重视协同刺激分子在母胎免疫耐受中的调控作用

协同刺激信号在免疫应答及免疫调节中至关重要.成功妊娠实际是成功的母胎免疫耐受.妊娠早期协同刺激信号调控直接关系着妊娠预后.现有研究证据表明,妊娠早期母胎界面协同刺激分子过表达导致妊娠失败:着床期干预协同刺激信号可改善自然流产模型的妊娠预后.可以预见的是:以协同刺激信号为主线索进行研究将丰富和发展母胎免疫调节理论;妊娠期干预协同刺激信号可改善病理性妊娠的妊娠预后.     

干预CD86协同刺激信号在诱导母胎界面Th2型免疫偏倚中的作用

目的 :探讨干预CD86协同刺激信号在诱导母胎界面局部形成Th2型免疫偏倚中的作用。方法 :将正常妊娠模型 (CBA×BALB/c)和自然流产模型 (CBA×DBA/ 2 )CBA孕鼠均分为两组 ,于孕第 4、6、8天 ,对照组腹腔注射大鼠IgG ,实验组腹腔注射大鼠抗小鼠CD86mAb ;孕第 9天 ,ELISA测定母胎界面组织培养上清中Th1型 (IFN γ、TNF α) /Th2型(IL 4、IL 10 )细胞因子表达水平 ,并计算IL 4 /IFN γ、IL 10 /IFN γ比值 ;孕第 12天比较两种模型各组的胚胎吸收率。结果 :正常妊娠模型中 ,干预CD86协同刺激信号对母胎界面原有的Th2型免疫偏离及妊娠预后均无显著影响。自然流产模型中 ,干预CD86协同刺激信号能够诱导母胎界面局部形成Th2型免疫偏倚并显著改善其妊娠预后。结论 :于孕早期 ,干预CD86协同刺激信号能够改善母胎界面局部细胞因子微环境 ,形成维持正常妊娠所需的Th2型免疫偏倚 ,诱导母胎免疫耐受     

干预CD86协同刺激信号对母胎界面Th1/Th2型细胞因子转录调控及妊娠结局的影响

目的探讨干预CD86协同刺激信号对母胎界面Th1/Th2型细胞因子转录调控及妊娠结局的影响。方法:将正常妊娠模型(CBA/J×BALB/c)和自然流产模型(CBA/J×DBA/2J)CBA孕鼠均分为两组:对照组(各10只)于孕d 4、d 6、d 8腹腔注射大鼠IgG;干预组(各10只)于孕d 4、d 6、d 8腹腔注射大鼠抗小鼠CD86 mAb。孕d 9竞争性半定量RT-PCR测定各组母胎界面组织中Th1型(IL-12、IFN-γ)/Th2型(IL-4、IL-10)细胞因子转录水平;孕d 12比较两种模型各组的胚胎吸收率。结果:正常妊娠模型中,干预CD86协同刺激信号对母胎界面Th1/Th2型细胞因子转录水平及妊娠预后均无显著影响(P>0.05)。自然流产模型中,干预CD86协同刺激信号能够升调节母胎界面局部Th2型而降调节Th1型细胞因子转录水平,并显著改善其妊娠预后(P<0.05)。结论:于孕早期干预CD86协同刺激信号能够调控母胎界面局部Th1/Th2型细胞因子转录,形成维持正常妊娠所需的Th2型免疫偏倚,诱导母胎免疫耐受。     

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…     

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…     

自然流产患者蜕膜组织协同刺激分子的表达

母-胎界面是一个非常复杂的免疫微环境，胎儿作为半同种移植物被母体接受，有赖于母-胎免疫耐受的建立；妊娠失败多因母体对胚胎免疫排斥所致。协同刺激分子与其配体结合所产生的协同刺激信号在T细胞活化、增殖、辅助性T细胞（Th）分化及效应性细胞因子分泌中均发挥重要调节作用。为了解协同刺激分子在人早孕蜕膜组织中的表达规律，     

