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。     

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。     

CTLA4Ig gene transfer alleviates abortion in mice by expanding CD4+CD25+ regulatory T cells and inducing indoleamine 2,3-dioxygenase

Successful pregnancy requires a state of immunological tolerance since normally the maternal immune system does not reject the semi-allogeneic conceptus. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a ligand for B7, delivers negative signals to antigen presenting cells (APCs) to compete with CD28 for binding to B7 molecules and down-regulate proinflammatory responses, thus inhibiting T cell activation. Using CBA/J × DBA/2 matings as an abortion-prone model, we observed that adenovirus-mediated CTLA4Ig (Ad-CTLA4Ig) gene transfer improves pregnancy outcome. Ad-CTLA4Ig therapy skewed the ability of serum cytokine production toward a Th2 bias. Flow cytometry revealed that Ad-CTLA4Ig administration expanded peripheral CD4⁺CD25⁺ regulatory T cell populations in CBA/J × DBA/2 matings. Furthermore, Ad-CTLA4Ig administration induced indoleamine 2,3-dioxygenase (IDO) and Foxp3 mRNA expression at the materno-fetal interface. Our results demonstrate that adenovirus-mediated CTLA4Ig gene transfer improves pregnancy outcome in a murine model of abortion by expanding the CD4⁺CD25⁺ regulatory T cell population and inducing IDO mRNA expression.     

CD4(+)CD25+ T regulatory cells in murine pregnancy

Mammalian pregnancy is thought to be a state of immunological tolerance and immunological pregnancy complications may result from incomplete allo-tolerance. We reported recently a higher frequency of Th1 cytokine-producing T cells specific against paternal antigens in abortion-prone mice compared to normal pregnant mice. Since Th2 cells were shown to be not essential for normal pregnancy; alloreactive Th1 cells must be differently regulated. In this context, T regulatory cells (Treg) were proposed to play an essential role. Normal pregnant mice show an expansion of CD4(+)CD25+ and IL-10+ Treg cells at the periphery compared to non-pregnant animals. Further, we reported significantly lower frequencies of Treg in abortion-prone mice. Interestingly, CD4(+)CD25+ Treg cells from normal pregnant mice were able to prevent fetal rejection. Accordingly, down-regulated levels of Treg were also reported during human miscarriage. The putative mechanisms involved in Treg-induced tolerance in mice and humans are discussed in this review.     

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     

CD4(+)CD25high regulatory T cells in human pregnancy

In both rodent and human systems, there is an emerging consensus that immunoregulatory activity specific for donor alloantigens is enriched in the CD4(+)CD25+ T cell population. The absence of CD4(+)CD25+ regulatory T (Treg) cells induces severe immunodeficiency with autoimmune disease, dermatitis and fatal infections in humans and mice. CD4(+)CD25+ Treg cells play a critical role in peripheral tolerance, transplantation tolerance and maternal tolerance to the fetus. Although both human and mouse CD4(+)CD25+ Treg have potent regulatory properties, surface phenotypes of human CD4(+)CD25+ Treg cells are not exactly the same as those of mouse CD4(+)CD25+ Treg cells. Murine CD4(+)CD25+ T cells are homogenous and exhibit regulatory function. On the other hand, CD4(+)CD25high T cells are the only cells which exhibit regulatory function in humans. Humans CD4(+)CD25low cells have no ability for immunosuppression. CD4(+)CD25high T cells inhibit the immunostimulation of conventional T cells through cell-to-cell contact or immunosuppressive cytokines such as interleukin 10 and transforming growth factor-beta. As another mechanism of immunosuppression, CTLA-4 on CD4(+)CD25+ regulatory T cells up-regulate indoleamine 2,3-dioxygenase (IDO) expression in dendritic cells which play important roles for immunosuppression. Here, we review the differences between humans and mouse Treg cells and the role of CD4(+)CD25+Treg during pregnancy.     

