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.
We conclude that the T helper cell type 1/2 (Th1/ Th2) paradigm, as useful as it has been to explain pregnancy, is no longer sufficient in view of the emerging complexity of the cytokine network at the materno-fetal interface. This is peculiarly true for implantation, which, as a step by step developmentally regulated process, involving inflammatory molecules, cannot fit into such a scheme.
SUMMARYThe involvement of some interleukins (ILs) in early and established pregnancy has been convincingly demonstrated, but little is known about the potential role of the more recently discovered ones. However, since many of these have positive or negative regulatory effects on both NK and T cells, it is highly probable that they also have regulatory functions in both implantation and placental development. Therefore, as a first step in tackling this problem, we have investigated whether several recently described pro-(IL-12, IL-15) and anti-inflammatory (IL-11, IL-13) cytokines were expressed at the uteroplacental interface by use of immunohistochemistry at different stages of gestation in mice.Each of these molecules was found at the foetomaternal interface, with specific distributions and patterns of expression depending on both the cytokine itself and the stage of pregnancy. The significance of these data is discussed.
Using a delayed implantation model, we show that mouse blastocysts express both IL-1alpha and IL-6 mRNA as well as their respective proteins. Both mRNA and the protein levels of IL-1alpha and IL-6 seem to be hormonally modulated in mouse blastocysts during implantation.
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