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Intrauterine insemination of cultured peripheral blood mononuclear cells prior to embryo transfer improves clinical outcome for patients with repeated implantation failures

Published online by Cambridge University Press:  23 January 2015

Aicha Madkour
Affiliation:
Anfa Fertility Center, Privante Clinic of Human Reproduction and Endoscopic Surgery, Casablanca, Morocco. Biochemistry and Immunology Laboratory, Mohammed V University, Faculty of Sciences, BP 1014, Avenue Ibn Batouta Agdal, Rabat, Morocco. Labomac, Laboratory of Medical Analysis, Casablanca, Morocco.
Nouzha Bouamoud
Affiliation:
Biochemistry and Immunology Laboratory, Mohammed V University, Faculty of Sciences, BP 1014, Avenue Ibn Batouta Agdal, Rabat, Morocco.
Noureddine Louanjli
Affiliation:
Anfa Fertility Center, Privante Clinic of Human Reproduction and Endoscopic Surgery, Casablanca, Morocco. Labomac, Laboratory of Medical Analysis, Casablanca, Morocco.
Ismail Kaarouch
Affiliation:
Anfa Fertility Center, Privante Clinic of Human Reproduction and Endoscopic Surgery, Casablanca, Morocco. Biochemistry and Immunology Laboratory, Mohammed V University, Faculty of Sciences, BP 1014, Avenue Ibn Batouta Agdal, Rabat, Morocco. Labomac, Laboratory of Medical Analysis, Casablanca, Morocco.
Henri Copin
Affiliation:
Reproductive Biology and Medical Cytogenetics Laboratory, Regional University Hospital & School of Medicine, Picardie University Jules Verne, Amiens, France.
Moncef Benkhalifa*
Affiliation:
Reproductive Biology and Medical Cytogenetics Laboratory, Regional University Hospital & School of Medicine, Picardie University Jules Verne. Amiens. France.
Omar Sefrioui
Affiliation:
Anfa Fertility Center, Privante Clinic of Human Reproduction and Endoscopic Surgery, Casablanca, Morocco.
*
All correspondence to: M Benkhalifa. Reproductive Biology and Medical Cytogenetics Laboratory, Regional University Hospital & School of Medicine, Picardie University Jules Verne. Amiens. France. Tel: +33 677867390. Fax: +33 130571934. e-mail: benkhalifamoncef78@gmail.com

Summary

Implantation failure is a major limiting factor in assisted reproduction improvement. Dysfunction of embryo–maternal immuno-tolerance pathways may be responsible for repeated implantation failures. This fact is supported by immunotropic theory stipulating that maternal immune cells, essentially uterine CD56+ natural killer cells, are determinants of implantation success. In order to test this hypothesis, we applied endometrium immuno-modulation prior to fresh embryo transfer for patients with repeated implantation failures. Peripheral blood mononuclear cells were isolated from repeated implantation failure patients undergoing assisted reproductive technology cycles. On the day of ovulation induction, cells were isolated and then cultured for 3 days and transferred into the endometrium cavity prior to fresh embryo transfer. This immunotherapy was performed on 27 patients with repeated implantation failures and compared with another 27 patients who served as controls. Implantation and clinical pregnancy were increased significantly in the peripheral blood mononuclear cell test versus control (21.54, 44.44 vs. 8.62, 14.81%). This finding suggests a clear role for endometrium immuno-modulation and the inflammation process in implantation success. Our study showed the feasibility of intrauterine administration of autologous peripheral blood mononuclear cells as an effective therapy to improve clinical outcomes for patients with repeated implantation failures and who are undergoing in vitro fertilization cycles.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2015 

