Abstract 027: T cell-Dependent B cell Activation Plays a Role in Mediating Hypertension and Pathophysiology in Response to CD4+ T cells from Reduced Uterine Perfusion Pregnant Rats

Abstract

Preeclampsia, (PE) newly developed hypertension during pregnancy, is associated with altered immune activation. We have previously shown that adoptive transfer of CD4+T cells from a rat model of PE, the RUPP Rat, increases blood pressure, endothelin (ET) expression, oxidative stress (ROS), inflammation, and agonist autoantibodies to the AT1 receptor in NP recipients, all of which have been shown to play a role in hypertension during pregnancy. The objective of this study was to determine if blockade of lymphocyte crosstalk via the CD40-CD40 ligand interaction between RUPP CD4+ T cells with endogenous B cells in NP recipient rats would improve pathophysiology observed previously with RUPP CD4+ T cells. To do so splenic CD4+ T lymphocytes were magnetically separated, incubated with 2.5 μg/mL anti-CD40 ligand (αCD40L) overnight and transferred into Normal Pregnant (NP) rats on day 12 of gestation (NP+ αCD40L RUPP T cells). On day 19 of gestation, blood pressure (MAP), blood, and tissues were collected from all groups of rats. MAP was 99+/-1.2 in NP (n=18), 120+/-2.3 mmHg in control RUPP rats (n=19;P<0.001); 121+/-1.2 in NP+RUPP T cells(n=5;P<0.001); but only increased to 103 +/-1.7 in NP + αCD40L RUPP T cells (n=21) (P<0.001 vs NP+RUPP T cells). Placental ROS increased from 160.4 +/- 31 in NP to 380.5 +/- 60.7 in RUPP (p<0.05) and 318.6 +/-89 in NP+RUPP T cells. CD40 ligand binding reduced placental ROS to 118.7 +/-24 in NP + αCD40L RUPP T cells (p<0.05). Plasma IL-6 increased from 38.71+/-8 in NP to 92.94+/-15 in RUPP (p<0.05) and 107.4+/-26 in NP+RUPP T cells and only increased to 50.1+/-3.6 pg/ml in NP + αCD40L RUPP T cells. TNF-alpha increased from 10.9+/-5 in NP to 79+/-15 in RUPP (p<0.05) and 23+/-17 in NP+RUPP T cells and was only 8+/-3 pg/ml in NP + αCD40L RUPP T cells. Plasma sFLT-1 increased from 79+/-14 in NP to 172+/-34 in RUPP (p<0.05) and 107+/-9 in NP+RUPP T cells and was only 74+/-21 pg/ml in NP + αCD40L RUPP T cells. These studies indicate that placental ischemic induced T cell communication with B cells is one important mechanism of PE that leads to much of the pathophysiology of the disease.