Our data allow the assumption that via blocking IL-12 production PIBF inhibits NK activation with a concomitant reduction of TNF alpha levels. Disturbances in this system might lead to the expression of the known synergistic effect of IL-12 and TNF alpha, resulting in a Th 1 type cytokine dominance and pregnancy termination.
Peripheral lymphocytes from healthy pregnant women secrete a mediator protein named the progesterone-induced blocking factor (PIBF) that exerts an immunomodulatory function and contributes to the maintenance of pregnancy in mice. The gene coding for PIBF mRNA has been cloned and sequenced, and now the recombinant human protein is available. The aim of this study was to develop an ELISA test for determining PIBF concentrations in biological samples of pregnant women. We determined urinary PIBF concentrations of 86 healthy nonpregnant individuals and from almost 500 pregnant women by ELISA. During normal pregnancy, the concentration of PIBF continuously increased until the 37th gestational week and was followed by a sharp decrease after the 41st week of gestation. In pathological pregnancies, urinary PIBF levels failed to increase. The onset of labor was predictable on the basis of this test, whether it was term or preterm delivery. In urine of patients with preeclampsia, PIBF concentrations were significantly lower than in normal pregnancy and showed a correlation with the number of symptoms presented. These data, in line with previous in vivo findings, suggest that PIBF production is a characteristic feature of normal pregnancy, and determination of PIBF concentration in urine might be of use for the diagnosis of threatened premature pregnancy termination.
The healthy trophoblast does not express classical HLA-A and HLA-B products; therefore, an MHC-restricted recognition of trophoblast-presented Ags is unlikely. In the decidua and also in peripheral blood of healthy pregnant women, γδ T cells significantly increase in number. We investigated the possible role of γδ T cells in recognition of trophoblast-presented Ags. PBL and isolated γδ T cells from healthy pregnant women as well as from those at risk for premature pregnancy termination were conjugated to choriocarcinoma cells (JAR) transfected with nonclassical HLA Ags (HLA-E, HLA-G). To investigate the involvement of killer-inhibitory/killer-activatory receptors in trophoblast recognition, we tested the effect of CD94 block on cytotoxic activity of Vδ2+ enriched γδ T cells to HLA-E- and/or HLA-G-transfected targets. Lymphocytes from healthy pregnant women preferentially recognized HLA− choriocarcinoma cells, whereas those from pathologically pregnant patients did not discriminate between HLA+ and HLA− cells. Normal pregnancy Vδ2+ T cells conjugated at a significantly increased rate to HLA-E transfectants, whereas Vδ2+ lymphocytes from pathologically pregnant women did not show a difference between those and HLA− cells. Blocking of the CD94 molecule of Vδ2+ lymphocytes from healthy pregnant women resulted in an increased cytotoxic activity to HLA-E-transfected target cells. These data indicate that Vδ2+ lymphocytes of healthy pregnant women recognize HLA-E on the trophoblast, whereas Vδ1 cells react with other than HLA Ags. In contrast to Vδ2+ lymphocytes from healthy pregnant women, those from women with pathological pregnancies do not recognize HLA-E via their killer-inhibitory receptors and this might account for their high cytotoxic activity.
Previous studies from our laboratory showed that the immunomodulatory effects of progesterone are mediated by a 34-kDa protein, named the progesterone-induced blocking factor (PIBF). Lymphocytes of women with threatened abortion fail to produce this factor. Via inducing a Th2 biased cytokine production and blocking of NK activity, PIBF prevents induced pregnancy loss in mice, suggesting that substitution therapy with PIBF could be useful as an alternative treatment of certain forms of recurrent spontaneous abortions. Our study was aimed at mapping the sequence and structure of PIBF coding cDNA and characterizing the encoded protein product. Screening of a human liver cDNA library revealed a 2765-bp clone with a 2271-bp open reading frame. The PIBF1 cDNA encodes a protein of 757 amino acid residues with an 89-kDa predicted molecular mass, which shows no significant amino acid sequence homology with any known protein. PIBF produced via recombinant technique is recognized by the Ab specific for the secreted lymphocyte PIBF Ab, and possesses the biological activities of the secreted lymphocyte PIBF. The full-length PIBF is associated with the nucleus, whereas secretion of shorter forms, such a 34-kDa protein is induced by activation of the cell. The 48-kDa N-terminal part of PIBF is biologically active, and the part of the molecule, responsible for modulating NK activity is encoded by exons 2–4. These data provide an initial step for exploiting the possible diagnostic and therapeutic potential of this immunomodulatory molecule.
These data suggest the involvement of an altered cytokine production pattern in the immunologic effects of progesterone.
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