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References

Abrahams, V.M., Straszewski-Chavez, S.L., Guller, S. & Mor, G. (2004). First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis. Mol. Hum. Reprod. 10 (1), 5563.Google Scholar
Ashkar, A.A., Black, J.P., Wei, Q., He, H., Liang, L., Head, J.R. & Croy, B.A. (2003). Assessment of requirements for IL 15 and INF regulatory factors in uterine NK cell differentiation and function during pregnancy. J. Immunol. 171, 2937–44.Google Scholar
Basu, S., Eriksson, M., Pioli, P.A., Conejo-Garcia, J., Mselle, T.F., Yamamoto, S., Wira, C.R. & Sentman, C.L. (2009). Human uterine NK cells interact with uterine macrophages via NKG2D upon stimulation with PAMPs. Am. J. Reprod. Immunol. 61, 5261 Google Scholar
Becknell, B. & Caligiuri, M.A. (2005). Interleukin-2, interleukin-15, and their roles in human natural killer cells. Adv. Immunol. 86, 209–39.Google Scholar
Bulmer, J.N. & Lash, G. E. (2005). Human uterine natural killer cells: a reappraisal. Mol. Immunol. 42, 511–21.CrossRefGoogle ScholarPubMed
Bulmer, J.N., Lunny, D.P. & Hagin, S.V. (1988). Immunohistochemical characterization of stromal leucocytes in nonpregnant human endometrium. Am. J. Reprod. Immunol. Microbiol. 17, 8390.CrossRefGoogle ScholarPubMed
Bulmer, J.N., Longfellow, M. & Ritson, A. (1991). Leukocytes and resident blood cells in endometrium. Ann. N. Y. Acad. Sci. 622, 5768.CrossRefGoogle ScholarPubMed
Challis, J.R., Lockwood, C.J., Myatt, L., Norman, J.E., Strauss, J.F.III. & Petraglia, F. (2009). Inflammation and pregnancy. Reprod. Sci. 2, 206–15.CrossRefGoogle Scholar
Chaouat, G., Dubanchet, S. & Ledee, N. (2007). Cytokines: important for implantation? J. Assist. Reprod. Genet. 11, 491505.CrossRefGoogle Scholar
Chernyshov, V.P., Sudoma, I.O., Dons’koi, B.V., Kostyuchyk, A.A. & Masliy, Y.V. (2010). Elevated NK cell cytotoxicity, CD158a expression in NK cells and activated T lymphocytes in peripheral blood of women with IVF failures. Am. J. Reprod. Immunol. 64, 5867.CrossRefGoogle ScholarPubMed
Coughlan, C., Ledger, W., Wang, Q., Demirol, A., Gurgan, T., Cutting, R., Ong, K., Sallam, H. & Li, T.C. (2014). Recurrent implantation failure: definition and management. Reprod. Biomed. Online 28, 1438.Google Scholar
Croy, B.A., Chantakru, S., Esadeg, S., Ashkar, A.A. & Wei, Q. (2002). Decidual natural killer cells: key regulators of placental development. J. Reprod. Immunol. 57 (1–2), 151–68.Google Scholar
Croy, B.A., Esadeg, S., Chantakru, S., van den Heuvel, M., Paffaro, V.A., He, H., Black, G.P., Ashkar, A.A., Kiso, Y. & Zhang, J. (2003). Update on pathways regulating the activation of uterine natural killer cells, their interactions with decidual spiral arteries and homing of their precursors to the uterus. J. Reprod. Immunol. 59, 175–91.Google Scholar
