Research Group Reproductive Immunology and Implantation (REIM)
The Research Group Reproductive Immunology and Implantation aims to study different aspects of implantation of a human embryo and, more specifically, the interaction between the endometrium and the embryo which leads to a successful implantation in natural and stimulated cycles for ART.
Successful implantation requires a coordinated dialogue between a receptive endometrium and a high-quality intrusive blastocyst. During the menstrual cycle, the human endometrium is only receptive during a very short time span of approximately 4 days (the "implantation window") (Wilcox, 1999). Histological dating of the endometrium according to Noyes criteria as the golden standard for endometrial evaluation has been challenged due to significant inter- and intra-observer variation and is unable to discriminate in a natural cycle between women from fertile and infertile couples (Coutifaris, 2004). Microarray technology has broadened the insight of the molecular mechanisms involved in human endometrial receptivity (Horcajadas, 2007).
However, the assessment of human endometrial receptivity is hampered by the ethical limitation to evaluate the cellular and molecular embryo-endometrial dialogue in vivo. Only little information is thus available from the endometrium in conceptional cycles. Endometrial secretion analysis has been proposed as an alternative non-invasive method to assess a receptive status but results remain preliminary and no correlation was made to date with endometrial tissue or endometrial cells present in the secretion fluid (Boomsma, 2009).
Immunological factors play a role in the interaction between embryo and endometrium. In the implantation period, 70% of the endometrial leukocytes are specific CD56bright/CD16-CD3- low-toxicity NK cells expressing KIR, receptors recognizing HLA-like ligands, especially HLA-C, the only classical class I MHC on trophoblast. The study of combinations of these ligands and their receptors is a possible tool to address the potential cross-talk of the embryo with the endometrial immune system. Particular combinations of KIR/HLA-C have been associated with implantation defects (Male, 2010). Ovarian stimulation for IVF induces a modification of endometrial CD56+ cell subtypes (Lukassen, 2004).
Recent research also points out a role for immune cells other than uNK cells, that are much less abundant in the endometrium, but that may be very important in reproduction. Dendritic cells form the foreground of fundamental research in different areas of medicine. It becomes more and more clear that these immune cells, although overall small in number, have the ability to influence other cell types, directing tissue responses in physiological and pathological settings. Several mice studies assign an orchestrating role to uterine dendritic cells in implantation and pregnancy (Plaks et al 2008, Krey et al 2008, Guerin et al 2009, Blois et al 2011).
To achieve a further optimization of ART technologies, studies are needed to determine reliable noninvasive predictive tests to select both a receptive endometrium and an embryo with high implantation potential for that specific endometrium.
In addition to the immunological factors, there is a growing amount of evidence showing that the coagulation system is involved in implantation of the embryo in the endometrium.
The placenta and trophoblast cells are a rich source of the initiator of coagulation, tissue factor (TF). When TF on trophoblast cells comes into contact with maternal coagulation factors, signal competent complexes can be formed. Trophoblast cells express surface receptors for activated coagulation factor complexes, the protease activated receptors (PARŐs). Involvement of these PAR receptors couple coagulation activation to trophoblast physiology and can thereby affect the development and function of the placenta. PAR2 and PAR4 are known to inhibit the proliferation of trophoblast cells, whereas PAR1 induces trophoblast proliferation and protects trophoblast from apoptosis.
By conducting a prospective study, we want to investigate whether thrombophilia (a group of hereditary and acquired risk factors which induce a hypercoagulable state of the blood) is more prevalent in couples with recurrent failure of assisted reproduction and, if possible, if there is a (causative) association between the presence of a certain thrombophilia factor and the recurrent failures.
