Use of experimental embryo transfer to study the role of the immune system in embryonic death

Summary Animal model systems of pregnancy failure are necessary for critical assessment of the mechanisms that are important to the success of pregnancy because experimental manipulations of the important elements should be able to reverse the outcome of these pregnancies. Most models of pregnancy failure have been described in interspecies pregnancies. This review describes an easily manipulated interspecies pregnancy system that has been developed between two species of mice, Mus caroli and Mus musculus , that do not interbreed. Using the techniques of embryo transfer and embryo surgery, this system has given new insight into the cellular and immunological mechanisms involved in embryonic death. M caroli embryos, transferred to the M musculus uterus, implant and develop to mid‐gestation but then die. However, failure of the xenogeneic M caroli embryonic cells can be prevented by the production of interspecies chimaeras in which the foetal trophoblast layer matches that of the recipient's uterus. Thus, trophoblast is the cellular component that determines success or failure of xenogeneic pregnancy. In failing M caroli pregnancies, anti‐foetal cytotoxic cells are demonstrable in the resorbing embryos. These resorptions can be inhibited by treatment with the immunosuppressive drug, cyclosporin A, and enhanced by preimmunisation. However, M caroli embryos transferred to tolerant or other immunosuppressed recipients resorb at mid‐gestation, thereby suggesting that specific anti‐ M caroli immune responses are not essential to M caroli failure and that trophoblast‐uterine interactions alone may be sufficient to cause foetal death in the absence of immune effectors.