A potential tolerogenic immune mechanism in a trophoblast cell line through the activation of chemokine-induced T cell death and regulatory T cell modulation

Fraccaroli, Laura Virginia; Alfieri, Julio Armando; Larocca, Luciana; Calafat, Mario Jose; Mor, Gil; Leirós, Claudia Pérez; Ramhorst, Rosanna

doi:10.1093/humrep/den344

Cited by 56 publications

(61 citation statements)

References 24 publications

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“…Unlike villous trophoblast, which seems to only marginally express CCL5, trophoblast cell lines Swan 71 and HTR-8/SVneo clearly produce CCL5 (ref. 23) and, moreover, show increased CCL5 secretion in response to lipopolysaccharide (LPS) and TNF-α. 24,25 Although increased CCL5 release in response to inflammatory stimuli is in line with the present study, it remains an open question whether basal CCL5 production found in trophoblast cell lines is the result of their immortalization or reflects their rather extravillous phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…There, both factors may interfere with either circulating maternal blood cells or the trophoblast. Although CCL5 may increase Tregs and induce apoptosis of maternal alloactivated T cells in favor of maternal tolerance, 23 GM-CSF may act on the villous trophoblast in an autocrine manner. 26 Indeed, GM-CSF receptor subunit GM-Rα is present on first trimester cytotrophoblast, extravillous trophoblasts, and at lower levels on the syncytiotrophoblast.…”

Section: Discussionmentioning

confidence: 99%

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TNF-α alters the inflammatory secretion profile of human first trimester placenta

Siwetz

Blaschitz

El‐Heliebi

et al. 2016

Laboratory Investigation

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Implantation and subsequent placental development depend on a well-orchestrated interaction between fetal and maternal tissues, involving a fine balanced synergistic cross-talk of inflammatory and immune-modulating factors. Tumor necrosis factor (TNF)-α has been increasingly recognized as pivotal factor for successful pregnancy, although high maternal TNF-α levels are associated with a number of adverse pregnancy conditions including gestational hypertension and gestational diabetes mellitus. This study describes effects of exogenously applied TNF-α, mimicking increased maternal TNF-α levels, on the secretion profile of inflammation associated factors in human first trimester villous placenta. Conditioned culture media from first trimester villous placental explants were analyzed by inflammation antibody arrays and ELISA after 48 h culture in the presence or absence of TNF-α. Inflammation antibody arrays identified interleukin (IL)-6, IL-8, chemokine (C-C motif) ligand 2 (CCL2), CCL4, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as the most abundantly secreted inflammation-associated factors under basal culture conditions. In the presence of TNF-α, secretion of GM-CSF, CCL5, and IL-10 increased, whereas IL-4 and macrophage CSF levels decreased compared with controls. ELISA analysis verified antibody arrays by showing significantly increased synthesis and release of GM-CSF and CCL5 by placental explants in response to TNF-α. Immunohistochemistry localized GM-CSF in the villous trophoblast compartment, whereas CCL5 was detected in maternal platelets adhering to perivillous fibrin deposits on the villous surface. mRNA-based in situ padlock probe approach localized GM-CSF and CCL5 transcripts in the villous trophoblast layer and the villous stroma. Results from this study suggest that the inflammatory secretion profile of human first trimester placenta shifts towards increased levels of GM-CSF, CCL5, and IL10 in response to elevated maternal TNF-α levels, whereas IL-6 and IL-8 remain unaffected. This shift may represent a protective mechanism by human first trimester villous placenta to sustain trophoblast function and dampen inflammatory processes in the intervillous space. Implantation and subsequent placenta development are mandatory steps for successful human pregnancy and depend on a well-orchestrated interaction between fetal and maternal tissues. Fetal-maternal interaction involves a fine balanced synergistic cross-talk of inflammaory and immune-modulating factors to allow maternal immune adaption and tolerance of the semiallogeneic fetus at the one hand, whereas maternal immune functions need to be maintained to fight off infections on the other hand. Various concepts and paradigms have been suggested trying to explain how the maternal immune system is modulated to guarantee a viable pregnancy. One of the proposed paradigms is based on studies by Wegmann et al, 1 describing a shift from an inflammatory T-helper 1 (Th1) cytokine profile to a rather anti-inflammatory T-helper 2 (Th2) profile. ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TNF-α alters the inflammatory secretion profile of human first trimester placenta

Siwetz

Blaschitz

El‐Heliebi

et al. 2016

Laboratory Investigation

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“…28 CCL5 promotes a Th1 profile and an adequate proimplantatory microenvironment, influencing trophoblast cell survival and balance of maternal T regulatory/T effector lymphocytes in favor of maternal tolerance. 29 CXCL12/CXCR4 crosslinking stimulates antiapoptotic pathways in cultured trophoblasts, suggesting that they are important in trophoblast survival. 30 CX3CR1 is present on invading human trophoblasts and promotes their migration by action of its ligand CX3CL1, which is expressed by endometrial vasculature, epithelial and decidual cells during early pregnancy.…”

Section: Immune Response In Acquired Toxoplasmosismentioning

confidence: 99%

Congenital toxoplasmosis: candidate host immune genes relevant for vertical transmission and pathogenesis

et al. 2010

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“…This molecule can additionally induce apoptosis of potentially harmful maternal CD3 + cells and increases the frequency of Treg. 64 Another molecule in the focus of the review by Perez Leiros is vasoactive intestinal peptide (VIP), whose anti-inflammatory and tolerogenic effects were already known. 65 It is now known that VIP levels rise at the fetal-maternal interface at early gestation peaking at placentation begin.…”

Section: Modulators Of the Immune Responses During Pregnancymentioning

confidence: 99%

“…67 Current data position VIP as an important immunomodulatory molecule as it can increase the frequency of Treg and LIF at implantation sites in mice 68 and supports a tolerogenic macrophage phenotype. 64 It seems that both hormones and polypeptides are involved in the recruitment of immune cells into the fetal-maternal interface and in the generation of a tolerogenic immune response toward the fetus.…”

Section: Modulators Of the Immune Responses During Pregnancymentioning

confidence: 99%

Adaptive Immune Responses During Pregnancy

Zenclussen

2013

American J Rep Immunol

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It has long been believed that there is no immune interaction between mother and conceptus during pregnancy. This concept changed after evidence was provided that the maternal immune system is aware of the semiallogeneic conceptus and develops strategies to tolerate it. Since then, finely regulated mechanisms of active tolerance toward the fetus have been described. This Special Issue of the American Journal of Reproductive Immunology deals with these mechanisms. It begins with the description of minor histocompatibility antigens in the placenta; it further goes through adaptive immune responses toward paternal fetal antigens, mostly concentrating on regulatory T cells and molecules modulating the Th1/Th2 balance. The participation of antibody‐producing B cells in normal and pathological pregnancies is also discussed. This introductory chapter resumes the concepts presented throughout the Issue and discusses the clinical applications raised from these concepts.

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A potential tolerogenic immune mechanism in a trophoblast cell line through the activation of chemokine-induced T cell death and regulatory T cell modulation

Abstract: RANTES promotes an adequate pro-implantatory microenvironment that influences trophoblast cell survival and modulates the balance of maternal Treg/T effector lymphocytes in favor of maternal tolerance.

Cited by 56 publications

References 24 publications

TNF-α alters the inflammatory secretion profile of human first trimester placenta

TNF-α alters the inflammatory secretion profile of human first trimester placenta

Congenital toxoplasmosis: candidate host immune genes relevant for vertical transmission and pathogenesis

Adaptive Immune Responses During Pregnancy

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