Regulatory T cells, maternal–foetal immune tolerance and recurrent miscarriage: New therapeutic challenging opportunities

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Bottom: After encountering paternal-derived antigens in the periphery or in the genital tract, antigen-specific Tregs are generated. This specific Treg population could expand later, as paternal–foetal alloantigens are continuously released to the periphery. Tregs would then migrate into foetal–maternal interface where they would help to create a site of immune privilege characterized by high levels of protective molecules, e.g. HO-1, LIF, IDO, TGFβ, IL-10 and PIBF. Furthermore, Tregs maintain adequate NK3/NK1 cell subpopulation preventing trophoblast injury and permit a sufficient angiogenesis. In the end, Tregs may down-regulate maternal allo-response to foetal–paternal antigens, preventing apoptosis of trophoblast cells." ] ] ] "textoCompleto" => "IntroductionOne of the most relevant features of reproductive biology is that healthy women with a normal immune system may successfully carry a semi-allogeneic conceptus to term without apparent immune rejection, since the maternal immune system must undergo changes for the foetus, which acts as a semi-allogeneic implant, to be tolerated.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Human reproduction is a poor efficiency process. Almost 70% of embryos are lost in healthy women. Spontaneous miscarriage occurs in approximately 15% of cases, and recurrent miscarriages in 2–5%.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> In recent years, early non-chromosome-related implantation failures and miscarriages have been associated with the allo-rejection of the foetus by the maternal immune system, which has led to the use of immunosuppressive drugs such as glucocorticoids or intravenous immunoglobulin, or immunomodulating substances/molecules such as lipid emulsions, or paternal lymph-mononuclear cell therapy, with disappointing results according to a recent meta-analysis.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Classical conceptsThe true mechanisms by which the maternal immune system tolerates semi-allogeneic foetus without starting immunological rejection reactions are still poorly understood and widely debated. For many years, pregnancy had been considered to be a localized and temporary immune-suppressed state. Recently, however, researchers are beginning to consider this situation to be a foetal–maternal tolerant symbiosis. Because maternal alloreactive lymphocytes are not systemically depleted, local mechanisms have to play a key role in avoiding the immune response.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> The special characteristics of foetal trophoblast in contact with maternal tissue have been proposed to aid maternal–foetal immune tolerance through mechanisms such as low tryptophan levels, lack of effectiveness of NK cells through HLA-G/HLA-E expression, high progesterone levels, or through anti-idiotype network modulation.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> However, none of these proposed mechanisms can fully explain tolerance during pregnancy (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>An altered Th1/Th2 cytokine balance with Th2–anti-inflammatory predominance has been observed, suggesting one possible mechanism allowing for the survival of the foetus in the maternal uterus.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> However, further studies performed in genetically deficient mice with an inability to secrete Th2 cytokines did not always show miscarriages, suggesting that the former is not essential for have normal pregnancies.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Thus, alloreactive Th1 cells must be differently blocked or regulated, for instance, by regulatory T cells (Tregs).A brief on regulatory T cellsT regulatory cells are a component of the immune system that suppresses immune responses of other cells. These cells are involved in shutting down immune responses after they have successfully eliminated invading organisms, and also in preventing autoimmunity. CD4+CD25+ Tregs are a unique subset of T cells. About 5–10% of peripheral CD4+ T cells in humans constitutively express CD25, the high-affinity α-chain of the interleukin 2 receptor. Some CD4+CD25+ Tregs also express a transcription factor of the forkhead/winged-helix family called forkhead box protein 3 (Foxp3).<a class="elsevierStyleCrossRef" href="#bib0035">7</a> Functionally, Tregs may be naturally occurring or thymus-derived (nTregs or tTregs) or peripheral induced Tregs (pTregs or iTregs). pTregs develop from mature CD4+ conventional T cells in the periphery, and are suppressive cells involved in tolerance. The contribution of nTregs vs. pTregs in maintaining tolerance is unknown, but both are important. Recent studies showed a Foxp3 enhancer element, conserved noncoding sequence 1 (CNS1), to be essential for pTregs but not tTregs generation, thereby suggesting different types of biological properties.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> The molecular mechanism by which regulatory T cells exert their suppressor/regulatory activity has not been definitively characterized and is the subject of intense research. In vitro experiments have given mixed results regarding the requirement of cell-to-cell contact with the cell being suppressed. The immunosuppressive cytokines TGF-beta and interleukin 10 (IL-10) have also been implicated in regulatory T cell function. Additional suppressor T cell populations include Tr1, Th3, CD8+CD28+, and Qa-1 restricted T cells (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). This is an important “self-check” built into the immune system to prevent excessive reactions.