Inhibiting B Cell Activating Factor Normalizes The Hypertension And Cytolytic Natural Killer Cells Associated With Placental Ischemia

Preeclampsia (PE) is new onset hypertension (HTN) during pregnancy and is associated with a pro-inflammatory state with increased T Cells, B Cells, cytolytic Natural Killer (cNK) Cells, and Agonistic Antibodies to the Angiotensin II Type 1 Receptor (AT1-AA) compared to Normal Pregnancy (NP). The Reduced Uterine Perfusion Pressure (RUPP) model of placental ischemia recapitulates these features. We have shown that blocking communication between T Cell CD40L and B Cell CD40 or B Cell depletion prevents HTN and AT1-AA in rat models of placental ischemia induced HTN. This suggests that T Cell dependent B Cell activation is involved in the HTN and AT1-AA seen in PE. B2 B cells maturing into antibody producing plasma cells are the product of T Cell Dependent B Cell Interactions. B Cell activating factor (BAFF) is an integral cytokine in the development of B2 cells specifically. Therapeutic antibodies against BAFF are used in treatment for Systemic Lupus Erythematosus with long-term treatment with Anti-BAFF antibodies reducing patient circulating B cells. Thus, we hypothesize that Anti-BAFF antibodies will selectively deplete B2 cells, therefore reducing HTN and cNK Cells in the RUPP rat model of PE. To test this hypothesis, Gestation Day (GD) 14 pregnant rats underwent the RUPP procedure and some were treated with 1 mg/kg Anti-BAFF antibodies by infusion via jugular catheters inserted 24 hours prior. On GD19, blood pressure (MAP) was measured and circulating, placental, and splenic B Cells and NK cells were measured by flow cytometry. RUPP rats had elevated MAP (119±2 mmHg, n=12) compared to NP (100±3 mmHg, n=9) which was normalized by Anti-BAFF treatment (100±3 mmHg, n=11)(p<0.05). RUPP fetuses were smaller at GD19 (1.97±0.08 g; n=12) compared to NP fetuses (2.207±0.1 g)(p<0.05), and this was unchanged with Anti-BAFF (1.82±0.1 g). RUPP rats had elevated cNK cells (9.1±2%, n=7) compared to NP (3.1±3%, n=3) which was attenuated with anti-BAFF therapy (3.6±1.3%, n=6). RUPP rats had elevated splenic B Cells (4±0.7%, n=8) compared to NP (2±0.7%, n=4) which was reduced by Anti-BAFF (2.8%±1.1%, n=4). In conclusion, Anti-BAFF treatment reduces B cells and cNK cells and normalizes the HTN associated with placental ischemia without worsening fetal weight in a rat model of PE.