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     

Over-expression of heme oxygenase-1 by adenoviral gene transfer improves pregnancy outcome in a murine model of abortion

Mammalian pregnancy is a complex phenomenon allowing the maternal immune system to support its allogeneic fetus. Physiological pathways protecting the fetus from rejection are thought to be comparable with those leading to allograft acceptance. Heme oxygenase (HO)-1 is known to protect locally against rejection in transplantation models due to its anti-oxidant, anti-inflammatory and cytoprotective functions. Based on previous data on low HO-1 levels in placenta from mice undergoing abortion, we hypothesized that an up-regulation of HO-1 during pregnancy would avoid fetal rejection in the murine abortion combination CBA/J x DBA/2J, using BALB/c-mated CBA/J as normal controls. We injected pregnant mice undergoing abortion with 1 x 10(5) PFU of an adenoviral vector containing HO-1 and GFP (AdHO-1/GFP), and compared the pregnancy outcome with PBS- or 1 x 10(5) AdEGFP-treated abortion-prone mice and with PBS-treated normal pregnant mice. The abortion rate diminished significantly after adenoviral gene transfer of AdHO-1/GFP. The systemic and local IL-4/IFN-gamma ratio was augmented in AdHO-1-treated mice compared to abortion-prone mice. Interestingly, the HO-1 treatment up-regulated the ratio IL-10/TNF-alpha in spleen but not in decidual lymphocytes. HO-1-treated mice further showed diminished apoptosis rate and increased Bag-1 mRNA levels at the materno-fetal interface. Thus, we propose HO-1 as a key regulator of pregnancy success. HO-1 would exert its action by locally up-regulating the Th2/Th1 cytokine ratio and by further protecting tissues from apoptosis.     

阻断协同刺激分子对MMP-9/TIMP-3的表达及妊娠结局的影响

目的：探讨阻断CD86协同刺激分子对自然流产模型孕鼠母胎界面MMP-9和TIMP-3的表达及妊娠结局的影响。方法：实验组于妊娠d 4．5腹腔注射大鼠抗小鼠CD86单抗,对照组注射大鼠同型IgG2b,而正常组不作任何处理。于妊娠d 13．5计算胚胎吸收率,并用免疫组化测定MMP- 9和TIMP-3的表达。结果：实验组的胚胎吸收率和MMP-9均显著低于对照组(P＜0．05),与正常对照组间均无差异；TIMP-3的表达与对照组和正常组比较均无显著差异(P＞0．05)。结论：在妊娠早期阻断CD86协同刺激分子能够通过某些机制诱导自然流产鼠MMP-9/TIMP-3的比值降低并且降低自然流产模型的胚胎吸收率,使模型组的胚胎吸收率恢复至正常妊娠水平。     

Murine CD45+CD86+ cells isolated from para-aortic lymph nodes in an abortion-prone model

The present study aims to address whether the analysis of CD45+CD86+ cells isolated from para-aortic lymph nodes (pLNs) is valuable in assessment of the status of local immunity at the murine feto-maternal interface. CBA/J x DBA/2 mice, virgin CBA/J mice, and CBA/J x BALB/c mice were used as an abortion-prone model (group A), nonpregnant controls (group N), and fertile controls (group F), respectively. The percentage of CD45+CD86+ cells in the CD45+ cell group (CD45+CD86+ percentage for short) and the absolute number of these cells were determined by means of flow cytometry (FCM), using mononuclear cells isolated from pLNs collected 5.5, 9.5, and 13.5 days post-coitum (dpc), respectively, and mononuclear cells isolated from placentas 13.5 dpc. To clarify the identity of these CD86+ cells, FCM was also performed with CD3, CD19, and DX5 as specific markers for murine T-cells, B-cells, and NK cells, respectively. Both resorption rate and absolute number of resorptions were significantly higher in group A (29.3%, 1.8+/-1.0) than in group F (4.8%, 0.3+/-0.5, P<0.001, respectively). Similarly, both cell percentage and absolute number of CD45+CD86+ cells in pLNs collected 13.5 dpc were significantly higher in group A than in group F (27.5+/-14.0% versus 12.3+/-7.1%, and 1362+/-687 versus 615+/-353, P=0.001, respectively). The CD45+CD86+ percentage was around 7.5% in nonpregnant CBA/J mice, similar to the 10.6% in CBA/JxDBA/2 mice 5.5 dpc, but had increased dramatically, to 23.9%, by 9.5 dpc (P<0.001 versus nonpregnant mice and P=0.002 versus CBA/JxDBA/2 mice 5.5 dpc), and remained at a higher level (27.5%) until 13.5 dpc. However, this trend was not observed in group F during pregnancy. The increased CD45+CD86+ percentage at day 9.5 of gestation, when resorption begins, may support the assumption that CD45+CD86+ cells play a role in the course of embryo resorption. Lymphocyte phenotypic analysis in the lymph nodes that drain the pregnant uterus may be helpful to assess the status of local immunity at the feto-maternal interface.     

