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.     

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.     

Adoptive transfer of CD4+CD25+ regulatory T cells for prevention and treatment of spontaneous abortion

Objectives

The purpose of this study was to examine whether adoptive transfer with in vitro expanded CD4⁺CD25⁺ regulatory T cells (Tregs) could prevent immune response-mediated spontaneous abortion in mice.

Study design

Female CBA/J mice were mated with male Balb/c as the control with normal pregnancy or with DBA/2J mice as a model of spontaneous abortion. The CBA/J mice mated with DBA/2J were treated intravenously with freshly isolated or in vitro expanded Tregs on day 1 or 4 of pregnancy, respectively. The numbers of surviving and reabsorbed fetuses in the different groups of mice were counted on day 14 of pregnancy, and the concentrations of cytokines in individual sera and the supernatants of cultured Tregs were measured by ELISA.

Results

Adoptive transfer with freshly isolated Tregs only slightly reduced the fetal resorption rate, which was not significantly different from that of the mice without Treg treatment, regardless of treatment at early stage and implementation of pregnancy. In contrast, adoptive transfer with in vitro expanded Tregs significantly reduced the fetal resorption rates, particularly for treatment at early stage of pregnancy (P < 0.05). Furthermore, adoptive transfer with in vitro expanded Tregs at early stage of pregnancy significantly increased the levels of serum IL-10, TGF-β1, and the ratios of IL-10 to IFN-γ.

Conclusions

Our data clearly indicated that adoptive transfer with in vitro expanded Tregs at early stage of pregnancy protected fetuses from spontaneous abortion by re-establishing immune tolerance in mice.     

Immune reactivity of allogeneically pregnant mice to paternal MHC antigens on fetal and placental cells assessed by second set rejection of ascites tumor cells

In vivo immunogenicity of fetus- and placenta-derived cells as well as the immune reactivity of pregnant mice to fetal cells were examined for graft rejecting response (GRR). Systemic administration of small numbers of fetal cells but not placental cells from allogeneically pregnant mice (10(6) cells per mouse) or adult allogeneic spleen cells (10(4) cells) sensitized mice for second-set rejection of an ascitic tumor bearing paternal major histocompatibility complex (MHC) antigens. Despite this fact and the known positive humoral response, pregnant and parous mice are not even minimally sensitized with fetal MHC antigens for GRR transplacentally. Nevertheless, any pregnancy-related systemically active control, which would selectively prevent the mother from being sensitized for GRR by limiting numbers of semi-allogeneic fetal cells, was not demonstrable in either allogeneically or syngeneically pregnant mice. Irrespective of pregnancy, mice did not, however, respond to repeated administration of very small numbers of allogeneic spleen cells (5 X 10(2) cells per mouse) for graft rejection. These findings support the notion that deviation of maternal immunity to fetal antigens away from harmful GRR is mediated principally by local mechanisms which inhibit fetal cells from gaining access to the mother for GRR, and additionally by the innate inability of mice to respond to very small numbers of allogeneic cells that might escape past the local maternal-fetal barrier.     

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.     

The predominance of Th17 lymphocytes and decreased number and function of Treg cells in preeclampsia

The aim of this study was to estimate the prevalence of CD3(+)CD4(+) T lymphocytes producing IL-17, IL-2, IFN-γ, and IL-4, plus CD4(+)CD25(+)FoxP3(+) T regulatory (Treg) cells, in peripheral blood of patients with preeclampsia and healthy women in the third trimester of normal pregnancy. Another purpose was to assess the immunosuppressive activity of Treg cells from patients with preeclampsia compared with controls. Thirty-four preeclampsia patients and 27 healthy pregnant women were included. The percentages of CD4(+)CD25(+)FoxP3(+) Treg cells and CD3(+)CD4(+) T lymphocytes with intracellular expressions of cytokines were estimated using monoclonal antibodies and flow cytometry. In vitro functional assays were performed using a Treg Cell Isolation Kit and (3)H-thymidine incorporation assays. The percentage of CD3(+)CD4(+) T lymphocytes producing IL-17A was significantly higher in preeclampsia than in healthy, normotensive pregnant women in the third trimester (p<0.001). The population of CD4(+)CD25(+)FoxP3(+) Treg cells was significantly lower in the study group compared with controls (p<0.05). There was no change in the stimulation index of CD3(+)CD4(+)CD25(-) T lymphocytes from preeclampsia patients without Treg cells and after addition of autologous Treg cells. In normal pregnancy, the stimulation index of CD3(+)CD4(+)CD25(-) T lymphocytes was significantly higher without Treg cells compared with the response after addition of autologous Treg cells (p<0.05). The results suggest up-regulation of the Th17 immune response in preeclampsia. The decreased number and function of Treg cells may be responsible for activating the inflammatory response characteristic of this disorder. In preeclampsia, the predominance of Th17 immunity could act through modulating the Th1/Th2 immune balance.     

