An insight into normal and pathological pregnancies using large-scale microarrays: lessons from microarrays.

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.

TH1/TH2 paradigm in pregnancy: paradigm lost? Cytokines in pregnancy/early abortion: reexamining the TH1/TH2 paradigm.

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.

Reproductive immunology 2003: reassessing the Th1/Th2 paradigm?

We briefly review the history of concepts (some of which are still valid) which have lead to the present situation where pregnancy is viewed as being a Th2 phenomenon. We recall some of the early evidence which has been taken as supporting the general validity of this concept in murine and human pregnancy. We then recall some of the recent data dealing with "newer" cytokines and the role of uterine natural killer (NK) cells at the feto-maternal interface which fit neither with a steady-state concept nor with inflammatory cytokines, being solely "bad guys" as the paradigm would predict, nor with the concept of reduction of NK "activity" being required for successful pregnancy.

Cytokines, implantation and early abortion: re-examining the Th1/Th2 paradigm leads to question the single pathway, single therapy concept.

Problem: Human in vitro fertilization (IVF) embryo transfer is accompanied by a low implantation rate even after a very successful IVF, and there are a certain number of 'idiopathic sterilities' which are due to repeated implantation failures. In the very same vein, the question of improving implantation rates is of prime importance in agricultural research to improve the management of livestock. Preimplantation prenatal diagnosis cannot be accomplished in individuals who have a high rate of implantation failure, whether women undergoing IVF, or animals, during genetic cloning.

Implantation: can immunological parameters of implantation failure be of interest for pre-eclampsia?

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.

New insights into maternal-fetal interactions at implantation.

The immunotrophic theory was enunciated by Tom Wegmann. Since then, the involvement of cytokines in implantation and materno-fetal tolerance has emerged as a central topic in reproductive immunology. This brief survey covers the historical background leading to the specification of the crucial role of cytokines at the feto-maternal interface, and the present known patterns of their function.

Expression of pro-inflammatory cytokines in mouse blastocysts during implantation: modulation by steroid hormones.

Problem: Expression and hormonal regulation of pro-inflammatory cytokines and their role in blastocyst activation and implantation is poorly known. The present study is aimed at analysing the expression and hormonal modulation of two pro-inflammatory cytokines [interleukin-1alpha (IL-1alpha) and IL-6] in mouse blastocysts during implantation.

Method Of Study: Blastocyst-uterine interactions are inhibited by progesterone during implantation and subsequent treatment with oestrogen triggers events that allow implantation to begin.

A brief review of recent data on some cytokine expressions at the materno-foetal interface which might challenge the classical Th1/Th2 dichotomy.

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.