T Cell Inhibition during Pregnancy Prevents Post‐partum Anxiety‐like Behavior in rats with a History of Severe Preeclampsia/HELLP Syndrome

Abstract

INTRODUCTIONSevere preeclampsia and Hemolysis elevated liver enzyme low platelet (HELLP) syndrome, are potentially life threatening conditions with high maternal mortality and morbidity. During pregnancy these women have hypertension, increases in inflammatory cytokines, blood brain barrier (BBB) permeability and increased T cells. During the post‐partum period these women are reported to be at an increased risk of developing psychological disorders such as post‐traumatic stress disorder (PTSD). We have recently shown that T cell suppression to experimental HELLP rats during pregnancy attenuates inflammation, BBB permeability and hypertension. As T cells have been implicated in contributing to behavioral abnormalities, we hypothesized that T cell reduction during pregnancy to rats with HELLP could decrease the occurrence of anxiety‐like behavior in the post‐partum period.METHODSOn gestational day (GD) 12, mini‐osmotic pumps infusing sFlt‐1 and sEng were placed into rats to induce HELLP syndrome (n=28). A subset of HELLP rats (n=13) received 2 mg/kg of Orencia (Abatacept) on GD13 and all rats had their mini‐osmotic pumps removed 12–24 hrs post‐delivery to remove the source of sFlt‐1 and sEng. Rats without mini‐osmotic pumps served as normal pregnant (NP; n=14) controls. Beginning in the 4th post‐partum week rats underwent testing in marble burying, elevated plus maze (EPM) and locomotor activity. Mean arterial pressure was measured between postpartum day 46–48, tissue and plasma collection or Evan's blue (EB) infusion to assess BBB permeability.RESULTSPost‐partum HELLP rats buried significantly more marbles compared to NP (61.4 vs 38.9%; p=0.01) and HELLP+O rats (34.7%; p=0.05). HELLP rats also spent significantly more time in the closed arms of the EPM compared to NP (170.9 ± 14.1 vs 103.2 ± 16.6 sec; p=0.009) and HELLP+O rats (108.7± 20.4 sec; p=0.02). HELLP rats traveled a greater distance in the open field compared to NP (2571 ± 219.2 vs. 1777 ± 219.7 cm; p=0.02) and HELLP+O (1560 ± 166.6 cm; p=0.03). Rats with a history of HELLP syndrome had increased BBB permeability in the brainstem compared to NP rats (1.8 ± 0.5 vs 0.58 ± 0.1 (pg/g EB tissue)/μg/mL EB plasma; p=0.04), however this was reversed by treatment with Orencia (0.48 ± 0.13 (pg/g EB tissue)/μg/mL EB plasma; p=0.03). HELLP rats had significantly more circulating CD4+ T cells compared to NP rats (5.3 vs 2.18%; p=0.02). Similar results were seen in the liver where HELLP rats had significantly more hepatic CD4+ T cells compared to NP rats (2.9 vs 0.53%; p=0.03). HELLP rats had a significant increase in hepatic levels of IL‐6 (4.2 ± 0.44 vs 2.7 ± 0.49 pg/mg/mL; p=0.04) and IL‐1beta (31.9 ± 3.08 vs 21.9 ± 3.1pg/mg/mL; p=0.04) as well as increased sFlt‐1 (128.9 ± 13.4 vs 76.8 ± 13.9pg/mg/mL; p=0.02) compared to NP rats. There were no statistically significant changes between the groups in plasma levels of these proteins. Results on inflammation from rats treated with Orencia are pending. HELLP rats had significantly increased MAP compared to NP (136.8 ± 4.9 vs 115.3 ± 7.4 mmHg; p=0.02) and HELLP+O rats (117.2±4.7 mmHg; p=0.01).DISCUSSIONThese results suggest that HELLP syndrome during pregnancy contributes to an increase in anxiety‐like behavior, BBB permeability, liver inflammation, increased CD4+ T cells and hypertension in the post‐partum. The current results suggest that T cell suppression during pregnancy can also help prevent chronic hypertension and increased anxiety in the post‐partum period.Support or Funding InformationThis work was supported by the National Institutes of Health IDea grant P30GM103328 to KW.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.