Reduction in popliteal lymph node graft-versus-host reactivity by homologous and heterologous pregnancy serum

The popliteal lymph node assay was used to investigate the effect of pregnancy on graft-versus-host reactivity (GvHR) of mouse spleen cells. After local injection of splenocytes from primiparous syngeneically pregnant (by BALB/cJ males) or allogeneically pregnant (by CBA/Ca males) mice no differences in lymph node weight gain were observed in F1 recipients (CBA/Ca x BALB/cJ) when compared to injections of cells from age-matched non-pregnant BALB/cJ mice. However, lymphocytes of pregnant BALB/cJ females which had previously been pregnant between 4 and 6 times by CBA/Ca males induced a significantly lower GvHR compared to cells of matched non-pregnant multiparous mice. These results suggested an inhibitory effect of gestation on cells possibly primed towards paternal antigens by multiple pregnancies. To test this hypothesis, virgin BALB/cJ mice were actively immunized with lymphocytes of male CBA/Ca mice. Before injection into F1 recipients, spleen cells of immunized animals were incubated for 1 h at 37 degrees C in heat-inactivated serum of primiparous pregnant or virgin non-pregnant mice. Pre-incubation in pregnancy serum had no effect on unprimed cells, but GvHR of cells derived from immunized donors was significantly depressed in female recipients. In male animals this effect was only irregularly observed. Inhibition of GvHR was also observed with serum from pregnant but not non-pregnant pigs. Depression of cellular immune response was observed as early as days 4-9 post-coitum (p.c.) with mouse serum and days 16-19 p.c. with pig serum. These results indicate that pregnancy serum contains factor(s) which modulates the GvHR of primed lymphocytes in both a species- and an antigen-non-specific manner while reactivity of naive spleen cells is not changed.     

Maintained allogeneic pregnancy in rats depleted of T cytotoxic/suppressor cells by OX8 monoclonal antibody treatment

It has been suggested that CD8 positive suppressor T-cells might be of importance in the non-rejection of the fetus. In the present investigation allogeneically pregnant (Lewix x DA) rats were subjected to in vivo treatment with monoclonal OX8 antibodies, reactive with the rat equivalent of CD8 receptor. This treatment protocol drastically reduced the numbers of OX8 positive cells in spleens and para-aortic lymph nodes. On the day of delivery these rats, together with normal IgG treated controls, were dissected and analysed for effects on: (1) fetal survival; (2) weight and immunohistology of spleens and para-aortic lymph nodes; (3) total numbers of IgM- and IgG-secreting cells within these organs. The OX8 treated rats passed through pregnancy as successfully as did the controls. Both groups showed the same type of pregnancy-induced changes in their lymphoid organs, including dramatic growth of the para-aortic lymph nodes and increase in Ig-secretors within both spleen and para-aortic lymph nodes. This pattern was the same in all pregnant rats investigated, including untreated syngeneically mated Lewis rats. It is concluded that OX8 positive T "suppressor" cells do not play an important role in the maintenance of the fetal-placental unit.     

Humoral immune responses in murine pregnancy. III. Relationship between anti-paternal alloantibody levels in maternal serum, placenta and fetus

Studies have been carried out on allogeneically mated pregnant female mice to examine the relationship between the levels of anti-paternal alloantibody occurring free or as soluble immune complexes in the maternal peripheral circulation and that existing in a bound form in the placenta and free in the fetal circulation. In a 'non-responder' strain of mouse, as defined by the inability to detect anti-paternal alloantibody in the peripheral serum of multiparous allogeneically mated females, no alloantibody could be detected as soluble immune complexes, bound to the placenta or in the fetal circulation. A similar situation existed in females of a 'responder' strain during their first pregnancy and in some individuals during their second. However, in 'responder' strain females possessing alloantibody in their peripheral serum, alloantibody could be eluted from the semi-allogeneic placenta when peripheral titres exceeded 1:16, and was found in the fetal serum when they exceeded 1:128. When such females were subsequently mated syngeneically, alloantibody was detected in placental eluates only when peripheral titres exceeded 1:128-256 and in the fetal serum when they exceeded 1:16. The alloantibody eluted from placentae and that found in neonatal serum exhibited similar isotype distribution to that in the peripheral serum. These results are discussed with reference to the relative importance of the yolk sac and the immunoabsorbent semi-allogeneic placenta in the restricted transfer of pregnancy-induced anti-paternal alloantibody to the fetus.     

