Abstract
Low molecular weight heparin (LMWH) is widely used in recurrent miscarriage treatment. The anti-coagulant effects are established, while immunological effects are not fully known. Our aim was to assess LMWH effects on activation and polarization of central regulatory immune cells from healthy women, and on placenta tissues from women undergoing elective abortions. Isolated blood monocytes and T helper (Th) cells under different activation and polarizing conditions were cultured with or without LMWH. Flow cytometry showed that LMWH exposure induced increased expression of HLA-DR and CD206 in macrophages. This phenotype was associated with increased secretion of Th17-associated CCL20, and decreased secretion of CCL2 (M2-associated) and CCL22 (Th2), as measured by multiplex bead array. In accordance, LMWH exposure to Th cells reduced the proportion of CD25highFoxp3+ regulatory T-cells, intensified IFN-γ secretion and showed a tendency to increase the lymphoblast proportions. Collectively, a mainly pro-inflammatory effect was noted on two essential tolerance-promoting cells. Although the biological significancies of these in vitro findings are uncertain and need to be confirmed in vivo, they suggest the possibility that immunological effects of LMWH may be beneficial mainly at an earlier gestational age to provide an appropriate implantation process in women with recurrent miscarriage.
Highlights
Low molecular weight heparin (LMWH) is widely used in clinical practice as an empirical therapy for recurrent miscarriages (RM)[1]
Decidual macrophages and regulatory T (Treg) cells are of particular relevance; both cell types being enriched in the decidua and with an immune regulatory profile[22,23]
granulocyte-macrophage colony-stimulating factor (GM-CSF)-macrophages generated in the presence of LMWH acquired a phenotype characterized by a significantly higher expression of HLA-DR (MFI, a relative increase of 25%) and CD206 (MFI, 17–33% increase), compared with GM-CSF-macrophages not exposed to LMWH (Fig. 1, representative histograms are shown in Supplemental Fig. 1), while CD163 and CD209 expression was not affected by LMWH (Supplemental Fig. 2)
Summary
Low molecular weight heparin (LMWH) is widely used in clinical practice as an empirical therapy for recurrent miscarriages (RM)[1]. RM is a clinical condition characterized by a predisposition to break tolerance involving different auto-antibodies (such as anti-cardiolipin antibodies, anti-nuclear antibodies (ANA), and anti-thyroid-peroxidase (TPO)-antibodies), increased pro-inflammatory responses (such as high plasma levels of TNF, IFN-γ and IL-6, increased T helper (Th)-17 and decreased Foxp3+ T regulatory cells in peripheral blood), and a dysregulation of maternal immune response to fetal or placental trophoblast antigens[2]. Decidual macrophages and regulatory T (Treg) cells are of particular relevance; both cell types being enriched in the decidua and with an immune regulatory profile[22,23]. The decidual macrophages are of a regulatory M2-like phenotype[24,25] and Treg cells[26,27] show an augmented suppressive profile in the decidua. The effects of LMWH on cytokine and chemokine secretion by 1st trimester placental tissue was evaluated, since this pathway could be an indirect way of modulating macrophages and Th cells
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