In this paper, we briefly survey the history of concepts in reproductive immunology from antibody-mediated tolerance to the ‘fetal allograft’ to the current concept of an embryo ‘bathing in a sea of cytokines’. We then review the paradigm that ‘allopregnancy is a Th2 phenomenon’ and some of the evidence gained in animals and humans supporting it. We continue by discussing the light it sheds on immunologically caused recurrent abortion, and the present status of the concepts. We next show the limits of the Th1/Th2 paradigm by reviewing the role of ‘inflammatory’ cytokines in implantation (as first seen with leukemia inhibitory factor). We go on to discuss recent data showing that interferon-γ is not solely a ‘bad guy’, e.g. abortifacient as the paradigm would predict, but is needed at low doses for the vascular development and transformation of uterine spiral arteries required for implantation and successful pregnancy. We conclude by discussing the emerging role of NK and IL-12, IL-15, IL-18 tripods and other cytokines in local angiogenesis and tissue remodelling, a series of new data bringing us well beyond the Th1/Th2 paradigm in pregnancy which, in this context, appears now obsolete and an oversimplification, although it has indeed been useful at first. Rather, step-specific events have to be considered and a key role is seen in local tissue remodelling, in which immune cytokines play an important role while not always being secreted by immune cells.

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.

BACKGROUND: There is strong evidence that locally secreted cytokines control the implantation process and can cause implantation failure. Uterine flushing fluids were analysed to determine their concentrations of leukaemia inhibitory factor (LIF) and tumour necrosis factor (TNF). METHODS AND RESULTS: We began by flushing the uterine cavities of 33 infertile patients on day 26 of two consecutive cycles. The concentrations of LIF (by enzyme-linked immunosorbent assay) and TNF (by bioassay) were significantly correlated during these cycles (r = 0.762, P = 0.0001 and r = 0.822, P = 0.001 respectively) and hence reliable. Then, after a reference flushing of 30 infertile patients, we followed the outcome of their first consecutive cycle of ovarian stimulation, which preceded either IVF or intrauterine insemination. A total of 10 patients became pregnant. The median concentration of LIF was 0 pg/ml (range: 0–177) and of TNF was 0 U/ml (range: 0–6.17) among those who became pregnant, and 203 pg/ml (range: 0–1620) and 2.14 U/ml (range: 0–16) respectively among those who did not. The LIF concentration was significantly lower in the pregnant group (P = 0.0013). CONCLUSION: A low concentration of LIF in the uterine flushing fluid at day 26 was predictive of subsequent implantation. Use of this procedure should increase the number of IVF attempts yielding successful pregnancies and also lead to corrective therapies.

BACKGROUND The cytokine/chemokine levels of individual follicular fluids (FFs) were measured to determine whether a biomarker could be linked to the developmental potential of the derived embryo.