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>New insights on Tregs in physiological and pathological maternal–foetal toleranceAs demonstrated, in both animal and human models, Tregs are increasingly produced in normal pregnancies. Conversely, Zenclussen et al.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> first observed an insufficient production of pregnancy-induced Tregs in abortion-prone mice. Interestingly, CD4+CD25+ T cells increased throughout pregnancy and diminished in the late puerperium. The same group has further demonstrated that the transfer of Tregs of normal pregnant mice into 0–2 days pregnant abortion-prone mice prevented spontaneous abortion, but not when Tregs were transferred from non-pregnant mice. Thus, it seems that Tregs are necessary in situ to prevent early abortion, although only those Tregs that have been previously exposed to paternal alloantigens.Maternal immune sensitization would provoke the expansion of both tTregs and pTregs. On the contrary, Tregs may migrate to the foetal–maternal interface and contribute to creating a “tolerant” microenvironment. In fact, this loss of maternal tolerance would explain the non-acceptance of paternal grafts after pregnancy. In some cases, continuous but very low-level maternal “sensitization” from paternal antigens through seminal proteins could be non-sufficient stimulus to maintain the allogeneic tolerance.Recent interesting advances have been made in the understanding of the role of Tregs in maternal–foetal tolerance. Samstein et al.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> hypothesized that pTregs have developed throughout the evolution of the mammalian placenta to attenuate the maternal–foetal response. In support of this theory, these authors showed CNS1 to be present in all 14 mammalian placentas analyzed and absent in non-placental mammals and non-mammals. In diverse animal experiments, these authors showed that pregnancy-induced maternal pTregs recognized paternal antigens. These pTregs are able to block maternal effector T cells, thereby reducing the maternal–foetal pathologic immune-responses to paternal antigens. By contrast, absence of this type of Tregs in the mother resulted in the accumulation and infiltration of activated T cells into the trophoblast or placentas, leading to implantation failure or spontaneous miscarriage. Another work deserving comment is that reported by Rowe et al.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> This group pointed out the key role played by Tregs when discovering that even transient partial ablation triggers foetal-specific effector T-cell activation and pregnancy loss. They showed that pregnancy selectively stimulates the accumulation of maternal Foxp3+CD4+CD25+ cells with foetal–paternally-derived alloantigen specificity. In an interesting way, after delivery, foetal-specific Tregs persist at elevated levels, keeping tolerance to pre-existing foetal antigen, and rapidly re-accumulate during further pregnancy. The accelerated expansion of Tregs during secondary pregnancy was driven almost exclusively by proliferation of foetal-specific Foxp3+ cells retained from prior pregnancy, whereas induced Foxp3 expression and proliferation of pre-existing FoxP3+ cells each contribute to Tregs expansion during primary pregnancy. Thus, pregnancy imprints Foxp3+ CD4+ cells that sustain protective regulatory memory to foetal antigen.Overall, these findings indicate that maternal–foetal alloimmune tolerance to paternal antigens is a dynamic and active process in which Tregs and particularly pTregs specifically respond to paternal antigens (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). These findings also permit to consider new strategies for improving pregnancy outcomes and novel approaches for therapeutically exploiting Treg cell memory. Although a recently proposed way of managing recurrent miscarriages is via the use of biologic therapy (anti-TNF-α blockers) to mitigate the inflammatory maternal–foetal response related to the Th1 cytokine profile, particularly TNF-α,<a class="elsevierStyleCrossRef" href="#bib0060">12</a> the findings regarding Tregs lead us to think that new therapies should aim not to suppress the maternal–foetal immune system but rather to enhance maternal tolerance. The evidence previously commented also provides biologic plausibility for the paradoxical observation that, in women suffering from unexplained RM or in ART patients with repetitive implantation failure syndrome, the administration of granulocyte-colony stimulating factors (G-SCF), such as filgrastim or lenograstim dramatically improved foetal outcomes.<a class="elsevierStyleCrossRefs" href="#bib0065">13,14</a> G-CSF are synthesized by uterine epithelial cells during induction of tolerance in early pregnancy. Insufficient G-CSF may impair optimal MHC class-II and class-I-mediated indirect presentation of reproductive antigens. Finally, G-CSF also play a major role in dendritic cell maturation. Conversely, these “tolerogenic” dendritic cells contribute actively to the selective Tregs maturation to male-derived antigens.