A successful pregnancy requires synchronized adaptation of maternal immune-endocrine mechanisms to the fetus. Here we show that galectin-1 (Gal-1), an immunoregulatory glycan-binding protein, has a pivotal role in conferring fetomaternal tolerance. Consistently with a marked decrease in Gal-1 expression during failing pregnancies, Gal-1-deficient (Lgals1-/-) mice showed higher rates of fetal loss compared to wild-type mice in allogeneic matings, whereas fetal survival was unaffected in syngeneic matings. Treatment with recombinant Gal-1 prevented fetal loss and restored tolerance through multiple mechanisms, including the induction of tolerogenic dendritic cells, which in turn promoted the expansion of interleukin-10 (IL-10)-secreting regulatory T cells in vivo. Accordingly, Gal-1's protective effects were abrogated in mice depleted of regulatory T cells or deficient in IL-10. In addition, we provide evidence for synergy between Gal-1 and progesterone in the maintenance of pregnancy. Thus, Gal-1 is a pivotal regulator of fetomaternal tolerance that has potential therapeutic implications in threatened pregnancies.

Progesterone is critical for the establishment and the maintenance of pregnancy, both by its endocrine and immunological effects. The genomic actions of progesterone are mediated by the intracellular progesterone receptors; A and B. A protein called P-induced blocking factor (PIBF), by inducing a T(H2) dominant cytokine production, mediates the immunological effects of progesterone. Progesterone plays a role in uterine homing of NK cells and up-regulates HLA-G gene expression, the ligand for various NK inhibitory receptors. At high concentrations progesterone is a potent inducer of Th2-type cytokines as well as of LIF and M-CSF production by T cells. Though a key role for progesterone in creating local immunosuppression has been conserved during the evolution of an epitheliochorial placenta, there has been some divergence in the pattern of endocrine-immunological cross talk in Bovidae. In sheep, uterine serpin, a progesterone-induced endometrial protein, mediates the immunosuppressive effects of progesterone. Epidemiological studies suggest the role of stress in premature pregnancy termination and exposure to stress induces abortion in mice via a significant reduction in progesterone levels, accompanied by reduced serum levels of PIBF. These effects are corrected by progesterone supplementation. These findings indicate the significance of a progesterone-dependent immuno-modulation in maternal tolerance of the fetus, which is discussed in this review.

The immunological relationship between the mother and the fetus is a bi-directional communication determined on the one hand by fetal antigen presentation and on the other hand by recognition of and reaction to these antigens by the maternal immune system. There is evidence now that immunological recognition of pregnancy is important for the maintenance of gestation, and that inadequate recognition of fetal antigens might result in failed pregnancy. In contrast to HLA-A and -B Class I genes that are downregulated in human trophoblast cells, nonpolymorphic Class I molecules, e.g., HLA-G Class Ib, are expressed in extravillous cytotrophoblast and also in endothelial cells of fetal vessels in the chorionic villi as well as in amnion cells and amniotic fluid. The trophoblast does not induce transplantation immunity and resists NK- and CTL-mediated lysis in vitro. According to our present knowledge, HLA-G presents antigens for gamma/delta T cells and at the same time defends the trophoblast from cytotoxic effector mechanisms. Since polymorphic MHC is absent from the trophoblast, presentation of fetally derived antigens is unlikely to be MHC restricted. gamma/delta T cells recognize a distinct group of ligands with a smaller receptor repertoire than alpha/beta T cells. Most gamma/delta T cells recognize unprocessed foreign antigens without MHC. In the decidua gamma/delta TCR-positive cells significantly increase in number and the majority of decidual gamma/delta T cells are in an activated form due to recognition of conserved mammalian molecules on the trophoblast. Following recognition of fetally derived antigens, the immune system reacts with the setting in of a wide range of protective mechanisms. Many observations suggest that pregnancy is associated with an altered TH1/TH2 balance. Maternal immune response is biased toward humoral immunity and away from cell-mediated immunity that could be harmful to the fetus. Cytokines of maternal origin act on placental development. On the other hand, antigen expression on the placenta determines maternal cytokine pattern. Normal human pregnancy is characterized by low peripheral NK activity, and increased NK activity seems to play a role in spontaneous abortions of unknown etiology. In early human pregnancy the majority of uterine lymphocytes are CD56(bright) granulated NK cells, which do not express CD16 or CD3. In rodents and humans, uterine NK cells are under hormonal control. In early pregnancy they are enriched at sites where fetal trophoblast infiltrates the decidua. The dynamics of the appearance of uterine NK cells suggest that one of the functions of these cells is control of placentation. Another protective mechanism operating in favor of pregnancy is progesterone-dependent immunomodulation. Due to stimulation by fetally derived antigens, pregnancy lymphocytes develop progesterone receptors and in the presence of progesterone produce a mediator (PIBF) that, through altering the cytokine balance, inhibits NK activity and exerts an antiabortive effect in mice.

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Many pregnancies are lost during early gestation, but clinicians still lack tools to recognize risk factors for miscarriage. Thus, the identification of risk factors for miscarriage during the first trimester in women with no obvious risk for a pregnancy loss was the aim of this prospective cohort trial. A total of 1098 women between gestation weeks 4 and 12 in whom no apparent signs of a threatened pregnancy could be diagnosed were recruited. Demographic, anamnestic, psychometric and biological data were documented at recruitment and pregnancy outcomes were registered subsequently. Among the cases with sufficiently available data, 809 successfully progressing pregnancies and 55 subsequent miscarriages were reported. In this cohort, risk of miscarriage was significantly increased in women at higher age (>33 years), lower body mass index (< or =20 kg/ m(2)) and lower serum progesterone concentrations (< or =12 ng/ml) prior to the onset of the miscarriage. Women with subsequent miscarriage also perceived higher levels of stress/demands (supported by higher concentrations of corticotrophin-releasing hormone) and revealed reduced concentrations of progesterone-induced blocking factor. These risk factors were even more pronounced in the subcohort of women (n = 335) recruited between gestation weeks 4 and 7. The identification of these risk factors and development of an interaction model of these factors, as introduced in this article, will help clinicians to recognize pregnant women who require extra monitoring and who might benefit from therapeutic interventions such as progestogen supplementation, especially during the first weeks of pregnancy, to prevent a miscarriage.