Fetal alloantigen is responsible for the expansion of the CD4(+)CD25(+) regulatory T cell pool during pregnancy

Increasing evidence suggests that CD4(+)CD25(+) regulatory T cells (Tregs) participate in the development of maternal tolerance to the fetus during pregnancy; however, the factors controlling the activities of Tregs are poorly understood. In the present study, CD4(+)CD25(+) Tregs were analyzed in syngeneically pregnant mice (BALB/cxBALB/c), allogeneically pregnant mice (BALB/cxC57), ovariectomized mice and pregnant women to investigate the influences of fetal alloantigens and pregnancy-related hormones on the activities of Tregs. It was demonstrated that the frequencies of CD4(+)CD25(+) Tregs increase more in allogeneically than in syngeneically pregnant mice, which contributes to a lowered alloreactivity against paternal antigens in allogeneically compared with syngeneically pregnant mice. The increased Tregs are most likely to be induced in peripheral lymphoid tissues, rather than develop in thymus. Allogeneically mated mice and humans share similar dynamic changes in Treg frequencies, markedly increasing during early pregnancy and progressively decreasing from mid-gestation onwards to return to non-pregnant levels at term. Induction of labor in humans appears to be associated with a decrease of CD4(+)CD25(high) Tregs and increase of CD4(+)CD25(low) T cells. Neither estrogen or progesterone alone, nor their combination, shows an impact on the frequencies of Tregs in ovariectomized mice. These results suggest that fetal alloantigen is responsible for the increase of Tregs during pregnancy, and the expansion of the Treg population is of importance for the allogeneic fetus to evade immune attack from the mother.     

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.     

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。     

An investigation of allogeneic pregnancy in multiparous mice subjected to in vivo depletion of CD8 (Ly2)-positive lymphocytes by monoclonal antibody treatment

Adult thymectomized C57/Bl (H-2b) and DBA/1 (H-2q) female mice were subjected to treatment with rat anti-mouse CD8 and mouse anti-rat Ig (kappa) prior to entering their third pregnancy with CBA/Ca (H-2k) males. The treatment protocol drastically reduced the number of CD8 (Ly2)-carrying lymphocytes (T-cytotoxic/suppressor phenotype) in the spleen and para-aortic lymph nodes, as assessed by immuno-staining. All mice were investigated on day 18 of their third gestation. The following data were collected from experimental and control groups: (1) resorption frequency, (2) weight of the placenta, fetuses, spleen and para-aortic lymph nodes, (3) immunohistochemical analysis of maternal lymphoid tissues, (4) level of anti-paternal IgG serum antibodies, (5) content of "background" IgM and IgG-secreting cells in spleen and para-aortic lymph nodes. Neither the resorption frequency nor placental/fetal weight was affected by anti-CD8 treatment. However, the formation of anti-paternal antibodies was enhanced in anti-CD8 treated C57/Bl mice.     

