IMMUNOLOGICAL PREVENTION OF SPONTANEOUS EARLY EMBRYO RESORPTION IS MEDIATED BY NONSPECIFIC IMMUNOSIMULATION

PROBLEM: Spontaneous early embryo resorption following implantation oc curs in many species, but little is known regarding the causes or the prevention of early pregnancy failure. Embryo and fetal loss have wide ly been assumed to be due to maternal allospecific immune rejection. A lloimmunization therapy with paternal tissues has been successfully us ed in human and murine pregnancies to prevent early embryo demise. The mechanisms of this treatment have been assumed to be the induction of antigen specific, fetal ''graft'' enhancing antibodies and suppressor cells. The purpose of this study was to investigate the validity of t his assumption. METHOD: To investigate these general assumptions, fema le CBA/J mice were immunized with either specific or nonspecific antig ens prior to mating with DBA/2 or Balb/c males. Further, a model syste m for the study of bacterial lipopolysaccharide (LPS) induced abortion was used to demonstrate the nature of antigen specific immune protect ion against abortion. RESULTS: Whereas the administration of 1 mu g of LPS to CEW female x CEW male pregnant mice on day 7 of gestation indu ced complete fetal resorption, prior immunization with 20 mu g of LPS completely prevented LPS induced abortion as long as the anti-LPS-anti body titers remained above a threshold value of about 1/500. Therefore , early embryo loss could be induced by a bacterial infection and coul d be prevented by appropriate immunity to abortogenic factors. However , due to the short half-life of IgM antibodies, immunity to LPS was sh ort-lived and the protective effect of LPS immunization against LPS in duced abortion waned after 5 nk. Through the use of the CBA/J female x DBA/2 male model system to study spontaneous early embryo loss, previ ous vaccination of CBA/J female mice with Batble spleen cells expressi ng paternal MHC antigens, complete Freund's adjuvant (CFA) or LPS, all decreased the incidence of spontaneous resorption in subsequent pregn ancies. Similarly, a previous mating with a Balb/c male prevented spon taneous embryo loss for a period of up to 6 wk. However, none of the i mmunotherapeutic vaccinations or matings had a permanent effect on CBA /J female x DBA/2 male embryo survival, which one would have expected if specific immune mediators were involved. CONCLUSION: The results of this study indicated that the decrease in the incidence of spontaneou s embryo resorption following alloimmunization was more likely to be d ue to nonspecific immunomodulatory effects on the immune system of the female mice, as opposed to specific antipaternal immunity. This may, in part, explain the placebo effects observed for alloimmunization the rapy for human habitual pregnancy loss. The relevance of these results to the development of immunotherapy strategies for the prevention of habitual abortion is discussed. (C) Munksgaard, Copenhagen