协同刺激分子CD86在母-胎免疫调节中的作用

目的　探讨协同刺激分子CD86在母 胎免疫调节中的作用。方法　建立自然流产模型(CBA×DBA/ 2 )及正常妊娠模型 (CBA×BALB/c)。两种模型分别再分为 3个组 :(1)以大鼠的IgG为对照的对照组 ;(2 )于妊娠第 4、6、8、10天 ,分别给CBA孕鼠腹腔注射大鼠抗小鼠CD86单克隆抗体的多次干预组 ;(3)仅于妊娠第 4天 ,给CBA孕鼠单次腹腔注射抗CD86单克隆抗体的单次干预组。每次腹腔注射的抗体剂量均为 10 0 μg。于妊娠第 14天计算各组胚胎吸收率。 结果　 (1)自然流产模型与正常妊娠模型的对照组胚胎吸收率分别为 2 7 78%和 8 42 %。 (2 )于妊娠第 4、6、8、10天腹腔注射抗CD86单克隆抗体后 ,自然流产模型的多次干预组胚胎吸收率下降至 9 6 8% (P <0 0 5 ) ;而正常妊娠模型的多次干预组胚胎吸收率上升至 13 5 4% (P >0 0 5 )。 (3)妊娠第 4天单次腹腔注射抗CD86单克隆抗体 ,自然流产模型单次干预组的胚胎吸收率下降至 7 14% (P <0 0 0 1) ;而正常妊娠模型单次干预组的胚胎吸收率上升至 11 39% (P >0 0 5 )。结论　妊娠早期 ,尤其在胚胎对母体的致敏阶段 (着床期 ) ,阻断母 胎界面的CD86协同刺激信号 ,将诱导母体对胚胎的免疫耐受 ,从而减少胚胎吸收 ,提高妊娠成功率     

TCR γδ T淋巴细胞和母胎免疫调节的关系

妊娠是一复杂的生理过程,妊娠早期母胎界面的免疫反应状态决定妊娠结局.TCRγδT淋巴细胞具有识别绒毛滋养细胞表达的人类白细胞抗原G和E,并通过某种机制调节Th1/Th2型细胞因子的平衡偏移及免疫效应细胞活性等作用,而这些因素是参与母胎界面免疫反应的关键环节,认为TCRγδT淋巴细胞在妊娠早期的母胎免疫调节中发挥重要作用.     

TCRγδT淋巴细胞和母胎免疫调节的关系

妊娠是一复杂的生理过程，妊娠早期母胎界面的免疫反应状态决定妊娠结局。TCRγδT淋巴细胞具有识别绒毛滋养细胞表达的人类白细胞抗原G和E，并通过某种机制调节Th1／Th2型细胞因子的平衡偏移及免疫效应细胞活性等作用，而这些因素是参与母胎界面免疫反应的关键环节，认为TCRγδT淋巴细胞在妊娠早期的母胎免疫调节中发挥重要作用。     

单细胞组学在早期妊娠母胎界面异质性中的研究进展

母胎界面是胚胎生长发育的重要环境,成功的妊娠有赖于母胎界面微环境的动态平衡。在单细胞组学技术的支持下,早期妊娠母胎界面的异质性问题得到了更深入的阐述与理解,对深刻认识生理及病理妊娠具有重要的意义。本综述旨在分析近年来单细胞组学技术在早期妊娠母胎界面组织异质性中的研究,深入探究母胎界面组织的异质性问题及母胎免疫耐受的潜在机制,为认识及治疗各种病理妊娠提供新的指导方向。     

Human decidual macrophages suppress IFN-γ production by T cells through costimulatory B7-H1:PD-1 signaling in early pregnancy

