Immunological prevention of spontaneous early embryo resorption is mediated by non-specific immunosimulation

Spontaneous early embryo resorption following implantation occurs in many species, but little is known regarding the causes or the prevention of early pregnancy failure. Embryo and fetal loss have widely been assumed to be due to maternal allospecific immune rejection. Alloimmunization therapy with paternal tissues has been successfully used 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 this assumption.

To investigate these general assumptions, female CBA/J mice were immunized with either specific or nonspecific antigens prior to mating with DBA/2 or Balb/c males. Further, a model system for the study of bacterial lipopolysaccharide (LPS) induced abortion was used to demonstrate the nature of antigen specific immune protection against abortion.

Whereas the administration of 1 microgram of LPS to CFW female x CFW male pregnant mice on day 7 of gestation induced complete fetal resorption, prior immunization with 20 micrograms of LPS completely prevented LPS induced abortion as long as the anti-LPS antibody titers remained above a threshold value of about 1/500. Therefore, early embryo loss could be induced by a bacterial infection and could be prevented by appropriate immunity to abortogenic factors. However, due to the short half-life of IgM antibodies, immunity to LPS was short-lived and the protective effect of LPS immunization against LPS induced abortion waned after 5 wk. Through the use of the CBA/J female x DBA/2 male model system to study spontaneous early embryo loss, previous vaccination of CBA/J female mice with Balb/c spleen cells expressing paternal MHC antigens, complete Freund's adjuvant (CFA) or LPS, all decreased the incidence of spontaneous resorption in subsequent pregnancies. Similarly, a previous mating with a Balb/c male prevented spontaneous embryo loss for a period of up to 6 wk. However, none of the immunotherapeutic 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.

The results of this study indicated that the decrease in the incidence of spontaneous embryo resorption following alloimmunization was more likely to be due 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 therapy for human habitual pregnancy loss. The relevance of these results to the development of immunotherapy strategies for the prevention of habitual abortion is discussed.