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>ConclusionSince maternal allo-reactive lymphocytes cannot be fully depleted, and the Th1/Th2 cytokine balance alone cannot prevent miscarriage, new immune cells such as CD4+CD25+ Foxp3+, also known as regulatory T cells (Tregs), emerge as a cornerstone of maternal–foetal tolerance.Peripheral regulatory T cells step in to regulate allo-reactive Th1/Th17 cells. Animal and human experiments showed Tregs cell number and/or function to be lowered in miscarriages. Tregs at the maternal–foetal interface are able to impede foetal allo-rejection, thereby favouring a “tolerant” microenvironment characterized by the expression of diverse immune-modulating cytokines, rather than by lowering Th1 ones. In vivo experiments showed Tregs sensitization from paternal antigens to be essential for maternal–foetal tolerance. These findings also permit us to consider new strategies for improving pregnancy outcomes and novel approaches to therapeutically exploit Treg+ cell memory. The best source of paternally derived antigens, the time to administer them and the effective amount to be injected, and its association with other Tregs modulating drugs, i.e. G-CSF cytokine family, are challenges that need to be addressed as soon as possible.From our short experience in this new way of understanding, studying – Tregs, killer-cell immunoglobulin-like receptors (KIR) – and treating couples with really “idiopathic” poor obstetric outcomes, we obtained preliminary good results by using drugs that increase the level of Tregs. We observed no valuable adverse effects. Thus, although better explanations exist for unexplained RM that open up new therapeutic opportunities, future data resulting from laboratory and clinical studies will hopefully improve our knowledge of this interesting and challenging topic.Conflict of interestThe authors declare no conflict of interest." 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Peripheral T regulatory cells (pTregs) at the maternal–foetal interface are necessary in situ to prevent early abortion, but only those pTregs that have been previously exposed to paternal alloantigens. It has been showed that pregnancy selectively stimulates the accumulation of maternal Foxp3+CD4+CD25+ (Foxp3Tregs) cells with foetal specificity. Interestingly, after delivery, foetal-specific pTregs persist at elevated levels, maintain tolerance to pre-existing foetal antigen, and rapidly re-accumulate during subsequent pregnancy. pTreg up-regulation could be hypothesized as a possible future therapeutic strategy in humans." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Considerando que los linfocitos T alorreactivos no son completamente eliminados durante la gestación, parece necesario que haya otros mecanismos locales y/o generales que colaboren en la modificación de la respuesta inmunitaria materna. Los linfocitos T reguladores periféricos (Tregs-p) de la interfaz maternofetal previamente expuestos a antígenos paternos son necesarios in situ para prevenir el aborto precoz. Se ha demostrado que durante la gestación se produce una acumulación de Tregs-p Foxp3+ CD4+CD25+ con especificidad para ciertos antígenos fetales. Tras la gestación, estos Tregs-p con especificidad para antígenos fetales persisten a títulos elevados y mantienen la tolerancia materna, incrementando su número y funcionalidad en la siguiente gestación. El incremento de los Tregs-p podría ser una nueva y esperanzadora estrategia terapéutica en humanos." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2375 "Ancho" => 3167 "Tamanyo" => 450488 ] ] "descripcion" => array:1 [ "en" => "Cells and cytokines related to the foetal–maternal “tolerant” microenvironment. Bottom: After encountering paternal-derived antigens in the periphery or in the genital tract, antigen-specific Tregs are generated. This specific Treg population could expand later, as paternal–foetal alloantigens are continuously released to the periphery. Tregs would then migrate into foetal–maternal interface where they would help to create a site of immune privilege characterized by high levels of protective molecules, e.g. HO-1, LIF, IDO, TGFβ, IL-10 and PIBF. Furthermore, Tregs maintain adequate NK3/NK1 cell subpopulation preventing trophoblast injury and permit a sufficient angiogenesis. In the end, Tregs may down-regulate maternal allo-response to foetal–paternal antigens, preventing apoptosis of trophoblast cells." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Modified from Alijotas-Reig.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">1. Maternal alloreactive T-lymphocyte depletion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">2. Alloreactive Th1 cell blocking (cells and derived cytokines, i.e. TNF-α) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">3. Increase in both progesterone and progesterone-induced blocking factor (PIBF) levels \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">4. Low tryptophan levels \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">5. High indoleamine 2,3-dioxygenase (IDO) levels \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">6. Increase of local levels of leukaemia inhibitory factor (LIF) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">7. High heme oxygenase isoform (HO-1) levels \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">8. Increasing apoptosis of activated maternal lymphocytes (Fas/FasL) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">9. Specific profile of NK cells during pregnancy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">10. Change in the balance of NK3/NK1 cells \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">11. Lack of trophoblast HLA “classical” class I/class II expression \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">12. Up-regulation of trophoblastic HLA-G/E expression \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">13. Presence of cytotoxic, asymmetric antibodies directed against paternal HLA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">14. Anti-idiotype network modulation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">15. Diminishing complement system activity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">16. Predominance of Th2 cytokine balance-(mainly, IL-4, IL-10, and IL-13) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">17. ↑Transforming Growth Factor βeta (TGF-β) isoforms (Th3 cells) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">18. Increase of the regulatory T-cells (CD4+CD25+Foxp3+) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab682097.