In human pregnancy, CD14⁺ decidual macrophages (DMs) are the dominant professional antigen-presenting cells in the decidua, comprising 20–30% of the local leukocyte population. Although the relevance of DMs to feto-maternal immune tolerance has been described, the molecular mechanisms underlying these functions have not been fully elucidated. B7-H1, a costimulatory ligand in the B7 family, negatively modulates T cell activity by binding to its corresponding receptor, PD-1. The present study aimed to investigate the functional significance of costimulatory interactions between DMs and T cells, with a particular focus on B7-H1:PD-1 signaling. An analysis of the expression profile of B7 ligands on human DMs revealed that B7-H1 was present on DMs isolated from early but not term pregnancies. B7-H1 was not expressed on the peripheral monocytes (PMs) of pregnant women. In response to IFN-γ, B7-H1 expression was induced on PMs and was enhanced on DMs, suggesting that this cytokine might be a key factor in the control of B7-H1 expression in the decidua. The majority of decidual T cells were noted to exhibit robust expression of PD-1, whereas the expression was limited to a small subpopulation of circulating T cells. Functional assays demonstrated that DMs are able to suppress T cell IFN-γ production via B7-H1:PD-1 interactions. This suppressive property was not observed for PMs, which lack B7-H1. B7-H1 on DMs may function as a key regulator of local IFN-γ production and thereby contribute to the development of appropriate maternal immune responses to the fetus in early pregnancy.     

外周CD4~+CD25~+T细胞降调节及CD28~+T细胞升调节参与人类自然流产

目的:探讨CD4+CD25+调节性T细胞及CD28、CTLA-4协同刺激分子在人孕早期母胎免疫耐受中的作用机制。方法:以15例黄体期育龄妇女外周血为对照,应用流式细胞术对15例早孕期正常妊娠者、15例早孕期自然流产患者外周血淋巴细胞中CD4+CD25+T细胞亚群及CD28、CTLA-4分子的表达进行分析。结果:早孕期正常妊娠者外周CD4+CD25+T细胞比例显著高于早孕期自然流产患者及黄体期育龄妇女(P<0.05);早孕期自然流产患者外周CD28分子的表达水平显著高于早孕期正常妊娠者及黄体期育龄妇女(P<0.05);各组淋巴细胞基本不表达表面CTLA-4(CTLA-4s)分子,而均表达细胞内CTLA-4(CTLA-4i)分子,各组间CTLA-4i分子表达水平比较无显著性差异。结论:人早孕期外周CD4+CD25+调节性T细胞比例下降及CD28分子表达水平上升可能与早期妊娠失败有关。     

CD80-modified tumor cell lines: implications for cell-based vaccinations in breast cancer patients

A number of genetic alterations are required for malignant transformation. However, these mutations provide the source for tumor-associated antigens which can be recognized by cellular effectors of the immune system. Recent advances in tumor immunology - such as the improved understanding of antigen presentation as well as T cell activation - have opened new perspectives for cancer immunotherapy. The advantage of using tumor cell based vaccines is that these comprise the complete antigen pool of an individual tumor for activating polyclonal immune responses. However, the induction of antigen-specific immune responses is impaired by the fact that T cell activation is depending on additional nonspecific costimulatory signals provided by the antigen-presenting cell. The majority of solid human tumors does not express costimulatory molecules and is unable to deliver all signals required for T cell activation. In contrast, tumors often induce immunologic tolerance. Therefore, the introduction of genes encoding costimulatory molecules such as CD80 or cytokines is aimed at conferring the immunostimulatory potential of tumor cells. We have undertaken efforts at endowing a breast carcinoma cell line expressing at least seven known tumor associated antigens with immunostimulatory competence by CD80 gene transfer. In preclinical studies this cell line was demonstrated to induce specific immune responses. We designed a phase I/II trial to administer the CD80-modified cell line to patients with metastatic breast cancer to determine the toxicities of the vaccination protocol and nature of the vaccine-induced immune response.     

Early embryonal signals

As early pregnancy signals are known up to now: early pregnancy factor (EPF), early pregnancy associated protein (EPAP), early pregnancy associated thrombocytopenia (EPAT), platelet activating factor (PAF) and the so-called amplified pregnancy signals. Clinical relevance in the near future may obtain EPF estimations for diagnosis of early pregnancy after sterility therapy and for monitoring of the first trimester of pregnancy.     