Darmochwal, K.D., Leszczynska, G.B., Rolinski, J. & Oleszczuk, J. (1999). T helper 1- and T helper 2-type cytokine imbalance in pregnant women with pre-eclampsia. Eur. J. Obstet. Gynecol. Reprod. Biol. 86, 165–70.CrossRefGoogle Scholar
David Dong, Z.M., Aplin, A.C. & Nicosia, R.F. (2009). Regulation of angiogenesis by macrophages, dendritic cells, and circulating myelomonocytic cells. Curr. Pharm. Des. 15, 365379.Google Scholar
Dons’koi, B.V., Chernyshov, V.P., Sudoma, I.O., Honcharova, I.O. & Osypchuk, D.V. (2013a). Qualitative analysis of accented CD158a receptor expression in NK-lymphocytes in women with reproductive failures. Lik. Sprava. 1, 8693.Google Scholar
Dons’koi, B.V., Chernyshov, V.P., Sirenko, V.Y., Strelko, G.V. & Osypchuk, D.V. (2013b). Peripheral blood natural killer cells activation status determined by CD69 upregulation predicts implantation outcome in IVF. Immunobiology 219, 167–71.Google Scholar
Fettback, P.B.T., Domingues, T.S., Hassun Filho, P.A., Motta, E.L.A., Serafini, P.C. & Baracat, E.C. (2009). Endometrial natural killer cells: What are they? What do they do? What do we need to know? Femina 37, 373–8.Google Scholar
Fukui, A., Ntrivalas, E., Gilman-Sachs, A., Kwak-Kim, J., Lee, S.K., Levine, R. & Beaman, K. (2006). Expression of natural cytotoxicity receptors and a2V-ATPase on peripheral blood NK cell subsets in women with recurrent spontaneous abortions and implantation failures. Am. J. Reprod. Immunol. 56, 312–20.Google Scholar
Guenther, S., Vrekoussis, T., Heublein, S., Bayer, B., Anz, D., Knabl, J., Navrozoglou, I., Dian, D., Friese, K., Makrigiannakis, A., & Jeschke, U. (2012). Decidual macrophages are significantly increased in spontaneous miscarriages and over-express FasL: a potential role for macrophages in trophoblast apoptosis. Int. J. Mol. Sci. 13, 90699080 Google Scholar
Hanna, J., Goldman-Wohl, D., Hamani, Y., Avraham, I., Greenfield, C., Natanson-Yaron, S., Prus, D., Cohen-Daniel, L., Arnon, T.I., Manaster, I., Gazit, R., Yutkin, V., Benharroch, D., Porgador, A., Keshet, E., Yagel, S. & Mandelboim, O. (2006). Decidual NK cells regulate key developmental processes at the human fetal–maternal interface. Nat. Med. 12, 1065–74.Google Scholar
Heublein, S., Lenhard, M., Vrekoussis, T., Schoepfer, J., Kuhn, C., Friese, K., Makrigiannakis, A., Mayr, D. & Jeschke, U. (2012). The G-protein-coupled estrogen receptor (GPER) is expressed in normal human ovaries and is upregulated in ovarian endometriosis and pelvic inflammatory disease involving the ovary. Reprod. Sci. 19, 1197–204.Google Scholar
Hill, J.A., Polgar, K. & Anderson, D.J. (1995). T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortion. J. Am. Med. Ass. 273, 1933–6.Google Scholar
Hutter, S., Heublein, S., Knabl, J., Andergassen, U., Vrekoussis, T., Makrigiannakis, A., Friese, K., Mayr, D. & Jeschke, U. (2013). Macrophages: are they involved in endometriosis, abortion and preeclampsia and how? J. Nippon. Med. Sch. 80, 97103.Google Scholar
Ideta, A., Sakai, S.I., Nakamura, Y., Urakawa, M., Hayama, K., Tsuchiya, K., Fujiwara, H. & Aoyagi, Y. (2010). Administration of peripheral blood mononuclear cells into the uterine horn to improve pregnancy rate following bovine embryo transfer. Anim. Reprod. Sci. 117, 1823.Google Scholar
