ABSTRACT
A unique endometrial immune reaction should occur to promote the human embryo implantation. We postulated that an immune disequilibrium may impact the initial dialogue between the mother and her embryo. In 2012, we set a method of uterine immune profiling for patients with unexplained repeated implantation failures (RIF). The method documents the local Th-1/ Th-2 equilibrium and the recruitment and state of maturation/activation of uNK cells. In function of the disequilibrium observed, personalization of assisted reproductive treatments was suggested. As the concept of personalization in function of the uterine immune profile had never been proposed, a large cohort study and a controlled cohort study were first conducted in RIF patients. 80 % of the RIF patients showed a local disequilibrium if compared to fertile controls. The local disequilibrium was identified in 3 categories: over-immune activation in 45 %, low- local immune activation in 25 % and mixed profile in 10 %. Personalization of treatments in function of the immune profile allowed to restore a live birth rate by 40 % at the following embryo transfer. RIF patients with endometriosis show some particularities regarding their immune profiles. We also suggested that immunotherapy (corticoids, intralipids) may have targeted indications based on a better understanding of the immune type of disequilibrium documented. Personalization of treatments for RIF patients seems to be essential to promote the subsequent live birth rate. The endometrial immune profiling is an innovative method aiming to detect a local immune disequilibrium and, if present, to test preventively its correction under treatment.
Subject(s)
Embryo Implantation/immunology , Embryo Transfer/adverse effects , Endometrium/immunology , Infertility/therapy , Sperm Injections, Intracytoplasmic/adverse effects , Adult , Birth Rate , Embryo Transfer/statistics & numerical data , Female , Humans , Pregnancy , Pregnancy Rate , Sperm Injections, Intracytoplasmic/statistics & numerical data , Treatment FailureABSTRACT
Identification of biomarkers of optimal uterine receptivity to the implanting embryo as well as biomarkers of oocyte competence would undoubtedly improve the efficiency of assisted reproductive technology (ART). Expression of IL-15 and IL-18 has been shown to be different in patients with failed implantation after IVF/ICSI compared with fertile controls and both correlate with local uNK (CD56+) recruitment and angiogenesis. Tumor necrosis factor weak inducer of apoptosis (TWEAK) has been described in mice as a potent early immune regulator able to protect the conceptus. The results of our studies in human suggest that TWEAK modulates the IL-18 related cytotoxicity of uNK cells. Quantification of IL-18, TWEAK and IL-15 mRNA expression by real-time PCR in endometrial tissue collected in mid-luteal phase of non-conception cycles allowed documentation of physiological events that occur at the time of uterine receptivity. Such information may be useful for the physician especially in patients where embryos fail to implant. Cytokine quantification may assist in understanding the mechanisms leading to repeated IVF/ICSI failure: either depletion of cytokines necessary for the apposition-adhesion, or an excess of cytokines leading to local cytotoxicity, may impair the implantation of the embryo. Other new data suggest that a pre-conception dialogue mediated by the oocyte and the follicular fluid and the oocyte may contribute to later implantation success. Follicular concentration of G-CSF appears as a useful biomarker of oocyte competence before fertilization. Moreover both in human and animal models, evidence of a role of the endometrium as a biosensor of the embryo is emerging.
Subject(s)
Endometrium/metabolism , Infertility, Female/diagnosis , Ovulation Detection , Animals , Biomarkers/metabolism , Cytokine TWEAK , Endometrium/immunology , Endometrium/pathology , Female , Fertilization in Vitro/methods , Granulocyte Colony-Stimulating Factor/genetics , Granulocyte Colony-Stimulating Factor/metabolism , Humans , Infertility, Female/therapy , Interleukin-15/genetics , Interleukin-15/immunology , Interleukin-15/metabolism , Interleukin-18/genetics , Interleukin-18/immunology , Interleukin-18/metabolism , Mice , Preconception Care , Pregnancy , Tumor Necrosis Factors/genetics , Tumor Necrosis Factors/metabolismABSTRACT
This article explains why we have had to come to a central role for innate immunity rather than the threat of maternal rejection of the foetal allograft. We encompass briefly the role of inflammation in implantation, not only for invasion adhesion, but also to prepare future "tolerance". In this context, we envisage the role of TWEAK and complement.