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Possible mechanisms involved in the maternal–foetal tolerant microenvironment." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Modified from Alijotas-Reig.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>" "tabla" => array:3 [ "leyenda" => "Abbreviations: APCs: antigen presenting cells; DCs: dendritic cells; Foxp3: forkhead box protein 3 (scurfin); IL: interleukin; ILT: immunoglobulin transcript; NKreg: regulatory natural killer cell; TCR: T cell receptor; Th3: T helper type 3; Tr1 cell: Tr1 regulatory T cell; Treg: regulatory T cell; TGF-β: transforming growth factor β." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treg subset \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Regulatory mechanism \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">TF<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> expressed \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Target cells \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Function \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CD4+CD25+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cell contact dependent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Foxp3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">T cells, \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autoimmunity– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IL-10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APCs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allograft rejection– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CD4+CD25− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cytokines \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Foxp3?<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">T/B cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autoimmunity– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APCs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Tr1cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IL-10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Foxp3;<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">T cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autoimmunity– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Th3 cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TGF-β \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">?<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">T cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autoimmunity– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">NKregs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IL-4, IL-10, TGF-β \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">T cells, \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autoimmunity– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APCs, \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tumour cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CD8+ T reg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cell contact dependent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">? <a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">T cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autoimmunity– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cytotoxicity, cytokines \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">? <a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Peripheral TCR \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Repertoire regulation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CD8+CD25− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Induction ILT3/ILT4 (DCs) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Foxp3? <a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DCs/APCs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autoimmunity– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Qa 1+CD8+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cytokines: IL-15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Foxp3− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">T/B cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autoimmunity– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab682096.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Subtypes detected in rodents and humans." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => 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Laubert" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/humrep/deq106" "Revista" => array:6 [ "tituloSerie" => "Hum Reprod" "fecha" => "2010" "volumen" => "25" "paginaInicial" => "2151" "paginaFinal" => "2153" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20522442" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack131257" "titulo" => "Acknowledgements" "texto" => "The authors thank Ms. Christine O’Hara for reviewing and correcting the style and grammar of the manuscript. The authors also thank Dr. Anna Galindo (Gravida, Advanced Fertility Centre, Hospital de Barcelona) and Dr. Silvia Gonzalez (IVI-Barcelona) for their help in collecting and managing patients." "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/00257753/0000014400000006/v2_201502230228/S0025775314001341/v2_201502230228/en/main.assets" "Apartado" => null "PDF" => "https://static.elsevier.es/multimedia/00257753/0000014400000006/v2_201502230228/S0025775314001341/v2_201502230228/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775314001341?idApp=UINPBA00004N"]

