In patients with PCO treated with FSH/GnRH antagonist, final oocyte maturation with GnRH agonist instead of HCG reduces significantly inhibin A, E2 and progesterone levels during the luteal phase. This phenomenon reflects the inhibition of the corpus luteum function and may explain, at least in part, the mechanism of OHSS prevention in high-risk patients. Our results do not support a crucial role for VEGF or TNFalpha in OHSS.
Anti-D can prevent immunization to the RhD Ag on RBCs, a phenomenon commonly termed Ab-mediated immune suppression (AMIS). The most accepted theory to explain this effect has been the rapid clearance of RBCs. In mouse models using SRBC, these xenogeneic cells are always rapidly cleared even without Ab, and involvement of epitope masking of the SRBC Ags by the AMIS-inducing Ab (anti-SRBC) has been suggested. To address these hypotheses, we immunized mice with murine transgenic RBCs expressing the HOD Ag (hen egg lysozyme [HEL], in sequence with ovalbumin, and the human Duffy transmembrane protein) in the presence of polyclonal Abs or mAbs to the HOD molecule. The isotype, specificity, and ability to induce AMIS of these Abs were compared with accelerated clearance as well as steric hindrance of the HOD Ag. Mice made IgM and IgG reactive with the HEL portion of the molecule only. All six of the mAbs could inhibit the response. The HEL-specific Abs (4B7, IgG1; GD7, IgG2b; 2F4, IgG1) did not accelerate clearance of the HOD-RBCs and displayed partial epitope masking. The Duffy-specific Abs (MIMA 29, IgG2a; CBC-512, IgG1; K6, IgG1) all caused rapid clearance of HOD RBCs without steric hindrance. To our knowledge, this is the first demonstration of AMIS to erythrocytes in an all-murine model and shows that AMIS can occur in the absence of RBC clearance or epitope masking. The AMIS effect was also independent of IgG isotype and epitope specificity of the AMIS-inducing Ab.
Preeclampsia is a pregnancy-specific disorder characterized by hypertension and systemic endothelial dysfunction. Interleukin (IL)-1β is a possible mediator of maternal endothelial dysfunction in preeclampsia. Serum IL-1β as well as its natural inhibitor IL-1 receptor antagonist (IL-1Ra) were reported to be increased in women with preeclampsia. In the current study, we addressed the role of the placenta in controlling the circulatory levels of IL-1β and its natural inhibitor IL-1Ra in preeclampsia, and the possible effect of magnesium sulfate (MgSO(4)) on these levels. Using an ex vivo placental perfusion system, placentas from preeclamptic (n = 9) and normotensive (n = 6) pregnancies were perfused in presence or absence of MgSO(4). Perfusate samples were collected from the maternal and the fetal circulations of the perfusion system, and IL-1β and IL-1Ra were examined by enzyme-linked immunoassay (ELISA). Preeclamptic placentas secreted higher levels of IL-1β (P < 0.001), and a tendentious higher levels of IL-1Ra, mainly into the maternal circulation, as compared with normotensive placentas, although no differences in IL-1β:IL-1Ra ratio were detected. However, there was only tendentious increase in the secretion levels of IL-1β or IL-1Ra into the fetal circulation of preeclamptic placentas, when compared with normotensive placentas. Administration of MgSO(4) to preeclamptic placentas resulted in an attenuation of the increased secretion of IL-1β into the maternal circulation (P < 0.001), and in a tendentious reduction in IL-1Ra. However, IL-1β:IL-1Ra ratio in preeclamptic placentas was not affected by MgSO(4). Interestingly, exposure of normotensive placenta to MgSO(4) resulted only in increased levels of IL-1Ra in the maternal circulation, without affecting IL-1β levels or IL-1β:IL-1Ra ratio. These findings suggest that the placenta may contribute to the elevation in serum IL-1β and IL-1Ra in preeclampsia by increased secretion of these cytokines into the maternal circulation, and that MgSO(4) is able to attenuate this increased secretion of IL-1β, and possibly IL-1Ra, in preeclampsia.
Polyclonal anti-D has been used to prevent RhD-negative mothers from becoming immunized against RhD positive fetal erythrocytes, and this mechanism has been referred as Ab or IgG-mediated immune suppression (AMIS). Although anti-D has been highly successful, the inhibitory mechanisms remain poorly understood. Two major theories behind AMIS involve the binding of IgG to activating or inhibitory FcγR, which can induce either erythrocyte clearance or immune inhibition, respectively. In this work, we explored the absolute role of activating and inhibitory FcγR in the AMIS mechanism using the HOD mouse model of RBC immunization. HOD mice contain a RBC-specific recombinant protein composed of hen egg lysozyme (HEL), OVA and human transmembrane Duffy Ag, and erythrocytes from HOD mice can stimulate an immune response to HEL. To assess the contribution of activating and inhibitory FcγR to AMIS, C57BL/6 versus FcRγ-chain−/− or FcγRIIB−/− mice were used as recipients of HOD-RBC alone or together with anti-HEL Abs (i.e., AMIS) and the resulting immune response to HEL evaluated. We show that anti-HEL polyclonal Abs induce the same degree of AMIS effect in mice lacking these IgG binding receptors as compared with wild-type mice. In agreement with this, F(ab′)2 fragments of the AMIS Ab also significantly reduced the Ab response to the HOD cells. In conclusion, successful inhibition of in vivo Ab responses to HOD-RBC by polyclonal IgG can occur independently of activating or inhibitory FcγR involvement. These results may have implications for the understanding of RhD prophylaxis.
Key Points• Effective inhibition of immunization by polyclonal IgG can be recapitulated by a blend of monoclonal antibodies to different epitopes.Although the prevention of hemolytic disease of the fetus and newborn is highly effective using polyclonal anti-D, a recombinant alternative is long overdue. Unfortunately, anti-D monoclonal antibodies have been, at best, disappointing. To determine the primary attribute defining an optimal antibody, we assessed suppression of murine red blood cell (RBC) immunization by single-monoclonal antibodies vs defined blends of subtypematched antibodies. Allogeneic RBCs expressing the HOD antigen (hen egg lysozyme [HEL]-ovalbumin-human transmembrane Duffy b ) were transfused into naïve mice alone or together with selected combinations of HEL-specific antibodies, and the resulting suppressive effect was assessed by evaluating the antibody response. Polyclonal HEL antibodies dramatically inhibited the antibody response to the HOD antigen, whereas single-monoclonal HEL antibodies were less effective despite the use of saturating doses. A blend of monoclonal HEL-specific antibodies reactive with different HEL epitopes significantly increased the suppressive effect, whereas a blend of monoclonal antibodies that block each other's binding to the HEL protein did not increase suppression. In conclusion, these data show that polyclonal antibodies are superior to monoclonal antibodies at suppressing the immune response to the HOD cells, a feature that can be completely recapitulated using monoclonal antibodies to different epitopes. (Blood. 2016;128(8):1076-1080
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