Johnson, P.M., Christmas, S.E. & Vince, G.S. (1999). Immunological aspects of implantation and implantation failure. Hum. Reprod. 14, 2636.Google Scholar
Jokhi, P.P., King, A., Sharkey, A.M., Smith, S.K. & Loke, Y.W. (1994). Screening for cytokine messenger ribonucleic acids in purified human decidual lymphocyte populations by the reverse-transcriptase polymerase chain reaction. J. Immunol. 153, 4427–35.CrossRefGoogle ScholarPubMed
Kachkache, M., Acker, G.M., Chaouat, G., Noun, A. & Garabedian, M. (1991). Hormonal and local factors control the immunohistochemical distribution of immunocytes in the rat uterus before conceptus implantation: effects of ovariectomy, fallopian tube section, and injection. Biol. Reprod. 45, 860–8.Google Scholar
Kalantaridou, S.N., Zoumakis, E., Weil, S., Lavasidis, L.G., Chrousos, G.P., Makrigiannakis, A. (2007). Reproductive corticotropin releasing hormone, implantation, and fetal immunotolerance. Crit. Rev. Clin. Lab. Sci. 44 (5–6), 461–81.CrossRefGoogle ScholarPubMed
Karami, N., Boroujerdnia, M.G., Nikbakht, R. & Khodadadi, A. (2012). Enhancement of peripheral blood CD56dim cell and NK cell cytotoxicity in women with recurrent spontaneous abortion or in vitro fertilization failure. J. Reprod. Immunol. 95 (1–2), 8792.CrossRefGoogle ScholarPubMed
Kimber, S.J. (2005). Leukaemia inhibitory factor in implantation and uterine biology. Reproduction 130, 131–45.Google Scholar
King, A. (2000). Uterine leukocytes and decidualization. Hum. Reprod. 6, 2836.Google Scholar
King, A., Jokhi, P.P., Smith, S.K., Sharkey, A.M. & Loke, Y.W. (1995). Screening for cytokine mRNA in human villous and extravillous trophoblasts using the reverse-transcriptase polymerase chain reaction (RT-PCR). Cytokine 7, 364–71.CrossRefGoogle ScholarPubMed
Klentzeris, L.D., Li, T.C., Dockery, P. & Cooke, I.D. (1992). The endometrial biopsy as a predictive factor of pregnancy rate in women with unexplained infertility. Euro. J. Obst. Gynec. Reprod. Biol. 45, 119–24.Google Scholar
Lash, G.E. & Bulmer, J.N. (2011). Do uterine natural killer (uNK) cells contribute to female reproductive disorders? J. Reprod. Immunol. 88, 156–64.Google Scholar
Makrigiannakis, A., Minas, V., Kalantaridou, S.N., Nikas, G. & Chrousos, G.P. (2006). Hormonal and cytokine regulation of early implantation. Trends Endocrinol. Metab. 17, 178–85.Google Scholar
Makrigiannakis, A., Karamouti, M., Drakakis, P., Loutradis, D. & Antsaklis, A. (2008). Fetomaternal immunotolerance. Am. J. Reprod. Immunol. 60, 482–96.Google Scholar
Makrigiannakis, A., Petsas, G., Toth, B., Relakis, K. & Jeschke, U. (2011). Recent advances in understanding immunology of reproductive failure. J. Reprod. Immunol. 90, 96104.Google Scholar
McMaster, M.T., Newton, R.C., Dey, S.K. & Andrews, G.K. (1992). Activation and distribution of inflammatory cells in the mouse uterus during the preimplantation period. J. Immunol. 148, 1699–705.CrossRefGoogle ScholarPubMed
Miyazaki, S., Tsuda, H., Sakai, M., Hori, S., Sasaki, Y., Futatani, T., Miyawaki, T. & Saito, S. (2003). Predominance of Th2-promoting dendritic cells in early human pregnancy decidua. J. Leukoc. Biol. 74, 514–22.Google Scholar