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Regulatory T cells, maternal–foetal immune tolerance and recurrent miscarriage: New therapeutic challenging opportunities

Linfocitos T reguladores, tolerancia maternofetal y aborto recurrente: nuevas oportunidades terapéuticas

Jaume Alijotas-Reiga,b,

Corresponding author

16297jar@comb.es
jalijotas@vhebron.net

Corresponding author.

, Taisiia Melnychukc, Josep Maria Grisd

a Systemic Autoimmune Disease Unit, Department of Internal Medicine I, Vall d’Hebron University Hospital, Spain

b Department of Medicine, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

c Obstetric Department, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain

d Reproductive Medicine Unit, Obstetric Department, Vall d’Hebron University Hospital, Universitat Autonòma de Barcelona, Barcelona, Spain

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early non-chromosome-related implantation failures and miscarriages have been associated with the allo-rejection of the foetus by the maternal immune system&#44; which has led to the use of immunosuppressive drugs such as glucocorticoids or intravenous immunoglobulin&#44; or immunomodulating substances&#47;molecules such as lipid emulsions&#44; or paternal lymph-mononuclear cell therapy&#44; with disappointing results according to a recent meta-analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Classical concepts</span><p id="par0015" class="elsevierStylePara elsevierViewall">The true mechanisms by which the maternal immune system tolerates semi-allogeneic foetus without starting immunological rejection reactions are still poorly understood and widely debated&#46; For many years&#44; pregnancy had been considered to be a localized and temporary immune-suppressed state&#46; Recently&#44; however&#44; researchers are beginning to consider this situation to be a foetal&#8211;maternal tolerant symbiosis&#46; Because maternal alloreactive lymphocytes are not systemically depleted&#44; local mechanisms have to play a key role in avoiding the immune response&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The special characteristics of foetal trophoblast in contact with maternal tissue have been proposed to aid maternal&#8211;foetal immune tolerance through mechanisms such as low tryptophan levels&#44; lack of effectiveness of NK cells through HLA-G&#47;HLA-E expression&#44; high progesterone levels&#44; or through anti-idiotype network modulation&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> However&#44; none of these proposed mechanisms can fully explain tolerance during pregnancy &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">An altered Th1&#47;Th2 cytokine balance with Th2&#8211;anti-inflammatory predominance has been observed&#44; suggesting one possible mechanism allowing for the survival of the foetus in the maternal uterus&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> However&#44; further studies performed in genetically deficient mice with an inability to secrete Th2 cytokines did not always show miscarriages&#44; suggesting that the former is not essential for have normal pregnancies&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Thus&#44; alloreactive Th1 cells must be differently blocked or regulated&#44; for instance&#44; by regulatory T cells &#40;Tregs&#41;&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">A brief on regulatory T cells</span><p id="par0025" class="elsevierStylePara elsevierViewall">T regulatory cells are a component of the immune system that suppresses immune responses of other cells&#46; These cells are involved in shutting down immune responses after they have successfully eliminated invading organisms&#44; and also in preventing autoimmunity&#46; CD4<span class="elsevierStyleSup">&#43;</span>CD25<span class="elsevierStyleSup">&#43;</span> Tregs are a unique subset of T cells&#46; About 5&#8211;10&#37; of peripheral CD4<span class="elsevierStyleSup">&#43;</span> T cells in humans constitutively express CD25&#44; the high-affinity &#945;-chain of the interleukin 2 receptor&#46; Some CD4<span class="elsevierStyleSup">&#43;</span>CD25<span class="elsevierStyleSup">&#43;</span> Tregs also express a transcription factor of the forkhead&#47;winged-helix family called forkhead box protein 3 &#40;Foxp3&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Functionally&#44; Tregs may be naturally occurring or thymus-derived &#40;nTregs or tTregs&#41; or peripheral induced Tregs &#40;pTregs or iTregs&#41;&#46; pTregs develop from mature CD4<span class="elsevierStyleSup">&#43;</span> conventional T cells in the periphery&#44; and are suppressive cells involved in tolerance&#46; The contribution of nTregs vs&#46; pTregs in maintaining tolerance is unknown&#44; but both are important&#46; Recent studies showed a Foxp3 enhancer element&#44; conserved noncoding sequence 1 &#40;CNS1&#41;&#44; to be essential for pTregs but not tTregs generation&#44; thereby suggesting different types of biological properties&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The molecular mechanism by which regulatory T cells exert their suppressor&#47;regulatory activity has not been definitively characterized and is the subject of intense research&#46; In vitro experiments have given mixed results regarding the requirement of cell-to-cell contact with the cell being suppressed&#46; The immunosuppressive cytokines TGF-beta and interleukin 10 &#40;IL-10&#41; have also been implicated in regulatory T cell function&#46; Additional suppressor T cell populations include Tr1&#44; Th3&#44; CD8<span class="elsevierStyleSup">&#43;</span>CD28<span class="elsevierStyleSup">&#43;</span>&#44; and Qa-1 restricted T cells &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; This is an important &#8220;self-check&#8221; built into the immune system to prevent excessive reactions&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">New insights on Tregs in physiological and pathological maternal&#8211;foetal tolerance</span><p id="par0030" class="elsevierStylePara elsevierViewall">As demonstrated&#44; in both animal and human models&#44; Tregs are increasingly produced in normal pregnancies&#46; Conversely&#44; Zenclussen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> first observed an insufficient production of pregnancy-induced Tregs in abortion-prone mice&#46; Interestingly&#44; CD4<span class="elsevierStyleSup">&#43;</span>CD25<span