby prevent from maternal natural killer (NK) and T cells attacking.
❖ LIT significantly reduces T helper (Th-1 and Th-17) and increases Th2 and regulatory T (Treg) cells levels and consequently causes an increase in cytokines produced by Th2 and Treg such as interleukin (IL) – 10, – 4 and transforming growth factor beta (TGFß) which act in favor of a successful gestation; while decreases Th1 and Th17 secreted cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor- alpha (TNF-a) that act against pregnancy.
❖ Overall, cell therapy mechanisms of action are inducing the production of cytokines, blocking antibodies and growth factors, the proliferation of B10 cells, reducing the activity of NK cells, increasingTh2 and Treg cells, and decreasing Th1 and Th17 cells.
❖  Immunotherapy is a treatment for unexplained pregnancy loss or IVF failure. A recent study reported from eighteen randomized, placebo-controlled trials that Immunotherapy performed before and during pregnancy had dramatically improved the live birth rate in women with unexplained pregnancy loss or IVF failure. The success rate of treatment group was significantly higher.
❖ Immunotherapy given before and during pregnancy is superior to given only before pregnancy, and the lower doses per treatment achieved a better outcome.
❖ Although cell therapy is a promising approach, can be an effective strategy as it provides an interactive, dynamic, specific, and individualized treatment.

Overall, LIT modulates the mother’s immune system to protect the fetus and make the pregnancy prosperous.

Possible mechanism by which leukocyte immunotherapy (LIT) enhances pregnancy rate in women with recurrent pregnancy loss

Figure: Possible mechanism by which leukocyte immunotherapy (LIT) enhances pregnancy rate in women with recurrent pregnancy loss. (Hajipour et al., 2018).

Immunotherapy is performed by various Gynecologists and IVF centres all over the world.
Some of the country listed below with reference:

India

    • 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(3): 161-72.
    • Kumar A. 2014. Immunomodulation in Recurrent Miscarriage. The Journal of Obstetrics and Gynecology of India. 2014, 64(3):165–168

Germany

    • Sibylle Wegener et al., Immunotherapy with Paternal Lymphocytes for Recurrent Miscarriages and Unsuccessful in vitro Fertilization Treatment. Transfus Med Hemother 2006;33:501–507

China

    • 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
    • Yan-Jiao Hua, et al. 2016. Lymphocyte immunotherapy for recurrent spontaneous abortion in patients with negative blocking antibody. Int J Clin Exp Med 2016;9(6):9856-9867
    • Wu et al. 2014. Alteration of Th17 and Treg cells in patients with unexplained recurrent spontaneous abortion before and after lymphocyte immunization therapy Reproductive Biology and Endocrinology 2014, 12:74
    • Ho HN, et al. 1991. Immunotherapy for recurrent spontaneous abortions in a Chinese population. Am J Reprod Immunol 1991; 25:10–15.

Iran

    • Mitra Rafiee et al. 2015. Altered Th17/Treg Ratio in Recurrent Miscarriage after Treatment with Paternal Lymphocytes and Vitamin D3: a Double-Blind Placebo-Controlled Study. Rafiee M, et al. Iran J Immunol. 2015; 12(4):252-262.

UK

    • Bansal A.S. et al. 2012. The basis and value of currently used immunomodulatory therapies in recurrent miscarriage. Journal of Reproductive Immunology 93 (2012) 41– 51
    • Kim D. Ly et al. 2010. Evidence-Based Management of Infertile Couples with Repeated Implantation Failure Following IVF. Current Women’s Health Reviews, 2010, 6, 200-218

Poland

    • Hanna Motak-Pochrzęst et al. 2015. Polish experiences with paternal lymphocyte immunization in women with recurrent miscarriages. Neuroendocrinology Letters Volume 36 No. 6 2015

Denmark

    • Mette Dahl et al. 2012. Human leucocyte antigen class Ib molecules in pregnancy success and early pregnancy loss. Human Reproduction Update, Vol.18, No.1 pp. 92–109

Japan

    • Hiroshi Fujiwara et al. 2010. Possible Contribution of Circulating Blood Cells to Embryo Implantation. Indian J Physiol Pharmacol 54 (5) 2010 ; 51-59