Preeclampsia: a view through the danger model

Classical thinking suggests that the immune system undergoes activation on the basis of discrimination between 'self' and 'non-self'. Accordingly, the fetus activates the mother's immune system because the fetus is in part 'non-self'. Thus, successful pregnancy depends on constraint of maternal immunity. Preeclampsia is an outcome of lost constraint. Instead, the danger model suggests that normal pregnancy, regardless of the expression of 'non-self' antigens, does not activate the maternal immune system unless that pregnancy expresses danger signals. Thus, preeclampsia stems from stress or abnormal cell death in pregnancy-related tissues. This compels expression of specific danger signals and potential activation of anti-fetal immunity, which secondarily feeds the syndrome. Study of preeclampsia from this perspective may bring forth novel mechanisms and indicators of vascular and metabolic dysfunction during pregnancy.     

Toll样受体在妊娠期疾病的作用机制

Toll样受体（TLR）作为一种病原体识别受体备受关注,其在固有免疫中能识别病原体相关的分子模式（PAMP）,通过刺激信号的级联反应导致细胞因子的产生和协同刺激因子的表达,从而在天然免疫和获得性免疫中发挥一系列作用.妊娠结局和先天性免疫密切相关,母胎界面特有的滋养细胞、羊膜细胞等也可以通过TLR参与先天性免疫反应,从而影响妊娠结局.综述TLR的结构、信号通路及其与妊娠期疾病的关系.     

Preeclampsia: a view through the danger model

Classical thinking suggests that the immune system undergoes activation on the basis of discrimination between ‘self’ and ‘non-self’. Accordingly, the fetus activates the mother's immune system because the fetus is in part ‘non-self’. Thus, successful pregnancy depends on constraint of maternal immunity. Preeclampsia is an outcome of lost constraint.Instead, the danger model suggests that normal pregnancy, regardless of the expression of ‘non-self’ antigens, does not activate the maternal immune system unless that pregnancy expresses danger signals. Thus, preeclampsia stems from stress or abnormal cell death in pregnancy-related tissues. This compels expression of specific danger signals and potential activation of anti-fetal immunity, which secondarily feeds the syndrome.Study of preeclampsia from this perspective may bring forth novel mechanisms and indicators of vascular and metabolic dysfunction during pregnancy.     

蛋白质组学应用于早期妊娠流产的研究进展

妊娠过程类似于半同种异体移植,母胎界面的功能失调与早期妊娠流产,如早期自然流产、复发性流产等有关,但具体发病机制仍不十分清楚。蛋白质组学是通过高通量、快速鉴定与定量分析细胞、组织、体液中的所有蛋白质组成、功能及蛋白之间的相互作用的学科,将蛋白质组学应用于早期妊娠流产病理机制研究,发现早期妊娠流产与胎盘滋养细胞的侵袭力不足、母胎界面血管形成异常、氧化应激、母胎界面免疫功能失调、凝血功能异常、肥胖等有关,有利于相关疾病的早期诊断。将蛋白质组学应用于不明原因复发性流产(URSA)的治疗研究,发现淋巴细胞主动免疫疗法可通过调整并恢复患者的免疫状态,从而维持妊娠,改善妊娠结局。综述蛋白质组学及其在早期妊娠流产中的应用。     

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.     

Th17及相关细胞因子在妊娠早期母-胎免疫耐受中的作用

目的:研究Th17细胞及相关细胞因子IL-22、IL-23在人孕早期不明原因的自发性流产母-胎免疫耐受中的作用。方法:以10例正常人工流产患者为正常早孕组,收集18例染色体正常自发性流产患者为自然流产组。分离两组患者外周血单个核细胞及蜕膜组织免疫细胞,用流式细胞术检测上述细胞中Th17细胞比例及相关细胞因子的表达,探讨其与自发性流产的关系。结果:自然流产组外周血Th17细胞比例显著高于正常早孕组(P<0.05),IL-23显著低于正常早孕组(P<0.01),但两组IL-22无显著差异;自然流产组蜕膜局部Th17细胞比例显著高于正常早孕组(P<0.01),IL-23亦显著高于正常早孕组(P<0.01),IL-22则显著低于正常早孕组(P<0.01)。结论:Th17细胞在孕早期蜕膜局部及外周血中的数量增多可能导致母胎免疫耐受失衡,在早期自然流产中发挥重要的正诱导作用,而IL-22、IL-23等细胞因子在其中的调控效应则具有明显的微环境相关性。