K. C. Ott1, M. Oria2, C. R. Redden1, H. K. Kang1, L. E. Turner1, A. A. Alhajjat1, S. Duru2, J. L. Peiro2, A. F. Shaaban1 2Center for Fetal and Placental Research,Division Of Pediatric General And Thoracic Surgery, Cincinnati Children’s Hospital Medical Center,Cincinnati, OH, USA 1Center for Fetal Cellular and Molecular Therapy, Ann and Robert H. Lurie Children’s Hospital,Department Of Surgery, Northwestern University Feinberg School Of Medicine,Chicago, IL, USA
Introduction: Neural tube defects (NTDs) are severe birth defects that originate during embryonic development when the neural tube fails to close completely. Stimulation of the maternal immune system in mice and humans reduces a wide variety of fetal irregularities suggesting that there is maternal immune surveillance of fetal anomalies such as NTDs. Given that the vast majority of maternal lymphocytes at the maternal-fetal interface are NK cells, we hypothesized that maternal NK cells are involved in protection against the development of NTDs in utero.
Methods: To challenge this hypothesis, we utilized a clinically-relevant murine model of valproic acid (VA) induced fetal neural tube teratogenesis with or without loss of maternal NK function. After pregnancy confirmation, groups of dams received either a depleting dose of an anti-NK cell mAb (PK136) or saline control on E7. VA-induced teratogenesis was performed on E8. All litters were then harvested on E14 and the litter size and prevalence of NTDs compared between the groups. The experiments were performed in both B6 (inbred) and CD1 (outbred) models.
Results: We found that 100% of the litters of NK cell-depleted dams (B6 and CD1) were affected by fetal NTDs. This was significantly higher when compared to litters of saline-treated dams (B6 = 60%; CD1 = 73%; p<0.05). Litter sizes were not significantly affected by the NK cell depletion (B6: 7.9 vs 8.6, p=NS; CD1: 12.9 vs 13.2, p=NS).
Conclusion: From these results, we conclude that maternal NK cells provide protection from the development of NTDs within the fetus. Further studies are needed to define the mechanisms by which maternal NK cells provide surveillance and protection from fetal teratogenesis.