USA

    • Check J.H et al. 2005. Lymphocyte immunotherapy can improve pregnancy outcome following embryo transfer (ET) in patients failing to conceive after two previous ET. Clin.Exp.Obst &Gyn-ISSN:0390-6663, XXXII, n 1, 2005.
    • Alan E. Beer Medical Center for Reproductive Immunology, USA

Greece

    • Antonis Makrigiannakis et al. 2015. Repeated implantation failure: a new potential treatment option. Department of Obstetrics and Gynecology, Medical School, University of Crete, Heraklion, Greece

London

  • The Fertility & Gynecology Academy

Reference

2020

    • R. Pourakbari, H. Ahmadi, M. Yousefi, et al., Cell therapy in female infertility-related diseases: Emphasis on recurrent miscarriage and repeated implantation failure, Life Sciences (2020)

2018

    • Hajipour H, et al. Lymphocyte immunotherapy for preserving pregnancy Mechanism and Challenges. Am J Reprod Immunol. 2018;e12853
    • Marcelo Borges Cavalcante et al., Lymphocyte immunotherapy for recurrent miscarriages: Predictors of therapeutic success. Am J Reprod Immunol. 2018;e12833.
    • Omar Sefrioui et al., Luteal progesterone level correlated with immunotherapy success of patients with repeated implantation failures.

2016

    • 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
    • Yan-Jiao Hua, et al. 2016. Lymphocyte immunotherapy for recurrent spontaneous abortion in patients with negative blocking antibody. Int J Clin Exp Med 2016;9(6):9856-9867

2015

    • Mitra Rafiee et al. 2015. Altered Th17/Treg Ratio in Recurrent Miscarriage after Treatment with Paternal Lymphocytes and Vitamin D3: a Double-Blind Placebo-Controlled Study. Rafiee M, et al. Iran J Immunol. 2015; 12(4):252-262.
    • Hanna Motak-Pochrzęst et al. 2015. Polish experiences with paternal lymphocyte immunization in women with recurrent miscarriages. Neuroendocrinology Letters Volume 36 No. 6 2015
    • Antonis Makrigiannakis et al. 2015. Repeated implantation failure: a new potential treatment option. Department of Obstetrics and Gynecology, Medical School, University of Crete, Heraklion, Greece

2014

    • 2014: Kumar A. 2014. Immunomodulation in Recurrent Miscarriage. The Journal of Obstetrics and Gynecology of India. 2014, 64(3):165–168
    • Wu et al. 2014. Alteration of Th17 and Treg cells in patients with unexplained recurrent spontaneous abortion before and after lymphocyte immunization therapy Reproductive Biology and Endocrinology 2014, 12:74

2012

    • Mette Dahl et al. 2012. Human leucocyte antigen class Ib molecules in pregnancy success and early pregnancy loss. Human Reproduction Update, Vol.18, No.1 pp. 92–109
    • Bansal A.S. et al. 2012. The basis and value of currently used immunomodulatory therapies in recurrent miscarriage. Journal of Reproductive Immunology 93 (2012) 41– 51

2010

    • Kim D. Ly et al. 2010. Evidence-Based Management of Infertile Couples with Repeated Implantation Failure Following IVF. Current Women’s Health Reviews, 2010, 6, 200-218
    • Hiroshi Fujiwara et al. 2010. Possible Contribution of Circulating Blood Cells to Embryo Implantation. Indian J Physiol Pharmacol 54 (5) 2010 ; 51-59

2006-1991

    • 2006: Sibylle Wegener et al., Immunotherapy with Paternal Lymphocytes for Recurrent Miscarriages and Unsuccessful in vitro Fertilization Treatment. Transfus Med Hemother 2006;33:501–507
    • Check J.H et al. 2005. Lymphocyte immunotherapy can improve pregnancy outcomes following embryo transfer (ET) in patients failing to conceive after two previous ET. Clin.Exp.Obst &Gyn-ISSN:0390-6663, XXXII, n 1, 2005.
    • 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(3): 161-72.
    • Ho HN, et al. 1991. Immunotherapy for recurrent spontaneous abortions in a Chinese population. Am J Reprod Immunol 1991; 25:10–15.

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