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Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface. Science

Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Science (Impact Factor: 31.48). 06/2012; 336(6086):1317-21. DOI: 10.1126/science.1220030
Source: PubMed

ABSTRACT The chemokine-mediated recruitment of effector T cells to sites of inflammation is a central feature of the immune response. The extent to which chemokine expression levels are limited by the intrinsic developmental characteristics of a tissue has remained unexplored. We show in mice that effector T cells cannot accumulate within the decidua, the specialized stromal tissue encapsulating the fetus and placenta. Impaired accumulation was in part attributable to the epigenetic silencing of key T cell-attracting inflammatory chemokine genes in decidual stromal cells, as evidenced by promoter accrual of repressive histone marks. These findings give insight into mechanisms of fetomaternal immune tolerance, as well as reveal the epigenetic modification of tissue stromal cells as a modality for limiting effector T cell trafficking.

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    • "The origin of uNK cells is still a matter of debate, with possibilities being self-renewal from local progenitor cells or the influx and tissue-specific differentiation of pNK cells (Manaster and Mandelboim, 2010). Work on human endometrial stromal cells indicates the close relationship between the immune and non-immune component of the endometrium, which supports the latter theory (Nancy et al., 2012). Decidualized stromal cells secrete interleukins (IL)-11 and IL-15, which are recognized as NK-differentiating factors aiding in local NK cell phenotypic differentiation (Caligiuri et al., 1990; Ashkar et al., 2003; Becknell and Caligiuri, 2005). "
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    ABSTRACT: Is there any scientific evidence to support the routine use of adjuvant therapies for women with elevated natural killer (NK) cells undergoing assisted reproduction techniques (ARTs) in order to improve live birth rate? Due to the poor quality evidence, this review does not support the use of described adjuvant treatments in women found to have elevated absolute numbers or activity of NK cells undergoing ART. Deregulation in the numbers of NK cells and/or their activity, in the blood as well as in the endometrium, has been associated with various manifestations of reproductive failure. NK cell analysis is becoming increasingly popular as a test offered to investigate the causes of reproductive failure. Adjuvant therapies influencing the NK cells have been postulated as therapeutic options for couples where deregulation of this component of the maternal immune system is suspected as the cause of infertility or implantation failure. Systematic review. Embase, LILACS, MEDLINE, PsycINFO, CENTRAL and CINAHL databases from 1946 to present were searched with no language restrictions. Studies evaluating the use of adjuvant therapies in women undergoing ART where NK cell numbers and/or activity were assessed were considered eligible for inclusion. Only three studies (one in abstract form only) meeting the inclusion criteria were identified: two reported the use of intravenous immunoglobulins (IVIg) and one the use of oral prednisolone. All studies demonstrated a beneficial effect of the interventions on clinical pregnancy rates with a risk ratio (RR) of 1.63 [95% confidence interval (CI) 1.00-2.66] for prednisolone and 3.41 (95%CI 1.90-6.11) for IVIg. Studies assessing the efficacy of IVIg have also reported live birth rate with an RR of 3.94 (95% CI 2.01-7.69) favoring the intervention. Data heterogeneity was substantial however (I(2) = 66%) suggesting a cautious interpretation of the results. Differing study populations, lack of statistical power, method of data presentation (per couple or per cycle), the use of additional medications and differing dosage regimes contribute to data heterogeneity and suggest a cautious approach to data interpretation. This review identified some data showing that adjuvant therapies (mainly IVIg) in this selected population seem to confer some benefit on ART outcome. However, overall, the review does not support the use of prednisolone, IVIg or any other adjuvant treatment in women undergoing ART who are found to have elevated absolute numbers or activity of NK cells, purely due to the paucity of, or poor quality of, the evidence. Agreement as to the most reliable NK cell testing method must be made by the scientific community as well as 'normal' NK cell levels unequivocally defined. Well designed, sufficiently powered RCTs with an appropriate population selection and using the same NK cell testing methodology are required to ascertain the actual benefit of using adjuvant therapy treatment for elevated NK cell levels or activity in the context of pregnancy outcome following IVF. None.
    Human Reproduction 11/2013; 29(1). DOI:10.1093/humrep/det414 · 4.59 Impact Factor
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    • "By activating feedback pathways, the inflammatory decidual response is self-limiting and followed by a profound anti-inflammatory response in decidualizing cells, characterized by simultaneous down-regulation of numerous chemokines and inflammatory mediators (Salker et al., 2012). Silencing of chemokine expression prevents effector T cells from entering the decidua (Nancy et al., 2012). In concert, continued progesterone signalling will massively up-regulate 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1), an enzyme that converts inert cortisone to active cortisol (Kuroda et al., 2013). "
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    ABSTRACT: Reproduction in humans is unique in two major aspects. First, the incidence of chromosomally abnormal and developmentally compromised human preimplantation embryos is exceptionally high, and second, the uterus decidualizes spontaneously each cycle, a process also responsible for the menstrual shedding of the endometrium in the absence of pregnancy. Emerging evidence suggests that these distinctive reproductive traits are functionally linked. Thus, the decidual process enables the mother to limit investment in compromised pregnancies, while menstruation imposes a need for constant recruitment of mesenchymal stem cells to regenerate and renew the endometrium each cycle. Endometrial stem cells are immune-privileged compared with other types of adult stem cells, suggesting a role for these cells in accommodating deeply invading semi-allogenic fetal trophoblast. Thus, by coupling reproductive competence to a process of constant tissue renewal, decidualization enables the human uterus to adapt to pregnancy failure and a changing ecology. By imposing the need for cyclic renewal of the endometrium, spontaneous decidualization followed by menstruation bestows unique functions on the human endometrium that are essential for reproductive success.
    Reproductive biomedicine online 10/2013; 27(6). DOI:10.1016/j.rbmo.2013.10.003 · 2.98 Impact Factor
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    • "By activating feedback pathways, the inflammatory decidual response is self-limiting and followed by a profound anti-inflammatory response in decidualizing cells, characterized by simultaneous down-regulation of numerous chemokines and inflammatory mediators (Salker et al., 2012). Silencing of chemokine expression prevents effector T cells from entering the decidua (Nancy et al., 2012). In concert, continued progesterone signalling will massively up-regulate 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1), an enzyme that converts inert cortisone to active cortisol (Kuroda et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Reproduction in humans is unique in two major aspects. First, the incidence of chromosomally abnormal and developmentally compromised human preimplantation embryos is exceptionally high, and second, the uterus decidualizes spontaneously each cycle, a process also responsible for the menstrual shedding of the endometrium in the absence of pregnancy. Emerging evidence suggests that these distinctive reproductive traits are functionally linked. Thus, the decidual process enables the mother to limit investment in compromised pregnancies, while menstruation imposes a need for constant recruitment of mesenchymal stem cells to regenerate and renew the endometrium each cycle. Endometrial stem cells are immune-privileged compared with other types of adult stem cells, suggesting a role for these cells in accommodating deeply invading semi-allogenic fetal trophoblast. Thus, by coupling reproductive competence to a process of constant tissue renewal, decidualization enables the human uterus to adapt to pregnancy failure and a changing ecology. By imposing the need for cyclic renewal of the endometrium, spontaneous decidualization followed by menstruation bestows unique functions on the human endometrium that are essential for reproductive success.
    Reproductive biomedicine online 07/2013; 27(5). DOI:10.1016/j.rbmo.2013.06.012 · 2.98 Impact Factor
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