EVIDENCE OF EMBRYO-TOXIC AND TROPHOBLAST-TOXIC CELLULAR IMMUNE RESPONSE(S) IN WOMEN WITH RECURRENT SPONTANEOUS-ABORTION

OBJECTIVE: The purpose of this study was to determine whether reproductive antigens stimulate lymphocytes and macrophages from women with recurrent abortion to secrete factors that are toxic to preimplantation embryos or trophoblast cells in vitro. STUDY DESIGN: Mononuclear cells were isolated from 30 fertile controls and 300 nonpregnant women being evaluated for recurrent abortion. Supernatants generated from these cells after separate culture with sperm and trophoblast antigen extracts were added to two-cell mouse embryo cultures and trophoblast proliferation assays. Toxicity was assumed when the median percentage of embryos developing to blastocysts or trophoblast proliferation was less-than-or-equal-to 50% of control values. Both parametric and nonparametric statistical methods were used where appropriate. RESULTS: Mouse embryo development and/or trophoblast proliferation were significantly inhibited by supernatants from trophoblast and/or sperm antigen-activated peripheral blood leukocyte cultures from a majority of 300 women with recurrent abortion but not from 30 women with normal reproductive histories. The mouse blastocyst development assay was more sensitive than the trophoblast proliferation assay in determining toxic factor production. Embryo-toxic factors were produced by activated leukocyte cultures from 90% of 180 women with a history of recurrent abortion of unexplained etiology, whereas trophoblast-inhibitory factors were detected in 50% of women from the same group. The embryo-toxic factor(s) was heat labile, had a molecular weight(s) between 10 and 30 kd, and was absorbed out by passage through affinity columns containing anti-interferon gamma beads. CONCLUSION: We conclude that recurrent abortion in some women is associated with embryo- and/or trophoblast-toxic factor production in response to stimulation by sperm or trophoblast antigens and that the principal factor may involve the 18 kd, heat-labile, T-lymphocyte cytokine interferon gamma. This study suggests a new cause of recurrent abortion.