Pregnant and pseudopregnant mice produce a low cytotoxic alloantibody response when challenged by fetal but not adult F1 alloantigens

The tertiary cytotoxic alloantibody response of syngeneically pregnant, pseudopregnant and non-pregnant BALB/c mice immunised with semi-allogeneic lymphocytes from fetal and adult (CBA X BALB/c)F1 donors was investigated by the microcytotoxicity method. The pregnant and pseudopregnant animals showed a significantly lower response to fetal alloantigens compared to that towards adult alloantigens (P less than 0.001). In contrast, control non-pregnant recipients showed no diminution of response to fetal alloantigens. These observations suggest that the hormonal status of pregnancy, even in the absence of a conceptus, permits a low cytotoxicity antibody response when challenged specifically by fetal, but not when challenged by adult, F1 alloantigens.     

What is the role of regulatory T cells in the success of implantation and early pregnancy?

Problem The immune system is well controlled by the balance between immunostimulation and immunoregulation. CD4⁺CD25⁺ regulatory T (Treg) cells and an enzyme called indoleamine-2, 3-dioxygenase (IDO) mediate maternal tolerance of the allogeneic fetus. Treg cells, therefore, may prevent early pregnancy loss due to maternal ‘rejection.’ Methods The latest understanding of tolerance during pregnancy is reviewed. Results and conclusions Recent data show that CD4⁺CD25⁺ Treg cells play essential roles in the induction and maintenance of tolerance, and that they augment the IDO activity in dendritic cells and macrophages. Therefore, CD4⁺CD25⁺ Treg cells and IDO enzyme may cooperate in the induction of tolerance during pregnancy. Treg deficiency is associated with very early post-implantation loss and spontaneous abortion in animal models, and low Treg levels are associated with recurrent miscarriages in humans.     

Existence of suppressor cells in the spleen of allogeneic and syngeneic primiparous pregnant mice

Mixed lymphocyte reaction (MLR) and in vitro induction of cytolytic cells against alloantigens were investigated using spleen cells from primiparous mice mated allogeneically or syngeneically. One-way MLR was reduced significantly in degree not only in allogeneic but also in syngeneic pregnant mice. MLR of virgin spleen cells was suppressed when mitomycin C-treated spleen cells taken from syngeneic or allogeneic pregnant mice were added as regulator cells. These suppressive effects disappeared when regulator cells were treated with anti-Thy 1 or anti-Lyt 2 serum plus complement. Generation of cytotoxic lymphocytes from syngeneic or allogeneic pregnancy spleen cells in MLR was depressed compared with that from virgin spleen cells. The addition of pregnancy spleen cells to MLR suppressed in vitro generation of cytotoxic lymphocytes from virgin spleen cells. These results indicated that reduction of in vitro cellular responses of pregnancy spleen cells was due to suppressor cells in the spleens. These cells suppressed non-specifically the reactions to alloantigens and could be detected both in allogeneic and syngeneic primiparous pregnancies.     

Inadequate tolerance induction may induce pre-eclampsia

The fetus is semi-allograft to the maternal host; therefore, a system of tolerance must be present during pregnancy. Epidemiological findings support a relationship between pre-eclampsia and the failure of tolerance induction. For induction of major histocompatibility complex (MHC) class I-specific tolerance, long-term exposure to seminal fluid, which contains paternal soluble MHC class I antigens, may induce paternal MHC class I-specific tolerance. Furthermore, soluble HLA-G1, which induces the deletion of CD8(+) T-cells, and the combination of maternal killer-immunoglobulin-like receptors (KIR) on NK cells and fetal HLA-C, which affects the balance between inhibition and activation signals of NK cells, regulatory CD8(+) T cells, and regulatory NK cells, may play very important roles in the induction of MHC class I-specific tolerance. On the other hand, exposure to sperm, which express paternal HLA-DR, and trophoblastic debris, which contain intracellular fetal HLA-DR, may induce paternal MHC class II-specific tolerance. In this process, CD4(+)CD25(+) regulatory T (Treg)-cells play central roles. In this review, we discuss the relationship between the risk of pre-eclampsia and tolerance induction.     

