Cellular Immunotherapy in Mice Prevents Maternal Hypertension and Restores Anti-Inflammatory Cytokine Balance in Maternal and Fetal Tissues

Abstract

AbstractPreeclampsia is the leading cause of maternal-fetal morbidity world-wide.The concept that persistent feto-placental intolerance is important in the pathogenesis of preeclampsia (PreE) has been demonstrated by our lab and others. Arginine vasopressin (AVP) infusion during pregnancy induces cardiovascular, renal, and T helper (Th) cell alterations in mice consistent with human PreE. In addition to their conventional immuno-stimulatory role, dendritic cells (DCs) also play a vital role in immune tolerance. In contrast to conventional DCs, regulatory DCs (DCregs) express low levels of co-stimulatory markers, produce anti-inflammatory cytokines, induce T regulatory (Treg) cells, and promote tolerance. In mice, DCregs prevent pro-inflammatory responses and induce antigen-specific tolerance. Given these known functions of DCregs, we hypothesize that DCregs will prevent the development of AVP-induced PreE in mice. C57BL/6J females were infused with AVP (24 ng/hour) or saline throughout gestation via osmotic minipump. Bone marrow derived DCregs were injected into AVP-infused dams at the time of pump implantation or on gestational day (GD) 7. Blood pressure was taken throughout pregnancy. Maternal urine protein and TH-associated cytokines in maternal and fetal tissues were measured on GD 18. Treatment with DCregs effectively prevented the elevation of maternal blood pressure, proteinuria, and fetal growth restriction that was observed in AVP-infused dams. Furthermore, we noted a reduction in pro-inflammatory TH-associated cytokines IFNγ and IL-17, while anti-inflammatory cytokines IL-4, IL-10, and TGFβ showed an increase following DCreg treatment. These outcomes provide strong evidence supporting the potential of DCregs as a valuable therapeutic approach in addressing PreE.