CD4＋T细胞在原因不明复发性流产中的研究进展

正常妊娠有赖于母体对胚胎半同种抗原的免疫耐受,一旦免疫耐受失衡,将导致免疫排斥、免疫攻击从而导致自然流产,原因不明复发性流产被认为与母胎免疫耐受失衡有关.CD4＋T在同种异体急性排斥反应中发挥重要作用,根据所分泌的细胞因子不同,CD4＋T 细胞分为Th1、Th2、调节性T细胞（Treg）及新近发现的Th17细胞.早期研究发现母体外周血、母胎界面CD4＋T细胞增高与复发性流产密切相关.随免疫耐受机制研究的不断深入,母胎免疫耐受的研究历经Th1/Th2平衡到Treg的免疫负调控作用,再到Th17/Treg平衡.综述CD4＋T细胞在原因不明复发性流产中的研究进展.     

淋巴细胞免疫治疗对小鼠自然流产模型母胎界面CD80~+表达及妊娠结局的影响

目的:评价CBA/J×DBA/2小鼠配对组合作为反复自然流产模型的生殖力特点,及其与母胎交界CD80表达间的关系,并研究淋巴细胞免疫治疗(lymphocyte immunotherapy,LIT)对CD80表达水平的影响。方法:对CBA/J×DBA/2小鼠的生殖力特点进行为期120d的观察,并与生殖力正常的4种对照组进行比较。另计算15对CBA/J×DBA/2小鼠孕13d的胚胎吸收率,并用CD80-FITC和CD45-PE双色流式细胞术检测CD80细胞在母胎交界面的构成比。为了明确CD80~+细胞的身份,检测了CD3、DX5(NK细胞)和MHC-Ⅱ在CD80细胞群中的表达水平。此外,检测LIT组与未治疗组CBA/J×DBA/2小鼠胚胎吸收率和CD80细胞的阳性率。结果:CBA/J×DBA/2小鼠的流产特点是为孕10d左右的反复流产。CBA/J×DBA/2小鼠孕13d的胚胎吸收率显著高于BALB/c×DBA/2小鼠(30.8％±16.6％vs.7.7％±6.7％,P相似文献   

抗原递呈细胞表面共刺激分子CD80/CD86表达与自然流产的关系

目的 :探讨共刺激分子CD80 /CD86与自然流产的关系。方法 :采用双标记流式细胞分析技术检测自然流产小鼠模型CBA/J×DBA/ 2脾脏及肠系膜淋巴结内 (MLN)抗原递呈细胞MΦ表面CD80 /CD86的表达情况 (n =10 ) ,以正常妊娠小鼠模型CBA/J×BALB /c为对照 (n =5 )。结果 :1、自然流产模型组脾脏内表达CD80MΦ含量为 1.82±0 .4 1% ,与正常妊娠模型组的 1.64%± 0 .61%差异无显著性 (P >0 .0 5 ) ,而表达CD86MΦ含量在自然流产模型组中为 2 .34%± 0 .67% ,明显低于正常妊娠模型组的 5 .98%±2 .4 3% (P <0 .0 5 ) ;2、自然流产模型组MLN内表达CD80MΦ含量为 10 .2 0 %± 5 .4 2 % ,明显高于正常妊娠模型组 1.5 8%± 0 .70 % ,差异有显著性 (P <0 .0 5 ) ,而表达CD86MΦ含量在自然流产模型组中为 1.4 6%± 0 .5 7% ,明显低于正常妊娠模型组 3.96%± 0 .39% (P <0 .0 0 1)。结论 :抗原递呈细胞表面共刺激分子CD80 /CD86的表达异常在自然流产的发病中起重要作用     