class="elsevierStyleSup">&#43;</span> T cells increased throughout pregnancy and diminished in the late puerperium&#46; The same group has further demonstrated that the transfer of Tregs of normal pregnant mice into 0&#8211;2 days pregnant abortion-prone mice prevented spontaneous abortion&#44; but not when Tregs were transferred from non-pregnant mice&#46; Thus&#44; it seems that Tregs are necessary in situ to prevent early abortion&#44; although only those Tregs that have been previously exposed to paternal alloantigens&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Maternal immune sensitization would provoke the expansion of both tTregs and pTregs&#46; On the contrary&#44; Tregs may migrate to the foetal&#8211;maternal interface and contribute to creating a &#8220;tolerant&#8221; microenvironment&#46; In fact&#44; this loss of maternal tolerance would explain the non-acceptance of paternal grafts after pregnancy&#46; In some cases&#44; continuous but very low-level maternal &#8220;sensitization&#8221; from paternal antigens through seminal proteins could be non-sufficient stimulus to maintain the allogeneic tolerance&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Recent interesting advances have been made in the understanding of the role of Tregs in maternal&#8211;foetal tolerance&#46; Samstein et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> hypothesized that pTregs have developed throughout the evolution of the mammalian placenta to attenuate the maternal&#8211;foetal response&#46; In support of this theory&#44; these authors showed CNS1 to be present in all 14 mammalian placentas analyzed and absent in non-placental mammals and non-mammals&#46; In diverse animal experiments&#44; these authors showed that pregnancy-induced maternal pTregs recognized paternal antigens&#46; These pTregs are able to block maternal effector T cells&#44; thereby reducing the maternal&#8211;foetal pathologic immune-responses to paternal antigens&#46; By contrast&#44; absence of this type of Tregs in the mother resulted in the accumulation and infiltration of activated T cells into the trophoblast or placentas&#44; leading to implantation failure or spontaneous miscarriage&#46; Another work deserving comment is that reported by Rowe et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> This group pointed out the key role played by Tregs when discovering that even transient partial ablation triggers foetal-specific effector T-cell activation and pregnancy loss&#46; They showed that pregnancy selectively stimulates the accumulation of maternal Foxp3<span class="elsevierStyleSup">&#43;</span>CD4<span class="elsevierStyleSup">&#43;</span>CD25<span class="elsevierStyleSup">&#43;</span> cells with foetal&#8211;paternally-derived alloantigen specificity&#46; In an interesting way&#44; after delivery&#44; foetal-specific Tregs persist at elevated levels&#44; keeping tolerance to pre-existing foetal antigen&#44; and rapidly re-accumulate during further pregnancy&#46; The accelerated expansion of Tregs during secondary pregnancy was driven almost exclusively by proliferation of foetal-specific Foxp3<span class="elsevierStyleSup">&#43;</span> cells retained from prior pregnancy&#44; whereas induced Foxp3 expression and proliferation of pre-existing FoxP3<span class="elsevierStyleSup">&#43;</span> cells each contribute to Tregs expansion during primary pregnancy&#46; Thus&#44; pregnancy imprints Foxp3<span class="elsevierStyleSup">&#43;</span> CD4<span class="elsevierStyleSup">&#43;</span> cells that sustain protective regulatory memory to foetal antigen&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Overall&#44; these findings indicate that maternal&#8211;foetal alloimmune tolerance to paternal antigens is a dynamic and active process in which Tregs and particularly pTregs specifically respond to paternal antigens &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; These findings also permit to consider new strategies for improving pregnancy outcomes and novel approaches for therapeutically exploiting Treg cell memory&#46; Although a recently proposed way of managing recurrent miscarriages is via the use of biologic therapy &#40;anti-TNF-&#945; blockers&#41; to mitigate the inflammatory maternal&#8211;foetal response related to the Th1 cytokine profile&#44; particularly TNF-&#945;&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> the findings regarding Tregs lead us to think that new therapies should aim not to suppress the maternal&#8211;foetal immune system but rather to enhance maternal tolerance&#46; The evidence previously commented also provides biologic plausibility for the paradoxical observation that&#44; in women suffering from unexplained RM or in ART patients with repetitive implantation failure syndrome&#44; the administration of granulocyte-colony stimulating factors &#40;G-SCF&#41;&#44; such as filgrastim or lenograstim dramatically improved foetal outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a> G-CSF are synthesized by uterine epithelial cells during induction of tolerance in early pregnancy&#46; Insufficient G-CSF may impair optimal MHC class-II and class-I-mediated indirect presentation of reproductive antigens&#46; Finally&#44; G-CSF also play a major role in dendritic cell maturation&#46; Conversely&#44; these &#8220;tolerogenic&#8221; dendritic cells contribute actively to the selective Tregs maturation to male-derived antigens&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conclusion</span><p id="par0050" class="elsevierStylePara elsevierViewall">Since maternal allo-reactive lymphocytes cannot be fully depleted&#44; and the Th1&#47;Th2 cytokine balance alone cannot prevent miscarriage&#44; new immune cells such as CD4<span class="elsevierStyleSup">&#43;</span>CD25<span class="elsevierStyleSup">&#43;</span> Foxp3<span class="elsevierStyleSup">&#43;</span>&#44; also known as regulatory T cells &#40;Tregs&#41;&#44; emerge as a cornerstone of maternal&#8211;foetal tolerance&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Peripheral regulatory T cells step in to regulate allo-reactive Th1&#47;Th17 cells&#46; Animal and human experiments showed Tregs cell number and&#47;or function to be lowered in miscarriages&#46; Tregs at the maternal&#8211;foetal interface are able to impede foetal allo-rejection&#44; thereby favouring a &#8220;tolerant&#8221; microenvironment characterized