胚胎种植与免疫

胚胎自受精卵到囊胚均包绕着致密的透明带,只有一些小分子物质能够进出胚胎。因此,在囊胚或胚胎孵出之前胚胎与母体的免疫系统基本隔离,直到囊胚在子宫孵出,胚胎才与母体通过滋养细胞直接接触。发生在母胎界面的免疫反应使胚胎能够成功侵入子宫内膜并使子宫内膜的血管发生重铸,从而胚胎能够从母体得到良好的血液供养而发育成熟。在妊娠胚胎发育的不同阶段子宫局部的免疫环境不同,这种免疫环境的改变和转换对成功妊娠十分必要。发生在胚胎种植阶段的免疫反应相对于胚胎宫内发育其他阶段的免疫反应尤为激烈和重要。约30%的妊娠期并发症与胚胎…     

妊娠鼠子宫引流淋巴结内的细胞免疫调节活性

同种异体妊娠是越过主要组织相容屏障而移植成功的天然例证。尽管发育中的胎儿能表达组织相容抗原和胚胎抗原,但母亲免疫系统并未对胎儿进行排斥,对此现象的解释是在围绕胎儿的环境中可能存在局部免疫抑制机理,对比已有很多报道。有些学者证实妊娠鼠子宫中存在免疫调节细胞,抑制母体抗胎儿的免疫应答。另发现同种异体妊娠时,子宫周围淋巴结的体积和重量增加,如果母体在交配前已对胎盘移植抗原耐受,上述改变消失。对此现象有些学者认为引流淋巴结中的细胞反应即代表抑制机理的激活,进而阻止母体对胎儿的免疫损伤,     

TRAIL在小鼠胚胎着床过程中子宫内膜的表达

目的:检测TRAIL在小鼠胚胎着床过程中子宫内膜的表达,探讨它在蜕膜细胞凋亡中的作 用。方法:采用RT-PCR及免疫组化技术检测妊娠d 1-8小鼠子宫组织TRAILmRNA及蛋白的表 达情况。结果:妊娠d 1-8的小鼠子宫组织均有TRAIL mRNA的表达,且着床期间的表达较着床前 明显增加(P<0．05)。妊娠d 1-3,小鼠子宫内膜无TRAIL蛋白表达;妊娠d 4,TRAIL表达在小鼠胚 胎定位、黏附点的子宫内膜腔上皮细胞;妊娠d 5-6,TRAIL定位于胚胎着床点附近的蜕膜细胞中; 妊娠d 7-8,TRAIL表达在与子宫蜕膜邻近的胚胎滋养层细胞中。结论:在小鼠胚胎着床过程中, TRAIL诱导子宫内膜腔上皮细胞凋亡可能是胚胎跨越上皮屏障的重要机制之一,且TRAIL诱导的 蜕膜细胞和胚胎滋养层细胞的凋亡在滋养层细胞对子宫内膜的适度侵入过程中起重要作用。     

反复胚胎植入失败和流产与子宫内膜免疫因素

胚胎着床及发育是一个母-胎相互识别、相互适应的复杂过程。在此过程中,滋养细胞表达胚胎抗原并分泌细胞因子,逃避母体免疫系统的攻击,母体蜕膜特征性免疫细胞的富集形成母-胎界面独特的免疫微环境,从而有利于胚胎着床及发育。虽然近年来体外受精-胚胎移植（IVF-ET）的成功率已有很大提高,反复种植失败（RIF）仍是困扰辅助生殖技术发展的难题。胚胎作为同种异体移植物不被母体免疫系统排斥是妊娠建立和维持的关键,母-胎免疫调节异常可致复发性流产（RSA）,给患者夫妇身心及经济均带来极大负担。随着生殖免疫学的发展,子宫内膜免疫因素在RIF和RSA发病中的作用日益受到关注,针对性的免疫治疗也在RIF和RSA的治疗方案中扮演着越来越重要的角色。文章就RIF和RSA子宫内膜免疫因素的分子病理机制及其免疫治疗的当今认识进行阐述,以期为未来的科学研究及临床治疗提供参考。     

