Project IV

University Of Mississippi Med Ctr, Jackson MS

Investigators

Abstract

Project Summary Preeclampsia (PE) affects 5-7% of all pregnancies in the U.S. Despite being a leading cause of maternal death and perinatal morbidity, the most widely accepted treatment is early delivery of the baby. Healthy pregnancy is associated with elevations in progesterone and CD4+THelper 2 cells/uterine, NK (non-cytolytic) profile favoring feto-immunotolerance. However, in PE CD4+THelper 1 cells are increased which allow the release of cytokines and B cells producing autoantibodies (AT1-AA) that contribute to hypertension, endothelial dysfunction and intrauterine growth restriction (IUGR). An important anti-inflammatory protein secreted from progesterone stimulated lymphocytes is PIBF-progesterone induced blocking factor which is decreased in pregnancy disorders. Importantly, PE patients delivering at UMMC have significantly lower circulating progesterone compared to normotensive pregnant women. Progesterone, in the form of 17-OHPC, was commonly used as early as 20 weeks of gestation for cessation of recurrent preterm labor in pregnancies not complicated by PE. However, whether or not 17-OHPC impacts factors that link abnormal maternal vascular and placental function with inflammatory mediators in PE is unknown. Our preliminary data show that PE patients have less PIBF and Progesterone and that supplementation with 17-OHPC improves PIBF levels. Associated with this change are lower inflammatory mediators and blood pressure which increases time to deliver by 50% in PE patients. Although we show that 17-OHPC improves pregnancy outcomes and PIBF, we don’t know if it is through PIBF. We hypothesize that decreased Progesterone/PIBF leads to decreased γδ T cells, TH2, uNK, and IL-4, which allows for increased TH1, cNK and inflammatory cytokines that stimulate vasoactive factors ET-1, AT1-AA, and sFlt-1 acting in concert to cause endothelial dysfunction (increased UARI), HTN and IUGR during PE. In order to answer this question, we will utilize a novel model of adoptive transfer of placental CD4+ T cells from PE women into pregnant nude athymic pregnant rats. This model of PE is characterized by HTN, decreased fetal weight, increased cytokines, ET-1 and sFlt-1 and AT1-AA. Pregnant nude athymic rats will be treated with CD4+ T cells from PE women with 17-OHPC administered during pregnancy and compared to rats with control PE CD4+ T cells. We will test the role of PIBF as the mechanism of improve pregnancy outcome through PIBF blockade in recipient rats of CD4+ T cells from PE women treated with 17 OHPC during pregnancy. Aim 1. To continue a clinical trial testing the hypothesis that administration of 17-OHPC to PE patients stimulates γδ T cells, PIBF and reduces inflammation, UARI, AT1-AA, sFlt-1, ET-1, and thus HTN and IUGR during pregnancy. We will also determine if 17-OHPC increases time to delivery in treated vs. untreated PE participants. Aim 2. To test the hypothesis that CD4+ T cells from PE women treated with 17-OHPC do not cause a PE phenotype in pregnant nude athymic recipient rats. Aim 3. To test the hypothesis that PIBF blockade in recipient rats of CD4+ T cells from PE women treated with 17-OHPC causes a PE phenotype.