Determining the Role of Natural Killer Cells in Immune‐Mediated Fetal Growth Restriction in Rats

Abstract

Pregnancy is a unique state in which two genetically foreign individuals – mother and fetus – coexist in immunological harmony. The mechanisms facilitating this immunological tolerance are not well understood; however, the uterus contains a unique population of immune cells belonging to the natural killer (NK) cell lineage that likely have a key role in promoting tolerance. Uterine NK cells are purported to promote uterine vascular remodeling as well as facilitate placental and fetal development during pregnancy. We hypothesize that exposure to pathogenic stimuli early in pregnancy disrupts normal functioning of uterine NK cells, thereby impacting uterine vascular remodeling and fetal growth. To test this hypothesis, the viral mimetic polyinosinic:polycytidylic acid (polyI:C) was injected into pregnant rats under control conditions or following NK cell depletion using anti‐asialo GM1 antibodies, and changes in uterine cytokine production and fetal growth were assessed. Rats were injected with 1, 5, or 10 mg/kg polyI:C on gestational day 8.5, while control rats were injected with saline. Dams injected with 10 mg/kg polyI:C exhibited a 15% decrease in fetal weight and a 4% decrease in fetal crown‐rump length, without affecting fetal viability. Decreased fetal weight correlated with increased production of inflammatory cytokines (interferon‐gamma, tumour necrosis factor‐alpha, and interleukin‐6) in both spleen and implantation sites, and increased perforin expression within implantation sites. Interestingly, immunodepletion of NK cells prior to injection of 10 mg/kg polyI:C resulted in a 38% decrease in fetal weight compared to control animals, indicating that uterine NK cells have a role in preventing fetal growth restriction caused by polyI:C exposure. In conclusion, injection of polyI:C into pregnant rats resulted in elevated cytokine production and fetal growth restriction that was exacerbated by a lack of NK cells.Support or Funding InformationChildren's Health Research Institute, Preeclampsia Foundation of Canada, Schulich Medicine and Dentistry