Prostaglandin E₂-mediated suppression of human maternal lymphocyte alloreactivity by first-trimester fetal macrophages

We examined the immunosuppressor role of the firsttrimester human placental macrophages on maternal lymphocyte alloreactivity in vitro to determine whether these macrophages and their secreted mediator(s) participate in the local immunoregulation at the fetomaternal interface. These cells were tested for their effects on maternal lymphocyte proliferation when added alone (as stimulator cells) or as regulator cells in 1) a one-way mixed lymphocyte reaction for six days and 2) lymphocyte cultures in the presence of phytohemagglutinin for three days. We detected a dosedependent inhibition of phytohemagglutinin-induced proliferation with 48-hour macrophage culture supernatants. Placental macrophages, when used alone as stimulator cells in the mixed lymphocyte reaction, were stimulatory only at a concentration of 1–2%; the stimulation was abolished at a concentration of 10%. When used as regulator cells, they showed a strong inhibition of mixed lymphocyte reaction and phytohemagglutinin-induced proliferation at a concentration of 10%; no effect was observed at a concentration of 1–2%. The major class of the molecules mediating the suppression was identified as prostaglandins, primarily prostaglandin E₂ (PGE₂), based on the findings that the presence of indomethacin (10^–5M) or various dilutions of an anti-PGE₂ antibody abrogated suppression substantially or completely. Prostaglandin E₂ levels measured in the mixed leukocyte culture wells containing placental macrophages as regulator cells correlated positively with the macrophage dose and its suppressive effect.