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This paper reports a summary of our comparative analysis of the uterine expression of interleukin-23 (IL-23), IL-27 and TWEAK in the CBA/J femalexDBA/2 male mouse mating combination, a model of immune-mediated early pregnancy loss. Compared with the MHC-identical CBA/JxBALB/c mating combination, which yields successful pregnancies, immunohistochemistry and qPCR in uterine tissue showed an immediate post-mating IL-27 hyper-expression after mating with DBA/2 males. Intra-uterine TWEAK expression was present in females mated with DBA/2 or Balb/c males from days 0.5 to 4.5 post-coitum (pc), peaking on day 0.5 pc together with uterine TNFalpha. In uteri of DBA/2 mated mice, TWEAK declined to almost undetectable levels on days 6.5-9.5 pc, a steeper drop than in BALB/c mated mice where TWEAK remained detectable. In both mating combinations, neutralisation of TWEAK by antibodies increased resorption rates, but surprisingly, so did IL-27 neutralisation. The complement regulator mannan binding lectin-A (MBL-A), but not MBL-C, was present on day 4.5 pc especially after mating with DBA/2 males. High levels of MBL are present in the uterine luminal fluid of sterile women, and possible functions for TWEAK and MBL in human implantation are indicated by their protein and mRNA expression in uterine biopsies from infertile and fertile individuals. Consistent with the results in mice, increased MBL expression is linked with pregnancy failure. Serum and uterine VEGF and VEGF receptor levels are also different between fertile and sterile patients. The implications of these findings for utilising the CBA/JxDBA/2 mating combination as an early onset model of preeclampsia are discussed.

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Main Session 3: Immuno-Endocrine Interactions in Reproduction.; absent

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Poster session 7: Statistical analyses of gene expression data; absent

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57 ref.; International audience

Background Malaria in pregnancy is characterised by the sequestration of Plasmodium falciparum-infected erythrocytes in placental intervillous spaces. Placental parasites express a specific phenotype, which allows them to cytoadhere to chondroitin sulfate A expressed by syncytiotrophoblasts. Malaria infection during pregnancy allows the acquisition of antibodies against placental parasites, these antibodies are thought to be involved in protection during subsequent pregnancies. Methods To investigate the development of a cellular response to placental parasites during pregnancy, peripheral blood mononuclear cells were collected from women at the time of their confinement. The study was performed in Cameroon where malaria transmission is perennial. In vitro cell proliferation and cytokine production were measured in response to non-malarial activators (concanavalin A and PPD), a recombinant protein from P. falciparum MSP-1, and erythrocytes infected by two P. falciparum lines, RP5 and W2. Like placental parasites, the RP5 line, but not W2, adheres to chondroitin sulfate A and to syncytiotrophoblasts. Results The proliferative response to all antigens was lower for cells obtained at delivery than 3 months later. Most interestingly, the cellular response to the RP5 line of P. falciparum was closely related to parity. The prevalence rate and the levels of response gradually increased with the number of previous pregnancies. No such relationship was observed with W2 line, or MSP-1 antigen. Conclusions This suggests the occurrence of an immune response more specific for the RP5 line in women having had multiple pregnancies, and who are likely to develop immunity to pregnancy-associated parasites. Both humoral and cellular mechanisms may account for the lower susceptibility of multigravidae to malaria.

To assess ultrasonic data in the context of repeated failure of implantation in assisted reproduction medicine.We reviewed ultrasonic data (uterine score at follicular and luteal phase). The same ultrasound exploration was repeated for two consecutive cycles to assess the changes in abnormalities observed and compare findings in 16 patients with repeated failure of implantation and in 14 controls. The controls were women who became pregnant within the three months following the exploration. We then introduced acetylsalicylic acid and prednisolone as first line treatment and nitroglycerin as second line treatment to measure the effects induced in 14 pathological uterine scores.The score obtained under hormonal treatment was representative of other cycles (r = 0.812, p0.0014). The score was significantly lower and the luteal uterine artery pulsatility index was significantly higher in the repeated failure group than in the control group (p0.0001 and p = 0.008 respectively). For the 14 patients, treatment improved the uterine score in 8 with acetylsalicylic acid and prednisolone and in 4 with nitroglycerin. Two patients did not respond to treatment. Concerning the effect of therapy, of 14 patients, 8 had an improved uterine score with A + P, and with T; 2 patients did not respond to any treatment.The uterine score and luteal artery pulsatility index may be valuable tools for patients with implantation failure who all do not respond to the same therapy.

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The immunotrophic theory was enunciated by Tom Wegmann. Since then, the involvement of cytokines in implantation and materno-fetal tolerance has emerged as a central topic in reproductive immunology. This brief survey covers the historical background leading to the specification of the crucial role of cytokines at the feto-maternal interface, and the present known patterns of their function. Focus is addressed to the most recent concept, e.g. pregnancy as a Th2 phenomenon (the immune response of the mother is biased towards the production of anti inflammatory cytokines, amongst them IL-10 which suppress inflammatory responses). A brief description of the role of inflammatory cytokines in implantation is presented to explain why it does not fit into such a scheme, and other recent data, for example on gamma interferon, also fails to accord with the Th2 phenomenon.

During pregnancy, a local and systemic Th2 bias of maternal immunity favors Th1-dependent infections such as malaria. This study measured cytokines secreted in cultures of chorionic villi, placental blood cells (PBC), and serum in term placentas from 88 malaria-infected and -noninfected Cameroon women. Interleukin (IL)-2 and-4 were consistently low ; IL-1Beta, IL-6, granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)-Beta2 were highest in PBC cultures. Malaria placental infection increased Th1-type cytokines, whereas Th-type cytokines and TGF-Beta2 were unchanged. Addition of lipopolysaccharide or infected erythrocytes to cultures increased TNF-alpha, IL-1Beta, IL-6,and IL-10 secretions but not those of IFN-gamma and IL-4. Overall, #Plasmodium falciparum$ induced a placental immune response involving both Th1- and Th2-type cell activation. Although the Th1 pathway was favored, IL-10 secretion was also increased, and this increase should be effective in protecting the placenta by controlling the negative effects of Th1 cytokines on pregnancy. (Résumé d'auteur)