Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: Adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model

Institut für Medizinische Immunologie, Biomedizinisches Forschungszentrum, Raum 2.0534, Charité, Campus Virchow Klinikum, Augustenburger Platz 1, D-13353, Berlin, Germany.
American Journal Of Pathology (Impact Factor: 4.59). 03/2005; 166(3):811-22.
Source: PubMed


Mammalian pregnancy is thought to be a state of immunological tolerance. The mechanisms underlying this phenomenon are still poorly understood. Here, we determined whether an inappropriate function of T regulatory (Treg) cells is involved in the pathogenesis of spontaneous abortion. We evaluated spleen and decidual lymphocytes from CBA/J mice undergoing immunological abortion (DBA/2J-mated) or having normal pregnancy (BALB/c-mated) on day 14 of gestation for ex vivo cytokine production after PMA or paternal antigen (alloantigen) stimulation. Treg activity was characterized by quantifying CD4(+)CD25(+) cells, foxp3 expression, and interleukin-10 secretion. Decidual lymphocytes from abortion CBA/J mice contained a significantly higher frequency of interferon-gamma-producing T cells specific for paternal antigens compared to those from normal pregnancy (7.8% versus 2.7%, P < 0.05). Compared to virgin CBA/J females, normal pregnant mice showed strongly elevated numbers of CD4(+)CD25(+) and interleukin-10(+) Treg cells in the thymus whereas significantly lower frequencies of Treg cells were observed in abortion mice. Very interestingly, CD4(+)CD25(+) Treg cells from normal pregnant and nonpregnant CBA/J mice could inhibit both proliferation and interferon-gamma secretion of lymphocytes from abortion mice in vitro whereas in vivo prevention of fetal rejection could only be achieved after adoptive transfer of Treg cells from normal pregnant mice. Our data suggest that pregnancy-induced Treg cells play a vital role in maternal tolerance to the allogeneic fetus.

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Available from: Ana C Zenclussen
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    • "More interestingly, immunization of women with recurrent miscarriage with paternal cells led to an increase in the Treg cell frequency comparable to levels of fertile women [24]. In mice models it has been shown that after increasing the levels of Treg cells abortion prone mice are protected against fetal loss [28] [39]. Although these latter results hold potential, there is no evidence yet that immunizing with paternal cells does improve pregnancy outcome. "
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    ABSTRACT: Recurrent miscarriage is a reproductive disorder affecting many couples. Although several factors are associated with recurrent miscarriage, in more than 50% of the cases the cause is unknown. Maladaptation of the maternal immune system is associated with recurrent miscarriage and could explain part of its pathophysiology. Modulating the maternal immune system toward pregnancy tolerance could benefit pregnancy outcome. Although there is a clear scientific rationale that modulating the maternal immune system could benefit recurrent miscarriage, only a few studies suggest possible beneficial effects of immune modulators as a therapy for recurrent miscarriage. Therapies skewing the maternal immune response to a tolerating regulatory T cell rich environment seem especially promising; however, more research is needed to find effective and safe maternal immune modulators for reproductive pathologies as recurrent miscarriage. Moreover, the possible side effects on maternal, fetal, and neonatal immune function are essentially unknown, and its elucidation is crucial before any possible therapeutic strategies could be clinically implemented.
    Full-text · Article · Aug 2014 · European Journal of Obstetrics & Gynecology and Reproductive Biology
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    • "Two studies confirmed this important role of Treg cells in human pregnancy (14, 23). Figure 1 depicts Treg cell blood levels during human pregnancy. Later, Zenclussen and her colleagues observed that a decrease in Treg cell activity leads to spontaneous abortion and they also demonstrated that adoptive transfer of Treg cells is able to prevent fetal rejection in a murine abortive model (24). They showed afterwards that the transferred Treg cells act by creating a privileged tolerant environment, and by up-regulating leukemia inhibitory factor (LIF), TGF-β, and HO-1 levels (25). "
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    ABSTRACT: Acceptance of the fetal semi-allograft by the mother's immune system has become the focus of intensive research. CD4+ T cells are important actors in the establishment of pregnancy. Th1/Th2 paradigm has been expanded to include CD4+ regulatory T (Treg) and T helper 17 (Th17) cells. Pregnancy hormones exert very significant modulatory properties on the maternal immune system. In this review, we describe mechanisms by which the endocrine milieu modulates CD4 T cell polarization during pregnancy. We first focused on Treg and Th17 cells and on their importance for pregnancy. Secondly, we review the effects of pregnancy hormones [progesterone (P4) and estradiol (E2)] on immune cells previously described, with a particular attention to human chorionic gonadotropin (hCG). The importance of Treg cells for pregnancy is evidenced. They are recruited before implantation and are essential for pregnancy maintenance. Decreased number or less efficient Treg cells are implicated in fertility disorders. As for Th17 cells, the few available studies suggest that they have a negative impact on fertility. Th17 frequency is increased in infertile patients. With the combination of its pro-effects on Th2 and Treg cells and anti-effects on Th1 and Th17 cells, P4 contributes to establishment of a favorable environment for pregnancy. E2 effects are more dependent on the context but it seems that E2 promotes Treg and Th2 cells while it inhibits Th1 cells. hCG positively influences activities of Treg and uterine natural killer cells. This embryo signal is an essential actor for the success of pregnancy, both as the endocrine factor regulating P4 secretion by the ovarian corpus luteum, but also as a paracrine agent during implantation as well as an angiogenic and immunologic mediator during the course of gestation. Luteinizing hormone (LH) immune properties begin to be studied but its positive impact on Treg cells suggests that LH could be a considerable immunomodulator in the mouse.
    Full-text · Article · Jul 2014 · Frontiers in Endocrinology
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    • "Total RNA was isolated from hormonal-treated and non-treated PBMCs as well as from placenta tissue samples as described elsewhere [29] and converted into cDNA for PCR analysis. Briefly, PBMCs and placental tissue (100 mg) were resolved in 1 ml Trizol® Reagent (Invitrogen, Darmstadt, Germany) and tissue samples were further disaggregated using a homogenizer (Ultra Turrax T8; Ika, Germany). "
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    ABSTRACT: Background The survival promoting peptide Y-P30 has a variety of neuritogenic and neuroprotective effects in vitro and in vivo. In previous work we reported the expression of Y-P30/dermcidin in maternal peripheral blood mononuclear cells (PBMCs) and the transport of the protein to the fetal brain. In this study we analyzed hormonal regulation of Y-P30 in human immune cells and expression of Y-P30 in the placenta. We further studied the stability and secretion of the Y-P30 peptide. Results We found indications that Y-P30 might be produced in human placenta. The Y-P30 mRNA was rarely found in isolated human PBMCs and alpha-feto-protein, human chorionic gonadotropin as well as estradiol combined with progesterone could not induce Y-P30 expression. Y-P30 was found to be extraordinarily stable; therefore, contamination with the peptide and the Y-P30/Dermcidin precursor mRNA is a serious concern in experiments looking at the expression of Y-P30/Dermcidin. In cultured cell lines and primary neurons we found that Y-P30 could be released, but neuronal uptake of Y-P30 was not observed. Conclusions Our data suggest that a source of Y-P30 apart from eccrine glands might be the placenta. The peptide can be secreted together with the signaling peptide and it might reach the fetal brain where it can exert its neuritogenic functions by binding to neuronal membranes.
    Full-text · Article · Jun 2014 · BMC Research Notes
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