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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. Am J Pathol

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: 4.6). 03/2005; 166(3):811-22.
Source: PubMed

ABSTRACT 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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    • "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.
    European Journal of Obstetrics & Gynecology and Reproductive Biology 08/2014; 181. DOI:10.1016/j.ejogrb.2014.07.038 · 1.63 Impact Factor
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    • "fetal alloantigens is induced (Moldenhauer et al., 2009; Zenclussen et al., 2005). In fact, alloantigens are present in human SP (Koelman et al., 2000; Politch et al., 2007) and may be responsible for the Treg expansion, as was previously shown in mice (Robertson et al., 2009). "
    Journal of Reproductive Immunology 03/2014; s 101–102:20. DOI:10.1016/j.jri.2013.12.079 · 2.37 Impact Factor
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    • "Maternal CD4 + CD25 + regulatory T cells (Tregs) have been reported to contribute to the maintenance of tolerance during pregnancy by suppressing maternal alloreactive immune responses against paternal structures in fetal cells (Zenclussen et al., 2005; Shima et al., 2010; Rowe et al., 2012; Samstein et al., 2012). It has been speculated the Tregs also participate at initial stages of pregnancy, e.g., implantation (Zenclussen et al., 2005; Schumacher et al., 2007), at which inflammatory processes and innate cell populations play an important role. However, conclusive experimental proof that Tregs are important for implantation was missing. "
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    ABSTRACT: Implantation of the fertilized egg into the maternal uterus depends on the fine balance between inflammatory and anti-inflammatory processes. Whilst regulatory T cells (Tregs) are reportedly involved in protection of allogeneic fetuses against rejection by the maternal immune system, their role for pregnancy to establish, e.g., blastocyst implantation, is not clear. By using 2-photon imaging we show that Foxp3(+) cells accumulated in the mouse uterus during the receptive phase of the estrus cycle. Seminal fluid further fostered Treg expansion. Depletion of Tregs in two Foxp3.DTR-based models prior to pairing drastically impaired implantation and resulted in infiltration of activated T effector cells as well as in uterine inflammation and fibrosis in both allogeneic and syngeneic mating combinations. Genetic deletion of the homing receptor CCR7 interfered with accumulation of Tregs in the uterus and implantation indicating that homing of Tregs to the uterus was mediated by CCR7. Our results demonstrate that Tregs play a critical role in embryo implantation by preventing the development of a hostile uterine microenvironment.
    Frontiers in Immunology 06/2013; 4:158. DOI:10.3389/fimmu.2013.00158
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