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In the introduction, we briefly recall old but classic evidence that there is no tolerance to paternal alloantigens in a first pregnancy. Therefore, we performed small- and large-scale microarrays in CBA × DBA/2 and CBA × BALB/c combinations, recently described as a murine model for preeclampsia. Our results are in line with other data suggesting a very early deregulation of local immune vascular events rather than a break of immune tolerance. Other data presented at the Tioman 2010 Preeclampsia Workshop supporting this hypothesis are briefly summarised, as well as indications and caveats from a recent human microarray on implantation failure and recurrent pregnancy loss., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

We restate briefly why we consider that the Th1/Th2 paradigm, as useful as it has been, is now no longer adequate and is obsolete. We take as an example the role of IL-18, abortifacient at high doses but cardinal for the control of natural killer (NK) cell effects on spiral artery remodelling in mice, and likely also in humans. We then describe briefly our recent studies on cytokine defects and implantation failure in humans, a key feature being the link between uterine cytokine dysregulation and abnormal uterine vascular scores. We draw lessons for preeclampsia, and describe features of a model for its immune aetiology.

Focussing attention on cytokines at the materno-foetal interface represents one of the major advances made in the field. This owes much to the visionary views of Tom Wegmann, and to the changes brought about in the field by immunotrophism and Th1/Th2 paradigms. We review these briefly and also point out some emerging problems.However, a certain number of newly discovered cytokines do not fit into the classical Th1/Th2 dichotomy. Yet, by their capacity to activate or downregulate NK cells, by their action on adhesion molecules, and by their regulatory effects on the vascularisation process, they are of possible interest within the materno-foetal relationship. Therefore, as a first step, we have undertaken a systematic study of the expression of IL-11, IL-12, IL-13, IL-15, IL-16, IL-17 and IL-18 in the uterus, the peri-implantation embryo, and later on decidual and placental tissues throughout pregnancy. These cytokines were detected in every case, with, in each case, a precise localisation, which will be detailed, and which indeed suggests important regulatory functions, especially during implantation. In some cases, as will be shown in the peri-implantation uterus, those cells are perfectly expressed by uterine GMG-NK-like cells. Comparative ELISAs and quantitative RT-PCR have been or are being conducted, but already the expression patterns that are observed, and the very precise window of appearance that is observed for some of the GMG NK-like cells, either around or in the implanting embryo, as well as the complexity of the respective distributions, strongly suggest that, as useful as it certainly was for a while, the Th1/Th2 paradigm must now be considered as an over-simplification. Rather, the existing data point to sequential windows and are suggestive of a system where an extreme complexity is allied to very precise timing and tuning. They also suggest that the materno-foetal relationship is not simply maternal tolerance of a foreign tissue, but a series of intricate mutual cytokine interactions governing selective immune regulation and also control of the adhesion and vascularisation processes during this dialogue.