Prevention of Defective Placentation and Pregnancy Loss by Blocking Innate Immune Pathways in a Syngeneic Model of Placental Insufficiency

Abstract

Defective placentation and subsequent placental insufficiency lead to maternal and fetal adverse pregnancy outcome (APO), but their pathologic mechanisms are unclear, and treatment remains elusive. The mildly hypertensive BPH/5 mouse recapitulates many features of human APO with pregnancies characterized by fetal loss, growth restriction, abnormal placental development, and defects in maternal decidual arteries. Using this model, we show that recruitment of neutrophils triggered by complement activation at the maternal fetal interface leads to elevation in local TNF-α levels, reduction of the essential angiogenic factor VEGF and, ultimately, abnormal placentation and fetal death. Blockade of complement with inhibitors specifically targeted to sites of complement activation, depletion of neutrophils, or blockade of TNF-α improves spiral artery remodeling and rescues pregnancies. These data underscore the importance of innate immune system activation in the pathogenesis of placental insufficiency and identify novel methods for treatment of pregnancy loss mediated by abnormal placentation.

Innate Immune System at the Maternal–Fetal Interface: Mechanisms of Disease and Targets of Therapy in Pregnancy Syndromes

“…100 Recently, it has been reported that an innate immune cells' population, the granulocytic myeloid-derived suppressor cells (MDSCs), accumulate in human placenta of healthy pregnancies but are diminished in patients with spontaneous abortions. 101 These MDSCs American Journal of Reproductive Immunology (2016) were reported to effectively suppress T responses suggesting their potential role in inducing and maintaining maternal-fetal tolerance. 102 The state of activation of decidual dendritic cells (DCs) seems to represent one of the players influencing the immunological mechanisms in the pathogenesis of HELLP syndrome.…”

“…141 Evidence concerning the effects of the blockade of CS or TNF-a on spiral artery remodeling and pregnancy outcome suggests novel methods for treatment of pregnancy loss mediated by abnormal placentation. 101 In this context, evidence reported that TNF-a inhibitors can be considered safe in the periconception period, but reports of exposure to TNFa-inhibitors during pregnancy are still limited and suggest caution. 142 Recent studies emphasized that activation of TLRs affects not only pregnant outcome but also offspring development.…”

The Complement System and Preeclampsia

“…This mouse is mildly hypertensive prior to pregnancy so it is most precisely described as a model of superimposed preeclampsia. Defective implantation leads to abnormal placentation and partial fetal loss early in pregnancy [48, 47, 49]. As the pregnancy continues, onset of hypertension and proteinuria are evident at the beginning of the last trimester (Table 1).…”

“…Litters are small and surviving pups are growth restricted. Gelber [49] hypothesized that neutrophil accumulation subsequent to complement activation was responsible for the defective placentation and fetal demise, and ultimately the hypertension and proteinuria. Significant C3 deposition was noted at embryonic (E)6.5 and neutrophil accumulation developed at E8.5, consistent with the hypothesized sequence of events.…”

“…Significant C3 deposition was noted at embryonic (E)6.5 and neutrophil accumulation developed at E8.5, consistent with the hypothesized sequence of events. Placental mass decreased and placental morphology at E10.5–12.5 [48, 49] showed decreased trophoblast invasion into the decidua and decrease in the area of the junctional zone suggesting impaired trophoblast invasion of blood vessels and interstitially. Blood vessels in the decidual wall had narrowed lumens and thick walls and the fetal labyrinth area had reduced endothelial cell branching.…”