Altered dendritic cell function in normal pregnancy

In pregnancy, maternal immunity is skewed to favour maintenance of gestation and immune tolerance of a semi-allogeneic fetus. Dendritic cells are thought to play a crucial role in mediating the balance between immunity and tolerance, and determining the type of T helper cell response. We postulated that myeloid dendritic cells would be modified in pregnancy to favour type 2 T helper cell responses. We show that the proportion of circulating myeloid dendritic cells expressing CD86 and staining for HLA-DR were significantly lower in the third trimester of pregnancy compared with non-pregnant women. As pregnancy progressed through the third trimester to term, CD86 expression increased. Furthermore, monocytes from pregnant women differentiated into less phenotypically mature dendritic cells which expressed lower levels of CD80, CD86 and HLA-DR molecules compared with non-pregnant women. In response to inflammatory stimuli, monocyte-derived dendritic cells, from pregnant women up-regulated CD86 more than CD80, and secreted less IL-12p70 but more IL-10, compared with monocyte-derived dendritic cells from non-pregnant controls. Our results demonstrate that, in pregnancy, the dendritic cell system is modified to favour type 2 T helper cell responses.     

早期妊娠的免疫耐受机制

胚胎对于母体来说是半异己的移植物 ,其表达部分父系抗原。孕早期母体免疫系统 ,尤其是子宫内膜局部的 NK细胞、巨噬细胞、TCR( γ+ δ+ ) T细胞和 B淋巴细胞等免疫细胞能否识别并耐受胚胎抗原 ,直接影响妊娠结局。近年来的研究表明 ,母体免疫系统在受到体内高浓度性激素水平抑制的基础上 ,通过子宫内膜局部 EAIF、HLA-G等分子产生免疫抑制 ;R80 K、BP和 PIBF等封闭因子产生免疫封闭 ;Fas L和 RCAS1诱导免疫清除 ;降调 CD1、CD80、CD86及增强 IL-1 0表达以诱导克隆无能和 /或非特异性的免疫调节等机制共同作用 ,产生对胚胎抗原的免疫耐受 ,而且这些因素之间存在相互作用 ,其中一种机制失调即引致母体对胚胎的免疫排斥 ,可导致妊娠失败     

Immunosuppressive effect of pregnant mouse serum on allostimulatory activity of dendritic cells

In normal pregnancy, the maternal immune system is directed towards tolerance or suppression in order to prevent rejection of the semi-allogenic fetus. Antigen-presenting cells, especially dendritic cells (DCs), are key cells in initiation and regulation of immune responses. The presence of potent immunostimulatory DCs in the decidual tissue of pregnancy has been demonstrated. The aim of this study was to determine how allostimulatory activity of DCs could be affected during pregnancy. DCs were isolated from spleen of pregnant or non-pregnant Balb/c mice and co-cultured with allogenic T lymphocytes prepared from brachial lymph nodes of C57BL/6 mice. Some cultures of non-pregnant female DCs were treated by 2.5% serum obtained from pregnant mice at early, middle or late gestational periods, and were used in the same mixed lymphocyte reaction (MLR) settings. Cell proliferation was measured by 3H-thymidine incorporation, and cytokine production measured in supernatants of MLR cultures using ELISA. The effect of pregnant mouse serum on expression of DC surface markers was evaluated by flow cytometry. No significant difference was found between stimulatory potential of splenic DCs from pregnant and non-pregnant mice in induction of allogenic T cell proliferative response. Moreover, serum of early or late pregnancy did not have any effect on DC function in comparison with non-pregnant mouse serum, while mid-pregnancy serum significantly inhibited allostimulatory activity of DCs. IFNgamma production in co-culture of DCs treated with pregnant mouse serum was significantly lower than that of the control group; however, no significant difference in IL-10 production was observed. Treatment of DCs with pregnant mouse serum did not influence the percentage of cells expressing MHC-II, CD86, CD8alpha or CD11b. However, a marked reduction of the mean fluorescence intensity of MHC-II was observed. Collectively, our results concerning the diminished capacity of DCs to induce production of Th1 cytokines and allogenic T cell proliferation after treatment with pregnant mouse serum reveal a new way of immunologic tolerance against the semi-allogenic fetus.