Regulatory T Cells Ameliorate Intrauterine Growth Retardation in a Transgenic Rat Model for Preeclampsia

Abstract

Preeclampsia is a multisystemic syndrome during pregnancy that is often associated with intrauterine growth retardation. Immunologic dysregulation, involving T cells, is implicated in the pathogenesis. The aim of this study was to evaluate the effect of upregulating regulatory T cells in an established transgenic rat model for preeclampsia. Application of superagonistic monoclonal antibody for CD28 has been shown to effectively upregulate regulatory T cells. In the first protocol (treatment protocol), we applied 1 mg of CD28 superagonist or control antibody on days 11 and 15 of pregnancy. In the second protocol (prevention protocol), the superagonist or control antibody was applied on days 1, 5, and 9. Superagonist increased regulatory T cells in circulation and placenta from 8.49±2.09% of CD4-positive T cells to 23.50±3.05% and from 3.85±1.45% to 23.27±7.64%, respectively. Blood pressure and albuminuria (30.6±15.1 versus 14.6±5.5 mg/d) were similar in the superagonist or control antibody–treated preeclamptic group for both protocols. Rats treated with CD28 superagonist showed increased pup weights in the prevention protocol (2.66±0.03 versus 2.37±0.05 g) and in the treatment protocol (3.04±0.04 versus 2.54±0.1 g). Intrauterine growth retardation, calculated by brain:liver weight ratio, was also decreased by the superagonist in both protocols. Further analysis of brain development revealed a 20% increase in brain volume by the superagonist. Induction of regulatory T cells in the circulation and the uteroplacental unit in an established preeclamptic rat model had no influence on maternal hypertension and proteinuria. However, it substantially improved fetal outcome by ameliorating intrauterine growth retardation.

Impact of Immune Deficiency on Remodeling of Maternal Resistance Vasculature 4 Weeks Postpartum in Mice

“…For example, interleukin 15 is tightly regulated 82 and important for vascular remodeling at the maternal fetal interface 83 for CD8 T-cell homeostasis 84,85 and for tissue-resident T-cell development. 86 Based on these findings herein, and others, 37,50 we speculate that unique interaction between immune and vascular systems is set by the experience of pregnancy and placenta-related factors 87 and continues in PP. This in turn influences subsequent susceptibility to cardiovascular stress.…”

“…[46][47][48][49] Because of these characteristics, we examined the effects of CD8 T-cell reconstitution in Rag1 ÀÀ mice. In light of the potential role played by CD4 TREGs in the immune homeostasis of pregnancy 18,50 and in the modification of cardiovascular disease, 46,[51][52][53][54] we also examined mice with genetic deficiency in CD4 T cells. 55 We chose mesenteric vessels because of their role in the regulation of systemic blood pressure.…”

Preeclampsia and health risks later in life: an immunological link

“…Although not completely understood yet, several studies have shown that patients with preeclampsia display decreased Treg expansion in peripheral blood and the decidua, suggesting an association between the failure of pregnancy compatible Treg transformation and the pathogenesis of preeclampsia [55][56][57][58]. In a transgenic model of preeclampsia, physiologic restoration of Tregs has been shown to improve intrauterine growth restriction without affecting hypertension and production of anti-angiogenic factors such as Flt-1 [59]. Although these results are very exciting, it is possible that overwhelming transgenic gene expression overrides the control of hypertension and other factors.…”

Preeclampsia and Pregnancy-Related Hypertensive Disorders

“…Przybyl et al recently evaluated the effect of upregulating regulatory T cells in transgenic rat model for preeclampsia achieved by mating female rats transgenic for human angiotensinogen with rats transgenic for human renin 25 . The authors utilized a superagonistic monoclonal antibody for CD28 to upregulate regulatory T cells.…”