反复胚胎植入失败和流产与子宫内膜免疫因素

胚胎着床及发育是一个母-胎相互识别、相互适应的复杂过程。在此过程中，滋养细胞表达胚胎抗原并分泌细胞因子，逃避母体免疫系统的攻击，母体蜕膜特征性免疫细胞的富集形成母-胎界面独特的免疫微环境，从而有利于胚胎着床及发育。虽然近年来体外受精-胚胎移植（IVF-ET）的成功率已有很大提高，反复种植失败（RIF）仍是困扰辅助生殖技术发展的难题。胚胎作为同种异体移植物不被母体免疫系统排斥是妊娠建立和维持的关键，母-胎免疫调节异常可致复发性流产（RSA），给患者夫妇身心及经济均带来极大负担。随着生殖免疫学的发展，子宫内膜免疫因素在RIF和RSA发病中的作用日益受到关注，针对性的免疫治疗也在RIF和RSA的治疗方案中扮演着越来越重要的角色。文章就RIF和RSA子宫内膜免疫因素的分子病理机制及其免疫治疗的当今认识进行阐述，以期为未来的科学研究及临床治疗提供参考。     

胚胎植入期母胎界面免疫耐受的研究

胚胎植入是妊娠中复杂的生理过程,受许多因素调控,其中母胎界面免疫调节平衡尤为重要.对母体来说胚胎是一种半同种移植物,但在整个植入过程中,胚胎并不被母体排斥,其中包含极其复杂的免疫调节过程.研究表明,胚胎通过上调滋养细胞人类白细胞抗原G(HLA-G)表达,与母体相应受体结合,产生免疫抑制;同时母体通过非特异性免疫应答中巨噬细胞功能的改变、自然杀伤(NK)细胞表型改变以及补体调节因子表达增加,特异性免疫应答中抗原提呈过程、协同刺激信号的产生受限以及T淋巴细胞功能状态改变等,产生对胚胎抗原的免疫耐受.这些因素之间存在相互作用,其中一种机制失调即引起母体对胚胎的免疫排斥,可导致胚胎植入失败.     

母—胎免疫调节的分子机制

母 -胎免疫调节机制的本质即母体免疫系统对胚胎抗原的耐受。这种母体对胚胎抗原的免疫耐受包括重要的母 -胎界面的免疫耐受及母体体循环对胚胎抗原的免疫耐受 ,包括对同种抗原的识别、免疫活性细胞增殖与记忆及免疫效应等三个层次的复杂调节。1　母 -胎界面抗原识别调节机制我们在实验中采用ＣＢＡ/Ｊ×ＤＢＡ/ 2小鼠胚胎作为妊娠失败模型 ;以ＣＢＡ×ＢＡＬＢ/ｃ小鼠胚胎作妊娠成功模型 ,以研究协同刺激分子在母 -胎免疫界面的可能作用。我们的研究结果显示 ,妊娠失败模型的胚胎吸收率为 2 7 8% ;妊娠成功模型的胚胎吸收率为 8 4%。我们从…     

胚胎植入期母胎界面免疫耐受的研究

胚胎植入是妊娠中复杂的生理过程，受许多因素调控，其中母胎界面免疫调节平衡尤为重要。对母体来说胚胎是一种半同种移植物，但在整个植入过程中，胚胎并不被母体排斥，其中包含极其复杂的免疫调节过程。研究表明，胚胎通过上调滋养细胞人类白细胞抗原G（HLA—G）表达，与母体相应受体结合，产生免疫抑制；同时母体通过非特异性免疫应答中巨噬细胞功能的改变、自然杀伤（NK）细胞表型改变以及补体调节因子表达增加，特异性免疫应答中抗原提呈过程、协同刺激信号的产生受限以及T淋巴细胞功能状态改变等，产生对胚胎抗原的免疫耐受。这些因素之间存在相互作用，其中一种机制失调即引起母体对胚胎的免疫排斥，可导致胚胎植入失败。     

妊娠过程中凋亡级联的作用和调节

细胞凋亡是一种级联事件,在妊娠过程中发挥了重要的作用,主要体现在胎盘形成过程中滋养细胞层分化为合体细胞滋养层,滋养层入侵确保了胎盘锚固于母体血管系统以保证胎儿氧气及营养的供应。滋养层细胞的凋亡限制了子宫壁侵入,维持母体完整性,凋亡产生的多肽是胎儿特异性耐受建立的诱导物。整个级联过程受母体免疫系统的监控,妊娠妇女的免疫应答并没有显著降低,母体免疫系统能够识别胎儿移植物这个外源性抗原并作出应答。母胎界面特定的免疫耐受诱导机制使绒毛外滋养细胞（EVT）限制和容忍相互联系。细胞因子主要由自然杀伤细胞、T细胞分泌,白细胞通过细胞因子发挥其免疫调节作用。凋亡过程受到基因调控、激素及氧化应激等因素的影响。     

