Anti-P- and E-selectin therapy prevents abortion in the CBA/J x DBA/2J combination by blocking the migration of Th1 lymphocytes into the foetal-maternal interface.

Institute of Medical Immunology, Charité, Medical University of Berlin, Berlin, Germany.
Cellular Immunology (Impact Factor: 1.87). 01/2006; 238(2):97-102. DOI: 10.1016/j.cellimm.2006.02.002
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ABSTRACT Leukocyte migration into inflamed tissues comprises dynamic interactions between immune and endothelial cells through events controlled by adhesion molecules, e.g., P- and E-selectins, which mediate Th1 cells recruitment after injury. Since miscarriage is known to be a Th1 event and selectins are expressed at the murine foetal-maternal interface, the purpose of our study was to investigate whether blocking P- and E-selectins before implantation could inhibit Th1 migration into the foetal-maternal interface and thus prevent foetal rejection. DBA/2J-mated CBA/J females were treated with monoclonal antibodies (mAbs) against P-selectin or with both, anti-P- and anti-E-selectins combined on days 2 and 4 of pregnancy. PBS-treated females served as controls. Our data revealed a significant improvement in pregnancy outcome in both treated groups compared to the control, which is due to the effectiveness of the mAb against P-selectin, since the treatment with anti-E-selectin alone could not prevent abortion. We further observed that there was diminished Th1 cytokine production by decidual immune cells in all treated groups in comparison to the controls. Our data first confirm the important role of P-selectin in mediating the extravasation of abortive cells, while opening new therapeutic opportunities.

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Available from: Ana C Zenclussen, Aug 31, 2015
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    • ") spontaneously provokes high abortion rates, whereas mating of CBA/J females with BALB/c mice, which also bear H2 d antigens, ends with completely normal pregnancies [13] [14]. With these backgrounds, the aim of the present work was to perform a simultaneous evaluation of immune states at the fetomaternal interface and systemic levels in CBA/J Â DBA/2 as abortion mouse model and CBA/J Â BALB/c as non-abortion mouse model or normal pregnancy control. "
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    ABSTRACT: OBJECTIVES: To determine the immune status of the abortion mouse model at the feto-maternal interface and at the systemic level simultaneously. STUDY DESIGN: Mid-pregnancy serum and decidual cell supernatants (DS) were obtained from abortion and non-abortion mouse models. The effect of serum and DS on PHA or LPS-induced lymphocyte proliferation was investigated by MTT reduction assay. Treated macrophages and LPS-stimulated macrophages were evaluated for viability and also for nitric oxide (NO) production by Griess reagent. RESULTS: Our results showed that DS from the abortion mouse model significantly decreased LPS-stimulated splenocyte proliferation, and increased proliferation in PHA-stimulated splenocytes, compared with that in the non-abortion mouse model. Proliferation assays for mid-pregnancy serum were the same on LPS- and PHA-stimulated splenocytes. NO production was decreased by non-abortion DS, similar to that observed for serum treatment in LPS-stimulated macrophages in abortion mice. CONCLUSIONS: These findings suggest that in the abortion mouse model, soluble factors within the decidua are more effective than serum soluble factors in altering immune responses that may be involved in the complex process of fetal rejection.
    European journal of obstetrics, gynecology, and reproductive biology 08/2012; 165(2). DOI:10.1016/j.ejogrb.2012.08.006 · 1.63 Impact Factor
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    ABSTRACT: Establishment and maintenance of pregnancy in the pig involve intricate communication between the developing conceptuses and maternal endometrium. Conceptus synthesis and release of estrogen during trophoblastic elongation are essential factors involved with establishing conceptus-uterine communication. The present study identified endometrial changes in gene expression associated with implantation failure and complete pregnancy loss after premature exposure of pregnant gilts to exogenous estrogen. Gilts were treated with either 5 mg estradiol cypionate (EC) or corn oil on d-9 and -10 gestation, which was associated with complete conceptus degeneration by d-17 gestation. Microarray analysis of gene expression revealed that a total of eight, 32, and five genes were up-regulated in the EC endometrium, whereas one, 39, and 16 genes were down-regulated, on d 10, 13, and 15, respectively. Four endometrial genes altered by EC, aldose reductase (AKR1B1), secreted phosphoprotein 1 (SPP1), CD24 antigen (CD24), and neuromedin B (NMB), were evaluated using quantitative RT-PCR and in situ hybridization. In situ hybridization localized gene expression for NMB, CD24, AKR1B1, and SPP1 in the luminal epithelium, and confirmed the expression patterns from RT-PCR analysis. The aberrant expression patterns of endometrial AKR1B1, SPP1, CD24, and NMB 3-4 d after premature estrogen exposure to pregnant gilts may be involved with conceptus attachment failure to the uterine surface epithelium and induction of endometrial responses that disrupt the establishment of a viable pregnancy.
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    ABSTRACT: Spontaneous abortions in the CBA x DBA/2 model are normally reported as number of resorptions/total number of implantations (R/T), pooling data from individual mice. The significance of differences between groups has been determined using non-parametric statistics (e.g. chi-square or Fisher's Exact test) based on a priori predictions. Recently, it has been argued that medians with box plots should replace the accepted standard, but this deprives readers of data needed to verify P-values, and leads to inferences incompatible with biological and statistical reality. Raw data on 173 individual CBA x DBA/2 matings were analyzed by median and mean, along with R/T data from 18 independent experiments containing 5-10 mice per group. Raw data from 19 CBA x BALB/c matings were similarly analyzed. Individual CBA x DBA/2 mouse resorption rates showed a non-Gaussian distribution, but the mean and median differed by <0.5%. Resorption data from 6 and 12 independent pools of mice were normally distributed. Only the mean enabled a between-group P-value calculation. CBA x BALB/c matings gave a median of 0 and mean of 5.1%; the data were not normally distributed, but that was because of a bimodal distribution. One group of mice had 0 abortions, and the second a mean of 13.9% abortions, and the data from the latter group were normally distributed. Although it is possible to compare individual mice, and even individual implantation sites, in resorption (abortion) studies, as the relevant question is the significance of differences between treatment groups of mice, and reproducibility, the established classical method of reporting R/T should continue to be provided. In CBA x BALB/c matings, where abortion rates are low, using the median is misleading and may obscure the existence of two distinct populations.
    American journal of reproductive immunology (New York, N.Y.: 1989) 09/2008; 60(3):192-6. DOI:10.1111/j.1600-0897.2008.00612.x · 2.67 Impact Factor
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