by the expression of diverse immune-modulating cytokines&#44; rather than by lowering Th1 ones&#46; In vivo experiments showed Tregs sensitization from paternal antigens to be essential for maternal&#8211;foetal tolerance&#46; These findings also permit us to consider new strategies for improving pregnancy outcomes and novel approaches to therapeutically exploit Treg<span class="elsevierStyleSup">&#43;</span> cell memory&#46; The best source of paternally derived antigens&#44; the time to administer them and the effective amount to be injected&#44; and its association with other Tregs modulating drugs&#44; i&#46;e&#46; G-CSF cytokine family&#44; are challenges that need to be addressed as soon as possible&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">From our short experience in this new way of understanding&#44; studying &#8211; Tregs&#44; killer-cell immunoglobulin-like receptors &#40;KIR&#41; &#8211; and treating couples with really &#8220;idiopathic&#8221; poor obstetric outcomes&#44; we obtained preliminary good results by using drugs that increase the level of Tregs&#46; We observed no valuable adverse effects&#46; Thus&#44; although better explanations exist for unexplained RM that open up new therapeutic opportunities&#44; future data resulting from laboratory and clinical studies will hopefully improve our knowledge of this interesting and challenging topic&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflict of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "titulo" => "New insights on Tregs in physiological and pathological maternal&#8211;foetal tolerance"
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    "fechaRecibido" => "2014-01-10"
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            1 => "Implantation failure"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Because maternal alloreactive lymphocytes are not depleted during pregnancy&#44; local and&#47;or systemic mechanisms have to play a key role in altering the maternal immune response&#46; Peripheral T regulatory cells &#40;pTregs&#41; at the maternal&#8211;foetal interface are necessary in situ to prevent early abortion&#44; but only those pTregs that have been previously exposed to paternal alloantigens&#46; It has been showed that pregnancy selectively stimulates the accumulation of maternal Foxp3<span class="elsevierStyleSup">&#43;</span>CD4<span class="elsevierStyleSup">&#43;</span>CD25<span class="elsevierStyleSup">&#43;</span> &#40;Foxp3Tregs&#41; cells with foetal specificity&#46; Interestingly&#44; after delivery&#44; foetal-specific pTregs persist at elevated levels&#44; maintain tolerance to pre-existing foetal antigen&#44; and rapidly re-accumulate during subsequent pregnancy&#46; pTreg up-regulation could be hypothesized as a possible future therapeutic strategy in humans&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Considerando que los linfocitos T alorreactivos no son completamente eliminados durante la gestaci&#243;n&#44; parece necesario que haya otros mecanismos locales y&#47;o generales que colaboren en la modificaci&#243;n de la respuesta inmunitaria materna&#46; Los linfocitos T reguladores perif&#233;ricos &#40;Tregs-p&#41; de la interfaz maternofetal previamente expuestos a ant&#237;genos paternos son necesarios <span class="elsevierStyleItalic">in situ</span> para prevenir el aborto precoz&#46; Se ha demostrado que durante la gestaci&#243;n se produce una acumulaci&#243;n de Tregs-p Foxp3<span class="elsevierStyleSup">&#43;</span> CD4<span class="elsevierStyleSup">&#43;</span>CD25<span class="elsevierStyleSup">&#43;</span> con especificidad para ciertos ant&#237;genos fetales&#46; Tras la gestaci&#243;n&#44; estos Tregs-p con especificidad para ant&#237;genos fetales persisten a t&#237;tulos elevados y mantienen la tolerancia materna&#44; incrementando su n&#250;mero y funcionalidad en la siguiente gestaci&#243;n&#46; El incremento de los Tregs-p podr&#237;a ser una nueva y esperanzadora estrategia terap&#233;utica en humanos&#46;</p></span>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">C</span>ells and cytokines related to the foetal&#8211;maternal &#8220;tolerant&#8221; microenvironment&#46; Bottom&#58; After encountering paternal-derived antigens in the periphery or in the genital tract&#44; antigen-specific Tregs are generated&#46; This specific Treg population could expand later&#44; as paternal&#8211;foetal alloantigens are continuously released to the periphery&#46; Tregs would then migrate into foetal&#8211;maternal interface where they would help to create a site of immune privilege characterized by high levels of protective molecules&#44; e&#46;g&#46; HO-1&#44; LIF&#44; IDO&#44; TGF&#946;&#44; IL-10 and PIBF&#46; Furthermore&#44; Tregs maintain adequate NK3&#47;NK1 cell subpopulation preventing trophoblast injury and permit a sufficient angiogenesis&#46; In the end&#44; Tregs may down-regulate maternal allo-response to foetal&#8211;paternal antigens&#44; preventing apoptosis of trophoblast cells&#46;</p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1&#46; Maternal alloreactive T-lymphocyte depletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">2&#46; Alloreactive Th1 cell blocking &#40;cells and derived cytokines&#44; i&#46;e&#46; TNF-&#945;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">3&#46; Increase in both progesterone and progesterone-induced blocking factor &#40;PIBF&#41; levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">4&#46; Low tryptophan levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">5&#46; High indoleamine 2&#44;3-dioxygenase &#40;IDO&#41; levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">6&#46; Increase of local levels of leukaemia inhibitory factor &#40;LIF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">7&#46; High heme oxygenase isoform &#40;HO-1&#41; levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">8&#46; Increasing apoptosis of activated maternal lymphocytes &#40;Fas&#47;FasL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">9&#46; Specific profile of NK cells during pregnancy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">10&#46; Change in the balance of NK3&#47;NK1 cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">11&#46; Lack of trophoblast HLA &#8220;classical&#8221; class I&#47;class II expression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">12&#46; Up-regulation of