105: Regulatory dendritic cell treatment prevents the development of vasopressin-induced preeclampsia in mice

Abstract

The concept that poor fetal tolerance is important in the pathogenesis of preeclampsia (PE) has been demonstrated by our lab and others. Arginine vasopressin (AVP) infusion throughout pregnancy phenocopies human PE in mice mirroring the tonically elevated AVP secretion throughout human PE pregnancy. These findings identify AVP as a potential contributor to poor fetal tolerance and the development of PE. 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 (DCreg) promote tolerance via regulatory T cell induction, cell-to-cell interactions, and anti-inflammatory cytokine production. The objective of this study is to determine if DCreg treatment will prevent PE in an AVP-induced mouse model of PE. C57BL/6 dams were infused with AVP (24 ng/hour) or saline throughout gestation via osmotic minipump. To generate DCreg, bone marrow derived cells from C57BL/6 mice were cultured with human TGFβ1 and murine GM- CSF and IL-10. At the time of pump implantation (gestational day, GD -3) or early post-placentation on GD 7, AVP dams received a single intravenous injection of DCreg. Blood pressure was taken throughout pregnancy and total urine protein was measured on GD 18. Maternal tissues were collected on GD 18. Cytokine concentrations were determined via ELISA and normalized to total protein. Treatment of AVP-infused dams with DCreg before mating (GD -3) or on GD 7 prevented PE development. DCreg prevented hypertension (AVP: 120 ±1.8, n=27 vs GD -3: 108 ±3.3, n=7 vs GD 7: 110 ±4.4, n=5 p<0.05) and elevations in proteinuria (AVP: 37.4 ±2.3, n=24 vs GD -3: 25.6 ±2.9, n=7 vs GD 7: 24.1 ±3.1, n=5 p<0.05) (Figure 1). Elevations in pro- inflammatory plasma IFNγ were reversed with treatment (AVP: 27.7 ±12.0, n=6 vs GD -3: 0.0±0.0, n=4 vs GD 7: 0.0±0.0, n=6 pg/g, p<0.05) (Figure 2A). DCreg also reversed suppression of anti-inflammatory TGFβ in the plasma (AVP: 1.3 ± 0.91, n=9 vs GD -3: 3.2 ±0.50, n=4 vs GD 7: 2.9 ±0.25, n=6 ug/g, p<0.05) (Figure 2B). These data support the hypothesis that DCreg treatment prevents AVP-induced PE. It further provides evidence for the potential use of personalized, cellular therapy in the prevention of cardiovascular, renal, and immune alterations induced by preeclampsia.View Large Image Figure ViewerDownload Hi-res image Download (PPT)