Mor, G., Cardenas, I., Abrahams, V. & Guller, S. (2011). Inflammation and pregnancy: the role of the immune system at the implantation site. Ann. N. Y. Acad. Sci. 1221, 80–7.Google Scholar
Nagamatsu, T. & Schust, D.J. (2010). The contribution of macrophages to normal and pathological pregnancies. Am. J. Reprod. Immunol. 63, 460–71.Google Scholar
Nakayama, T., Fujiwara, H., Maeda, M., Inoue, T., Yoshioka, S., Mori, T. & Fujii, S. (2002). Human peripheral blood mononuclear cells (PBMC) in early pregnancy promote embryo invasion in vitro: hCG enhances the effects of PBMC. Hum. Reprod. 17, 207–12.CrossRefGoogle ScholarPubMed
Oh, M.J. & Croy, B.A.A. (2008). A map of relationships between uterine natural killer cells and progesterone receptor expressing cells during mouse pregnancy. Placenta. 29, 317–23.Google Scholar
Okitsu, O., Kiyokawa, M., Oda, T., Miyake, K., Sato, Y. & Fujiwara, H. (2011). Intrauterine administration of autologous peripheral blood mononuclear cells increases clinical pregnancy rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. J. Reprod. Immunol. 92 (1–2), 82–7.Google Scholar
Pandey, M.K., Rani, R. & Agrawal, S. (2005). An update in recurrent spontaneous abortion. Arch. Gynecol. Obstet. 272, 95108.Google Scholar
Parham, P. (2004). NK cells and trophoblasts: partners in pregnancy. J. Exp. Med. 200, 951–5.Google Scholar
Perricone, R., De Carolis, C., Giacomelli, R., Guarino, M.D., De Sanctis, G. & Fontana, L. (2003). GM-CSF and pregnancy: evidence of significantly reduced blood concentrations in unexplained recurrent abortion efficiently reverted by intravenous immunoglobulin treatment, Am. J. Reprod. Immunol. 50, 232–7.Google Scholar
Raghupathy, R., Makhseed, M., Azizieh, F., Hassan, N., Al-Azemi, M. & Al-Shamali, E. (1999). Maternal Th1- and Th2-type reactivity to placental antigens in normal human pregnancy and unexplained recurrent spontaneous abortions. Cell. Immunol. 196, 122–30.Google Scholar
Rivera, R., Yacobson, I., & Grimes, D. (1999). The mechanism of hormonal contraceptives and intrauterine contraceptive devices. Am. J. Obstet. Gynecol. 181, 1263–69.Google Scholar
Sacks, G., Yang, Y., Gowen, E., Smith, S., Fay, L. & Chapman, M. (2012). Detailed analysis of peripheral blood natural killer cells in women with repeated IVF failure. Am. J. Reprod. Immunol. 67, 434–42.Google Scholar
Saito, S., Shima, T., Nakashima, A., Shiozaki, A., Ito, M. & Sasaki, Y. (2007). What is the role of regulatory T cells in the success of implantation and early pregnancy? J. Assist. Reprod. Gen. 24, 379–86.Google Scholar
Salamonsen, L.A. (2003). Tissue injury and repair in the female human reproductive tract. Reprod. 125, 301–11.Google Scholar
Sanford, T.R. & Wood, G.W. (1992). Expression of colony-stimulating factors and inflammatory cytokines in the uterus of CD1 mice during days 1 to 3 of pregnancy. J. Reprod. Fert. 94, 213–20.Google Scholar
Schulten, R.J., Lobl, R.T. & Ward, P. (1975). Neutrophils and the mechanism of IUD action in rats. Fertil. Steril. 26, 131–6.Google Scholar
Segerer, S., Kammerer, U., Kapp, M., Dietl, J. & Rieger, L. (2009). Upregulation of chemokine and cytokine production during pregnancy. Gynecol. Obstet. Invest. 67:145–50.Google Scholar
Simon, C., Moreno, C., Remohi, J. & Pellicer, A. (1998). Cytokines and embryo implantation. J. Reprod. Immunol. 39, 117–31.Google Scholar
