Preeclampsia (PE), new onset hypertension during pregnancy, is the leading cause of death and morbidity for the mother and low birth weight in offspring. PE women have activated B cells producing agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA). We have shown Rituximab (R), used clinically for B cell depletion, lowers mean arterial pressure (MAP), B cells, and AT1-AA in the RUPP rat model of PE. Clinical studies show no untoward effects on offspring of pregnant women maintained on R for treating lymphoma, however, R is not used during PE therefore, effects of maternal B cell depletion on offspring survival and growth in response to placental ischemia is unknown. We hypothesize that R will deplete maternal B cells in RUPP rats without worsening the effect of placental ischemia on pup growth and survival. To test this hypothesis, R (250 mcg/kg) was given on gestation day (GD) 14 via mini-osmotic pump. On GD 19 B cells were measured by flow cytometry, and MAP and pup weights were recorded. A separate group of dams were allowed to deliver, pup weights were recorded within 12 hours and weekly until 16 weeks, and B cells were analyzed. A one-way ANOVA was used for statistical analysis. MAP increased in RUPP 123±2 (n=19, p<0.05) compared to NP controls 101±1 (n=18) and was 106±3 mmHg in RUPP+R (n=8, p<0.05). On GD19, maternal circulating B cells were 16±2 % (n=14) in RUPPs, 8±2 % in NP rats, (n=7, p<0.05), and 5.5±1% gate in RUPP+R (n=5, p<0.05). RUPP male and female offspring were smaller 5.11±0.23 g, 5.19±0.14 g (n=4, n=4) at birth than NP offspring 6.09±0.15 g, 5.87±0.12 g (n=6, p<0.05; n=6, p<0.05) or RUPP+R offspring 5.75±0.24 g, 5.36±0.28 g (n=6, p=0.11; n=6, p=0.67). At 12 weeks, male and female RUPP offspring had elevated circulating B cells (21±3, 20±1 % (n=6; n=9)) compared to NP (1±0.23, 1.6±0.06 % (n=4, p<0.05; n=3, p<0.04)) which was normalized in RUPP+R offspring (0.4±0.1, 0.3±0.03 % gate (n=3, p<0.05; n=8, p<0.05)). At 16 weeks, B cells were comparable in male offspring from NP (0.78±0.09 % (n=10)) and RUPP+R rats (0.80±0.04 % gate (n=3)). Our findings indicate that R lowers maternal circulating B cells and MAP in RUPP rats and improves fetal weight and circulating B cells, indicating that R does not worsen adverse fetal outcomes in response to placental ischemia.
Maternal B-cell depletion nor TNF-α blockade worsen offspring outcomes in a rat model of preeclampsia