杀伤细胞抑制性受体在母胎免疫耐受中的调节作用

母胎免疫耐受机理一直是许多免疫学家研究的热点。在一定意义上说 ,妊娠相当于一次成功的同种异体移植 ,胎儿所携带的父系人类白细胞抗原 (ＨＬＡ)刺激母体免疫系统 ,产生各种免疫细胞参与的排斥反应。但实际上母体却对胎儿形成免疫耐受 ,这种免疫调节作用不仅发生于母体全身免疫系统 ,而且也发生在妊娠子宫局部 ,这种局部的免疫调节 ,更直接地影响母胎之间的相互作用。在母胎界面免疫微环境中 ,有多种细胞和细胞因子参与这种免疫调节作用 ,其中自然杀伤 (ＮＫ)细胞 ,通过分泌细胞因子以及表达细胞表面抑制性受体 ,而转导抑制信号 ,在维持母…     

妊娠早期阻断协同刺激分子诱导自然流产模型孕鼠脾脏细胞母-胎免疫耐受的研究

目的　探讨阻断协同刺激分子———CD80 和CD86对自然流产模型孕鼠妊娠结局及孕鼠脾脏免疫细胞对父系抗原免疫耐受状态的影响。方法　将雌性小鼠 (CBA/J)分别与BALB/c及DBA/2两种雄性小鼠合笼交配 ,分别建立正常妊娠模型CBA/J×BALB/c( 2 0只 ,对照组 )和自然流产模型CBA/J×DBA/2 ( 2 0只 ,研究组 )。CBA/J小鼠于妊娠第 4天 (着床期 )腹腔分别注射大鼠同型IgG 0 2mg( 10只 ) ,或大鼠抗小鼠CD80 和CD86单克隆抗体 ( 10只 )。妊娠第 9天 ,采用单向混合淋巴细胞反应 ,分析孕鼠脾脏免疫细胞对父系抗原的增殖能力 ,并测定细胞培养上清液中白细胞介素 2(IL 2 )水平 ,以研究脾脏细胞母 胎免疫耐受状态 ;妊娠第 14天观察两组的胚胎吸收率。结果　 ( 1)研究组中 ,腹腔注射大鼠IgG的孕鼠胚胎吸收率为 2 4 3% ,而注射大鼠抗小鼠CD80 和CD86单克隆抗体的孕鼠胚胎吸收率为 9 8% ,两者比较 ,差异有显著性 (P <0 0 5 )。 ( 2 )应用大鼠抗小鼠CD80 和CD86单克隆抗体 ,使妊娠 9d的孕鼠脾脏免疫细胞对父系抗原的增殖能力及IL 2水平显著下降(P <0 0 5 )。结论　孕早期阻断协同刺激分子 ,可诱导产生孕鼠脾脏免疫细胞对父系抗原的免疫耐受 ,从而使自然流产模型孕鼠的妊娠结局达到正常妊娠水平。     

NK cells and pre-eclampsia

The immunological interaction between the mother and fetus has classically been thought of as one between paternal antigen and maternal T cells. However, the MHC antigen expression on human trophoblast and the immune cell populations present in the decidua suggest that this interaction primarily involves decidual NK cells rather than T cells, and this is supported by new functional studies. It is becoming apparent also that the maternal systemic immune response in pregnancy (Th1/Th2 shift) primarily involves NK cells. Aberrant NK cell activation both locally in the decidua and systemically in the maternal blood may be the cause of pre-eclampsia.     

Which immunologic mechanisms facilitate a successful pregnancy

Three possibilities are discussed for the immunological mechanisms which may be operative in establishing and maintaining a successful grafting of a semiallogenic embryo: (1) The lack of maternal allogenic recognition due to either the absence or a decreased alloantigenicity of paternal alloantigens (HLA). (2) The local suppression of maternal immune reactions against the embryo by hormonally induced decidual suppressor cells and by molecules released from the placenta. (3) The placenta may serve as an immunological barrier filtering potentially cytotoxic cells and molecules out of the maternal circulation before they reach the fetus.     

Welche immunologische Mechanismen ermöglichen eine erfolgreiche Schwangerschaft

Zusammenfassung Gegenw?rtig werden drei immunologische Mechanismen diskutiert, die eine erfolgreiche Schwangerschaft erm?glichen k?nnten: 1. Fehlende allogene Erkennung des Embryo, entweder weil keine v?terlichen Alloantigene exprimiert sind, oder weil deren allogene Wirkung zu gering ist. 2. Lokale Immunsuppression durch hormonell induzierte Suppressorzellen in der Dezidua und durch Substanzen, die von der Plazenta abgegeben werden, und 3. die Plazenta wirkt als immunologische Barriere und filtert potentiell cytotoxische Immuneffektoren, aus der mütterlichen Zirkulation bevor sie den eigentlichen Feten erreichen.

