Dr Natasha De Alwis1,2,3, Chloe Miles1,2, Dr Natalie Binder1,2, Anjali Garg1,2, Lydia Baird1,2, Rose Freemantle1,2, Bianca Fato1,2, Prof Lisa Hui2,3,4, Prof Tu'uhevaha Kaitu'u-Lino2,5, Prof Natalie Hannan1,2,3
1Therapeutics Discovery & Vascular Function in Pregnancy Group, The University of Melbourne, Melbourne, Australia, 2Mercy Hospital for Women, Heidelberg, Australia, 3Northern Health, Epping, Australia, 4The University of Melbourne, Melbourne, Australia, 5Translational Obstetrics Group, The University of Melbourne, Melbourne, Australia
Biography:
Dr Natasha de Alwis is a Postdoctoral Researcher in the Therapeutics Discovery & Vascular Function group at the University of Melbourne. Her research focus is in understanding the development of pregnancy complications, particularly preeclampsia and fetal growth restriction, and in developing novel therapeutic strategies to prevent and treat them.
Abstract:
Background: Elevated complement pathway activation and systemic complement component C5 levels are associated with preeclampsia. As such, inhibiting the immune complement pathway by targeting the terminal C5 component has been proposed as a potential treatment strategy. Here we investigate C5 expression in healthy and preeclamptic placenta, and examine if C5 inhibition mitigates placental pro-inflammatory and anti-angiogenic factors that drive preeclampsia.
Methods: C5 placental mRNA expression was examined in healthy and pathological placentas collected from: first trimester surgical terminations (7-11 weeks), preterm (24-30 weeks), and term (38-39 weeks) caesarean deliveries, as well as preterm (<34 weeks) and term (>37 weeks) preeclampsia and gestation-matched controls (via qPCR). Placental explants collected from term healthy and preeclamptic pregnancies were treated with 125-1000nM eculizumab (biologic inhibiting C5) for 48h. Expression of inflammatory genes: interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF), NLR family pyrin domain containing 3 (NLRP3), and anti-angiogenic factor soluble fms-like tyrosine kinase (sFLT-1) were assessed. sFLT-1 secretion was measured via ELISA.
Results: Placental C5 gene expression was unaltered across gestation (n=10-15/group), and downregulated in cases of preterm preeclampsia, but unaltered in term preeclampsia (n=10-25/group). Inhibiting C5 with eculizumab in placental tissue from normotensive pregnancies did not alter expression of IL-1β, IL-6, TNF, or NLRP3. At the highest dose (1000nM) eculizumab significantly increased sFLT-1 expression, but did not alter sFLT-1 secretion (n=4). Eculizumab treatment of preeclamptic placental tissue did not alter any genes assessed (n=5).
Conclusion: Our study finds that C5 mRNA is not dysregulated in the placenta in term preeclampsia, and inhibiting C5 did not alter regulation of inflammatory or anti-angiogenesis pathways. This suggests targeting placental C5 is unlikely to treat placental dysfunction in term preeclampsia. Future studies will evaluate the potential of C5 inhibition to treat preeclampsia-associated vascular dysfunction.
Keywords
preeclampsia,placenta,treatment