trophoblastic HLA-G&#47;E expression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">13&#46; Presence of cytotoxic&#44; asymmetric antibodies directed against paternal HLA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">14&#46; Anti-idiotype network modulation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">15&#46; Diminishing complement system activity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">16&#46; Predominance of Th2 cytokine balance-&#40;mainly&#44; IL-4&#44; IL-10&#44; and IL-13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">17&#46; &#8593;Transforming Growth Factor &#946;eta &#40;TGF-&#946;&#41; isoforms &#40;Th3 cells&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">18&#46; Increase of the regulatory T-cells &#40;CD4<span class="elsevierStyleSup">&#43;</span>CD25<span class="elsevierStyleSup">&#43;</span>Foxp3<span class="elsevierStyleSup">&#43;</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Possible mechanisms involved in the maternal&#8211;foetal tolerant microenvironment&#46;</p>"
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        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; APCs&#58; antigen presenting cells&#59; DCs&#58; dendritic cells&#59; Foxp3&#58; forkhead box protein 3 &#40;scurfin&#41;&#59; IL&#58; interleukin&#59; ILT&#58; immunoglobulin transcript&#59; NKreg&#58; regulatory natural killer cell&#59; TCR&#58; T cell receptor&#59; Th3&#58; T helper type 3&#59; Tr1 cell&#58; Tr1 regulatory T cell&#59; Treg&#58; regulatory T cell&#59; TGF-&#946;&#58; transforming growth factor &#946;&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treg subset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Regulatory mechanism&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Target cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">CD4<span class="elsevierStyleSup">&#43;</span>CD25<span class="elsevierStyleSup">&#43;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">T cells&#44;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Autoimmunity&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IL-10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APCs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Allograft rejection&#8211;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cytokines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Foxp3&#63;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">T&#47;B cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Autoimmunity&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APCs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Tr1cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IL-10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Foxp3&#59;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Autoimmunity&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Th3 cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TGF-&#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#63;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">T cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Autoimmunity&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">NKregs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IL-4&#44; IL-10&#44; TGF-&#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Autoimmunity&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APCs&#44;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tumour cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">CD8<span class="elsevierStyleSup">&#43;</span> T reg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cell contact dependent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#63; <a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">T cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Autoimmunity&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cytotoxicity&#44; cytokines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#63; <a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Peripheral TCR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Repertoire regulation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">CD8<span class="elsevierStyleSup">&#43;</span>CD25<span class="elsevierStyleSup">&#8722;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Induction ILT3&#47;ILT4 &#40;DCs&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Foxp3&#63; <a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DCs&#47;APCs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Autoimmunity&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Qa 1<span class="elsevierStyleSup">&#43;</span>CD8<span class="elsevierStyleSup">&#43;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cytokines&#58; IL-15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Foxp3<span class="elsevierStyleSup">&#8722;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">T&#47;B cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Autoimmunity&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Z&#46; Williams"
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                      "doi" => "10.1056/NEJMcibr1207279"
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                        "tituloSerie" => "N Engl J Med"
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                        "volumen" => "367"
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                            2 => "R&#46;M&#46; Silver"
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                      "doi" => "10.1056/NEJMcp1005330"
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                      "doi" => "10.1038/ni904"
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                      "doi" => "10.1111/j.0105-2896.2005.00247.x"
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        "texto" => "<p id="par0075" class="elsevierStylePara elsevierViewall">The authors thank Ms&#46; Christine O&#8217;Hara for reviewing and correcting the style and grammar of the manuscript&#46; The authors also thank Dr&#46; Anna Galindo &#40;Gravida&#44; Advanced Fertility Centre&#44; Hospital de Barcelona&#41; and Dr&#46; Silvia Gonzalez &#40;IVI-Barcelona&#41; for their help in collecting and managing patients&#46;</p>"
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Article information

ISSN: 00257753
Original language: English

DOI:10.1016/j.medcli.2014.01.033

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