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Immunological mechanisms leading to successful pregnancy

Summary Three possibilities are discussed for the immunological mechanisms which may be operative in establishing and maintaining a successful grafting of a semiallogenic embryo: (1) The lack of maternal allogenic recognition due to either the absence or a decreased alloantigenicity of paternal alloantigens (HLA). (2) The local suppression of maternal immune reactions against the embryo by hormonally induced decidual suppressor cells and by molecules released from the placenta. (3) The placenta may serve as an immunological barrier, filtering potentially cytotoxic cells and molecules out of the maternal circulation before they reach the fetus.

     

Embryo-maternal interactions at the implantation site: a delicate equilibrium

Blastocyst implantation and successful establishment of pregnancy require delicate interactions between the embryo and the maternal environment. During preimplantation, maternal/embryo communication is mediated by the trophectoderm. In the late luteal phase, physiological changes occur in the endometrium to allow blastocyst implantation. The "window of implantation" represents the period of maximum uterine receptivity for implantation. In response to signals from the embryo, pregnancy-specific proteins are released in maternal serum and a series of morphological, biochemical and immunological changes occur in the uterine environment. These systemic and local modifications can be considered to constitute "the maternal recognition of pregnancy". The human hemochorial placenta arises primarily through proliferation, migration and invasion of the endometrium and its vasculature by the embryonic trophoblast. The complex invasive processes accompanying implantation of the embryo are controlled at the embryo-maternal interface by factors from decidualized endometrium and the trophoblast itself. An inflammatory reaction and a proper maternal immune response allow survival and development of the feto-placental unit. In this review, we focus on interactions between trophoblast and uterine tissues and on cellular mechanisms and molecular signals involved in the closely regulated process of implantation.     

Activating T regulatory cells for tolerance in early pregnancy — the contribution of seminal fluid

A state of active tolerance mediated by T regulatory (Treg) cells must be functional from the time of embryo implantation to prevent the conceptus from maternal immune attack. Male seminal fluid and ovarian steroid hormones are implicated in regulating the size and suppressive function of the Treg cell pool during the peri-implantation phase of early pregnancy. Evidence that antigens and cytokine signals in seminal fluid regulate the maternal immune response includes the following: (1) the Treg cell-inducing cytokine TGFβ and male alloantigens are present in seminal fluid; (2) seminal fluid delivery at coitus is sufficient to induce a state of active immune tolerance to paternal alloantigen, even in the absence of conceptus tissue; (3) female dendritic cells can cross-present seminal fluid antigens to activate both CD8⁺ and CD4⁺ T cells, and (4) mating events deficient in either sperm or seminal plasma result in diminished CD4⁺ CD25⁺ Foxp3⁺ Treg cell populations at the time of embryo implantation. Ongoing studies indicate that the cytokine environment during priming to male seminal fluid antigens influences the phenotype of responding T cells, and impacts fetal survival in later gestation. Collectively, these observations implicate factors in the peri-conceptual environment of both male and female origin as important determinants of maternal immune tolerance. Defining the mechanisms controlling tolerance induction will be helpful for developing new therapies for immune-mediated pathologies of pregnancy such as miscarriage and pre-eclampsia.     

Functions of interferon tau as an immunological regulator for establishment of pregnancy

The establishment of a successful pregnancy requires a “fine quality embryo”, “maternal recognition of pregnancy”, and a “receptive uterus” during the period of conceptus implantation to the uterine endometrium. In ruminants, a conceptus cytokine, interferon tau (IFNT), a major cytokine produced by the peri‐implantation trophectoderm, is known as a key factor for maternal recognition of pregnancy. IFNT can be considered one of the main factors in conceptus–uterus cross‐talk, resulting in the rescue of ovarian corpus luteum (CL), induction of endometrial gene expressions, activation of residual immune cells, and recruitment of immune cells. Much research on IFNT has focused on the CL life‐span (pregnancy recognition) and uterine gene expression through IFNT and related genes; however, immunological acceptance of the conceptus by the mother has not been well characterized. In this review, we will discuss the progress in IFNT and implantation research made by us and others for over 10 years, and relate this progress to pregnancy in mammalian species other than ruminants.     

