The Uterine Immune Profile May Help Women With Repeated Unexplained Embryo Implantation Failure After In Vitro Fertilization

Nathalie Lédée, Marie Petitbarat, Lucie Chevrier, Dominique Vitoux, Katia Vezmar, Mona Rahmati, Sylvie Dubanchet, Hanne Gahéry, Armand Bensussan, Gerard Chaouat, Nathalie Lédée, Marie Petitbarat, Lucie Chevrier, Dominique Vitoux, Katia Vezmar, Mona Rahmati, Sylvie Dubanchet, Hanne Gahéry, Armand Bensussan, Gerard Chaouat

Abstract

Labeled problem: Embryo implantation remains the main limiting factor in assisted reproductive medicine (20% success rate).

Methods of study: An endometrial immune profiling was performed among 394 women with the previous history of repeated embryo implantation failures (RIF). The endometrial immune profile documented the ratio of IL-15/Fn-14 mRNA as a biomarker of uNK cell activation/maturation (together with the uNK cell count) and the IL-18/TWEAK mRNA ratio as a biomarker of both angiogenesis and the Th1/Th2 balance. According to their profile, we recommended personalized care to counteract the documented dysregulation and assessed its effects by the live birth rate (LBR) for the next embryo transfer.

Results: Endometrial immune profiles appeared to be dysregulated in 81.7% of the RIF patients compared to control. Overactivation was diagnosed in 56.6% and low activation in 25%. The LBR among these dysregulated/treated patients at the first subsequent embryo transfer was 39.8%.

Conclusion: Endometrial immune profiling may improve our understanding of RIF and subsequent LBR if treated.

Keywords: Birth rates; Immunology; Implantation failure; human endometrium; in vitro fertilization; uterine natural killer cells; uterine receptivity.

© 2016 The Authors. American Journal of Reproductive Immunology Published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Focus on IL15 and IL18 environment during the implantation window. In the mid‐luteal phase, stromal and endothelial endometrial cells secrete IL‐15, Fn‐14, IL‐18, and TWEAK at specific levels. Increased IL‐15 allows the recruitment and maturation of uNK cells. IL‐18 and mature uNK cells stimulate Th2 cytokine production and lead to a predominantly Th2 balance. This equilibrium promotes immunotrophism and angiogenesis, while inhibiting inflammatory and cytotoxic pathways.
Figure 2
Figure 2
Study design. The study was conducted by three sets of contributors. MatriceLab Innove (MLI) designed the study, performed the endometrial immune profile (with its molecular analyses and CD56+ cell count), suggested personalized care, and remained in contact with physicians to follow‐up each IVF/ICSI attempt. Physicians recruited patients, performed the endometrial biopsies, and provided the personalized care before and after performing the IVF/ICSI. The Centre de pathologie (Passy, France) conducted the histological dating of the biopsies and the CD56 immunohistochemistry (IHC).
Figure 3
Figure 3
Distribution of the ratios of IL‐15/Fn‐14 mRNA and IL‐18/TWEAK mRNA and of the CD56+ cell count in the control fertile group and in the RIF cohort. Figure 3 presents the data dispersion for the log‐transformed IL‐15/Fn‐14 mRNA ratio, log‐transformed IL‐18/TWEAK mRNA ratio, and log‐transformed CD56+ cell count in the fertile control group and in the RIF cohort.
Figure 4
Figure 4
Personalization of treatment according to the endometrial immune profile. This figure summarizes the personalization of care recommended according to the uterine immune profile in the groups with low immune activation, over immune activation, and with or without immature uNK cells.
Figure 5
Figure 5
Adaptation of therapy in patients with an overactivated immune profile. Forty‐one women with an overactivated immune profile were first treated with prednisolone or Intralipid® and had another biopsy during the treatment to evaluate its effects on their immune profile. Patients responsive to prednisolone (18 cases) or Intralipid® (six cases) underwent ET with the same treatment in the following cycle. Treatment for women not responsive to prednisolone was changed to Intralipid®, and ET took place under Intralipid®. Inversely, treatment for women unresponsive to Intralipid® was changed to prednisolone, and ET took place under prednisolone.

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Source: PubMed

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