Hilde Van de Velde
Inge Van Vaerenbergh
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- Bourgain C, Smitz J, Camus M, Erard P, Devroey P, Van Steirteghem AC, Kloppel G. Human endometrial maturation is markedly improved after luteal supplementation of gonadotrophin-releasing hormone analogue/human menopausal gonadotrophin (GnRH agonist/hMG) stimulated cycles. Hum Reprod 1994, 9(1): 32-40. (IF 3.4)
- Bourgain C, Ubaldi F, Tavianotou A, Smitz J, Van Steirteghem A, Devroey P. Endometrial hormone receptors and proliferation index in the periovulatory phase of GnRH agonist/hMG stimulated cycles with embryo transfer. Comparison to natural cycles and relation to clinical pregnancies. Fertil Steril 2002, 78 (2): 237-44. (IF 3.2)
- Bourgain C, Devroey P. The endometrium in stimulated cycles for IVF. Hum Reprod Update. 2003;9(6):515-22. (IF 4.2)
- Van Vaerenbergh I, Van Lommel L, Ghislain V, In't Veld P, Schuit F, Fatemi HM, Devroey P, Bourgain C. In GnRH antagonist/rec-FSH stimulated cycles, advanced endometrial maturation on the day of oocyte retrieval correlates with altered gene expression. Hum Reprod 2009 May;24(5):1085-91. Epub 2009 Jan 27. (IF(2009) 3.859)
- Van Vaerenbergh I, McIntire R, Van Lommel L, Devroey P, Giudice L, Bourgain C. Gene expression during successful implantation in a natural cycle Fertil Steril 2010 Jan;93(1):268.e15-8. Epub 2009 Oct 31. (IF(2010): 3.958)
- Van Vaerenbergh I, Blockeel C, Van Lommel L, Ghislain V, In't Veld P, Schuit F, Fatemi HM, Devroey P, Bourgain C. Cyclooxygenase-2 network as predictive molecular marker for clinical pregnancy in in vitro fertilization Fertil Steril. 2011 Jan;95(1):448-51, 451.e1-2. Epub 2010 Aug 25.
- Van Vaerenbergh I, Fatemi HM, Blockeel C, Van Lommel L, In't Veld P, Schuit F, Kolibianakis EM, Devroey P, Bourgain C. Progesterone rise on hCG day in GnRH antagonist/rFSH stimulated cycles affects endometrial gene expression Reprod Biomed Online. 2011 Mar;22(3):263-71. Epub 2010 Nov 13.
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Steirteghem AC.Timing of oocyte activation, pronucleus formation and cleavage in humans
after intracytoplasmic sperm injection (ICSI) with testicular spermatozoa and after ICSI or invitro
fertilization on sibling oocytes with ejaculated spermatozoa. Hum Reprod. 1998
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H, Liebaers I, Van de Velde H. Human embryonic stem cell lines derived from single
blastomeres of two 4-cell stage embryos.Hum Reprod. 2009 Nov;24(11):2709-17. Epub 2009
Jul 24. (IF 3.859)
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a 4-cell stage human embryo are able to develop individually into blastocysts with inner cell
mass and trophectoderm. Hum Reprod. 2008 Aug;23(8):1742-7. Epub 2008 May 24. (IF 3.7)
- HLA-G expression in human embryonic stem cells and preimplantation embryos.
Verloes A, Van de Velde H, LeMaoult J, Mateizel I, Cauffman G, Horn PA, Carosella ED,
Devroey P, De Waele M, Rebmann V, Vercammen M. Journal of Immunology,
2011;186;2663-2671. Epub 2011 Jan 19. (IF (2009): 5.65)
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Cell surface antibodies in type 1 (insulin-dependent) diabetic patients. I. Presence of
immunoglobulins M which bind to rat pituitary cells. Diabetologia. 1989 Aug;32(8):611-7.
- Vercammen M, Verloes A, Van de Velde H, Haentjens P. Accuracy of soluble human
leukocyte antigen-G (sHLA-G) for predicting pregnancy among women undergoing infertility
treatment: meta-analysis. Human Reproduction Update, 14 (3):209-218, 2008. (IF 7.59)
- Vercammen M, Verloes A, Haentjens P, Van de Velde H. Can soluble human leucocyte
antigen-G predict successful pregnancy in assisted reproductive technology? Curr Opin
Obstet Gynecol. 2009 Jun;21(3):285-90. IF 2.491
- Rizzo R, Vercammen M, van de Velde H, Horn PA, Rebmann V.The importance of HLAG
expression in embryos, trophoblast cells, and embryonic stem cells.Cell Mol Life Sci. 2011
Feb;68(3):341-52. Epub 2010 Nov 16. Review. (IF (2009) 6.09)
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