Preterm delivery induced by LPS in syngeneically impregnated BALB/c and NOD/SCID mice

Strategies of lipopolysaccharide (LPS) stimulation with or without previous toll-like receptor 4 (TLR4) blocking were pursued to investigate the mechanism of LPS-induced preterm delivery in syngeneically impregnated BALB/c and non-obese diabetic (NOD)/LtSz-scid/scid (NOD/SCID [severe combined immunodeficiency] for short) mice. The LPS-stimulated mice were killed at the beginning of preterm labor and pooled placentas were collected in each mouse. Cell surface expression of TLR4, CD80, and intracellular TNF-alpha in placenta CD45(+) cell population was determined by flow cytometry. It displayed that preterm delivery could be induced by LPS in BALB/c, while the NOD/SCID seemed to be resistant to LPS induction. TLR4 expression was not changed in either BALB/c or NOD/SCID mice upon LPS-stimulation, but the CD45(+)CD80(+) cell percentage was elevated in both groups. The CD45(+)TNF-alpha(+) cell percentage was increased merely in BALB/c after the stimulation, while no such trend was observed in NOD/SCID mice. In BALB/c, the effect of LPS on CD80 and TNF-alpha expression could be abrogated by previous TLR4 blocking, subsequently prevent LPS-induced preterm delivery. In another design, NK cell blocking was performed at earlier stage of gestation by injections of anti-asialo GM1 antiserum (ASGM1). It appeared that LPS-induced preterm delivery could be partially prevented by this blocking in BALB/c mice. Such data, together with the diversity of sensitivity to LPS induction observed in BALB/c and NOD/SCID mice, imply that LPS interacts with TLR4, triggers the mobilization of CD45(+)CD80(+) cells, results in elevated production of inflammatory cytokines, and finally results in preterm delivery. In addition, NK cells may be involved in the signaling cascade, and the lack of functional NK cells in the NOD/SCID may be why these mice appeared to be less sensitive to LPS-induced premature labor.     

Murine fetal resorption and experimental pre-eclampsia are induced by both excessive Th1 and Th2 activation

It has been proposed that immune responses in mammalian normal pregnancy are Th2-like, thereby protecting the fetus and placenta from being rejected. Administration of exogenous Th1 cytokines into pregnant mice is reported to induce feto-placental resorption. However, the effects of exogenous Th2 cytokines and Th2 directed responses in pregnant animals have not been well studied. In this study, we examined IL-4 and IL-12, which play decisive roles in the development of Th2 and Th1 responses, respectively, in the induction of fetal resorption and development of experimental pre-eclampsia. Transfer of either IL-4 and/or IL-12 stimulated splenocytes from BALB/C virgin female mice into BALB/C pregnant mice mated with either C57BL/6 or BALB/C male mice resulted in fetal resorption and glomerular nephritis associated with hypertension and proteinuria. In mice treated with IL-12 stimulated splenocytes, fatty liver degeneration associated with bile retention was observed. These results indicate that both excessive Th1 and Th2 activation contribute to the development of fetal resorption and pre-eclampsia, but that Th1 is critical to the development of liver degeneration.     

体外受精-胚胎移植反复失败患者外周血中CD4~+CD25~+Treg的表达

目的:探讨外周血中CD4+CD25+调节性T淋巴细胞(CD4+CD25+Treg)在体外受精-胚胎移植反复失败(RIF)发病机制中的作用。方法:用流式细胞分析技术检测12例RIF组、15例胚胎移植妊娠组、15例正常未孕组患者外周血中CD4+CD25+Treg的表达。结果:RIF组患者外周血中CD4+CD25+Treg的表达率为(0.80±0.56)%,低于正常未孕组的(4.05±0.91)%,两组差异有统计学意义(P<0.05);胚胎移植妊娠组患者外周血中CD4+CD25+Treg的表达率为(11.01±2.09)%,高于RIF组,两组差异有统计学意义(P<0.05)。结论:辅助生殖中反复植入失败可能与CD4+CD25+Treg的表达下降有关,这为免疫治疗提供了理论依据。     

Significant differences of lymphocytes isolated from ascites of patients with ovarian cancer compared to blood and tumor lymphocytes. Association of CD3+CD56+ cells with platinum resistance