Potentiating maternal immune tolerance in pregnancy: A new challenging role for regulatory T cells

The maternal immune system needs to adapt to tolerate the semi-allogeneic conceptus. Since maternal allo-reactive lymphocytes are not fully depleted, other local/systemic mechanisms play a key role in altering the immune response. The Th1/Th2 cytokine balance is not essential for a pregnancy to be normal. The immune cells, CD4+CD25+Foxp3+, also known as regulatory T cells (Tregs), step in to regulate the allo-reactive Th1 cells. In this review we discuss the role of Tregs in foeto-maternal immune tolerance and in recurrent miscarriage as well as their potential use as a new target for infertility treatment. Animal and human experiments showed Treg cell number and/or function to be diminished in miscarriages. Murine miscarriage can be prevented by transferring Tregs from normal pregnant mice. Tregs at the maternal–fetal interface prevented fetal allo-rejection by creating a “tolerant” microenvironment characterised by the expression of IL-10, TGF-β and haem oxygenase isoform 1 (HO-1) rather than by lowering Th1 cytokines. Tregs increase placental HO-1. In turn, HO-1 may lead to up-regulation of TGF-β, IL-10 and CTLA-4. In vivo experiments showed Tregs sensitisation from paternal antigens to be essential for maternal–fetal tolerance. Tregs increase throughout pregnancy and diminish in late puerperium. Recent data also support the capacity of Tregs to block maternal effector T cells, thereby reducing the maternal–fetal pathological responses to paternal antigens. These findings also permit us to consider new strategies for improving pregnancy outcomes, i.e., anti-TNF blockers and granulocyte-colony stimulating factors as well as novel approaches to therapeutically exploiting Treg + cell memory.     

Trophoblast debris modulates the expression of immune proteins in macrophages: a key to maternal tolerance of the fetal allograft?

Interactions between maternal immune cells and the placenta are of substantial interest since diseases of pregnancy, such as recurrent miscarriage, villitis of unknown etiology and preeclampsia may arise due to inadequate adaptation of the maternal immune system. During normal pregnancy trophoblast debris is shed from the placenta into the maternal blood in large quantities. This trophoblast debris is then rapidly cleared from the maternal circulation. In this study, we exposed trophoblast debris generated from an in vitro placental explant model to peripheral blood-derived macrophages and quantified a variety of molecules that are important in immune responses by ELISA or flow cytometry. Phagocytosis of trophoblast debris resulted in reduced cell-surface expression of MHC-II molecules, the costimulatory molecules (CD80, CD86, CD40 and B7H3), monocyte chemoattractant protein-1 (MCP-1), inter-cellular adhesion molecule 1 (ICAM-1) and IL-8 receptors in macrophages while the expression of programmed death-1 ligand 1 (PD-L1) was upregulated. In addition, phagocytosis of trophoblast debris induced the secretion of the anti-inflammatory cytokines IL-10, IL6 and IL1Ra and decreased the secretion of pro-inflammatory cytokines IL-1β, IL12p70 and IL-8 by macrophages. Phagocytosis of trophoblast debris also increased macrophage expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO). We have shown that phagocytosis of trophoblast debris from normal placentae alters the phenotype of macrophages such that they are likely to deviate maternal immune responses towards tolerance and away from inflammation. This may be one of the mechanisms that allow the human fetal allograft to survive in direct contact with the maternal immune system.     

Selective distribution and pregnancy-specific expression of DC-SIGN at the maternal-fetal interface in the rhesus macaque: DC-SIGN is a putative marker of the recognition of pregnancy

We performed immunohistochemical analysis of DC-SIGN expression at the maternal-fetal interface at different stages of pregnancy in the rhesus monkey. Natural killer cells, monocytes and macrophages were observed in the nonpregnant endometrium, particularly in the luteal phase, and were increased in pregnant endometrium. No DC-SIGN+ cells were observed in the nonpregnant uterus. We observed decidual DC-SIGN+ cells within 1 week of implantation, and they increased in number during the first 5 weeks of gestation. DC-SIGN+ cells showed a clear differential distribution in the decidua in the first 2 weeks of pregnancy, being found only adjacent to the implantation site, in marked contrast to the widespread distribution of CD68+ macrophages and CD56+ NK cells throughout the endometrium. DC-SIGN+ cells also showed a more dendritic morphology than the general CD68+ cell population, and analysis of serial sections indicated an overlapping but not identical localization of these markers. Mature dendritic cells could not be detected as judged by total absence of immunostaining for CD83, CD86, DEC-205, or CD1a. DC-SIGN+ cells were defined as MHC class II+ and CD14+ by flow cytometry. We conclude that DC-SIGN expression is an early response by the primate maternal immune system to the implanting embryo. The selectively distributed population of DC-SIGN+ decidual leukocytes may represent a morphologically and phenotypically distinct subpopulation of decidual macrophages of early pregnancy that could contribute to the establishment of maternal-fetal immune tolerance.