Stewart, C.L., Kaspar, P., Brunet, L.J., Bhatt, H., Gadi, I., Köntgen, F. & Abbondanzo, S.J. (1992). Blastocyst implantation depends on maternal expression of leukemia inhibitory factor. Nature 359, 76–9.Google Scholar
Tabiasco, J., Rabot, M., Aguerre-Girr, M., El Costa, H., Berrebi, A., Parant, O., Laskarin, G., Juretic, K., Bensussan, A., Rukavina, D. & Le Bouteiller, P. (2006). Human decidual NK cells: unique phenotype and functional properties. Placenta 27, 34–9.Google Scholar
Toth, B., Haufe, T., Scholz, C., Kuhn, C., Friese, K., Karamouti, M., Makrigiannakis, A. & Jeschke, U. (2010). Placental interleukin-15 expression in recurrent miscarriage. Am. J. Reprod. Immunol. 64, 402–10.Google Scholar
Toth, B., Würfel, W., Germeyer, A., Hirv, K., Makrigiannakis, A. & Strowitzki, T. (2011). Disorders of implantation are there diagnostic and therapeutic options? J. Reprod. Immunol. 90, 117–23.Google Scholar
Vassiliadis, S., Ranella, A., Papadimitriou, L., Makrygiannakis, A. & Athanassakis, I. (1998). Serum levels of pro- and anti-inflammatory cytokines in non-pregnant women, during pregnancy, labor and abortion. Mediat. Inflamm. 7, 6972.CrossRefGoogle ScholarPubMed
Wegmann, T.G., Lin, H., Guilbert, L. & Mosmann, T.R. (1993). Bidirectional cytokine interactions in the maternal–fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol. Today 14, 353–6.Google Scholar
Wu, L., Luo, L.H., Zhang, Y.X., Li, Q., Xu, B., Zhou, G.X., Luan, H.B. & Liu, Y.S. (2014). Alteration of Th17 and Treg cells in patients with unexplained recurrent spontaneous abortion before and after lymphocyte immunization therapy. Reprod. Biol. Endocrino. 12, 74.Google Scholar
Yoshioka, S., Fujiwara, H., Nakayama, T., Kosaka, K., Mori, T. & Fujii, S. (2006). Intrauterine administration of autologous peripheral blood mononuclear cells promotes implantation rates in patients with repeated failure of IVF–embryo transfer. Hum. Reprod. 21, 3290–4.Google Scholar
Yu, N., Yang, J., Guo, Y., Fang, J., Yin, T., Luo, J., Li, X., Li, W., Zhao, Q., Zou, Y. & Xu, W. (2014). Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves endometrial receptivity in mice with embryonic implantation dysfunction. Am. J. Reprod. Immunol. 71, 2433.Google Scholar
Zhou, J., Wang, Z., Zhao, X., Wang, J., Sun, H. & Hu, Y. (2012). An increase of Treg cells in the peripheral blood is associated with a better in vitro fertilization treatment outcome. Am. J. Reprod. Immunol. 68,100–6.CrossRefGoogle ScholarPubMed
Zhylkova, I., Feskov, A., Feskova, I., Somova, O. & Chumakova, N. (2010). Influence of peripheral blood mononuclear cells intrauterine transfer on implantation rates in patients with unsuccessful IVF cycles. Hum. Reprod. 25, P–257.Google Scholar
Ziebe, S., Loft, A., Povlsen, B.B., Erb, K., Agerholm, I., Aasted, M., Gabrielsen, A., Hnida, C., Zobel, D.P., Munding, B., Bendz, S.H. & Robertson, S.A. (2013). A randomized clinical trial to evaluate the effect of granulocyte–macrophage colony-stimulating factor (GM-CSF) in embryo culture medium for in vitro fertilization. Fertil. Steril. 99, 1600–9.Google Scholar
Zoumakis, E., Kalantaridou, S.N., Makrigiannakis, A. (2009). CRH-like peptides in human reproduction. Curr. Med. Chem. 16, 4230–5.Google Scholar