OBJECTIVES: Tumor infiltrating lymphocytes (TILs) and T regulatory cells (Tregs) have been associated with prognosis in ovarian cancer, but their prognostic significance in ascites has not been studied. We performed a prospective study of T lymphocytes isolated from ascites from patients with ovarian carcinoma and we compared them with the respective populations in blood and tumors. METHODS: Mononuclear cells from ascites (n=71) and blood were isolated by Ficoll, while tumor lymphocytes (n=20) were obtained upon mechanical dissociation. Phenotypic analysis was performed with flow cytometry. Ascites from 10 patients with cirrhosis was used as control. RESULTS: Tregs containing CD4(+)CD25(+) cells, NK-T containing CD3(+)CD56(+) cells and CD69 and HLADR expression of CD4 and CD8 lymphocytes were significantly increased in tumor ascites compared to blood and control ascites. A selective accumulation of these populations in the ascites of cancer patients, was suggested by the significantly higher ascites/blood (A/B) ratios in cancer patients but not controls. Cancer cell content in ascites was correlated with CD4(+)CD25(+), CD4(+)CD69(+), CD4(+)HLADR(+) and CD8(+)CD69(+) cells. There was no correlation of lymphocyte populations between ascites and samples from peritoneal metastases. Higher tumor grade was associated with increased A/B CD4(+)CD25(+) ratio and reduced CD3(+)CD56(+) cells, while platinum resistance was associated with reduced A/B CD3(+)CD56(+) ratio. CONCLUSIONS: There are significant differences of CD3(+)CD56(+) and CD25(+)CD4(+) lymphocytes and increase in lymphocyte activation between blood, ascites and peritoneal metastases from patients with ovarian cancer. The selective accumulation of CD3(+)CD56(+) population in ascites may be a predictive factor for platinum resistance.     

CD83(+)dendritic cells in the decidua of women with recurrent miscarriage and normal pregnancy

Immunological factors have been postulated to play a role in the aetiology of recurrent miscarriage as the fetus and placenta are semi-allogenic to the mother. Potent immunostimulatory (CD83(+)) dendritic cells have recently been identified in the uterine decidua. This study was conducted to examine whether decidual dendritic cells could play a role in the aetiology of recurrent miscarriage. First trimester placental and decidual biopsies were obtained from 40 women with recurrent miscarriage and 15 gestation-matched normal controls. These biopsies were screened by immunohistochemistry for CD83(+)cells. Staining was analysed by light microscopy and digital image analysis. In both recurrent miscarriage and normal pregnancy, CD83(+)dendritic cells were localized to the decidua. Individual dendritic cells were present in the decidual stroma or in clusters of 3-4 dendritic cells, in lymphoid aggregates. There were no significant differences in decidual CD83(+)dendritic cell density between women with recurrent miscarriage and normal pregnancy when the groups were compared as a whole. However, when segregated by gestational age, decidua from women with recurrent miscarriage at 8 weeks' gestation contained significantly more dendritic cells than gestational age-matched normal controls. This suggests dendritic cells may play a role in the aetiology of some cases of recurrent miscarriage.     

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     

Blockade of CD80 and CD86 at the time of implantation inhibits maternal rejection to the allogeneic fetus in abortion-prone matings

CD28/CTLA-4 interactions with their specific B7-ligands (CD80 and CD86) play a decisive role in antigenic and allogenic responses. Recently, experimental transplant studies demonstrated that donor-specific tolerance was achieved by blocking these interactions. However, the role of blockade of CD28/B7 costimulatory pathway in the maintenance of materno-fetal tolerance has received little attention. In the present study, abortion-prone CBA/J females mated with DBA/2 males were administered with anti-CD80 and anti-CD86 monoclonal antibodies (mAbs) on day 4 of gestation (time of murine implantation). We demonstrated that the combined use of anti-CD80 and anti-CD86 mAbs induced maternal tolerance to the fetus in the abortion-prone CBA/J mice, and displayed expansion of the maternal CD4(+)CD25+ regulatory T cell population and up-regulated expression of CTLA-4, suggesting an active mechanism of regulatory T cells in suppressing maternal rejection to the fetus. In addition, the anti-CD80/86 mAbs treatment enhanced Th2 and reduced Th1 cytokine production in mice, implying that the development of Th2 cells might contribute to maternal tolerance to her fetus. Together, these findings indicated that blocking CD80 and CD86 enhanced maternal tolerance to her fetus in mice by increasing regulatory T cell function and skewing toward a Th2 response. Our data might provide an enhanced understanding of the maternal-fetal immune relationship and be helpful in clinical trials for immunotherapy of recurrent spontaneous abortion.