Autoimmunity represents immunologic reaction against self antigen. Several models have been developed to address the induction and breaking of tolerance in the development of autoimmune phenomena. However, most transgenic models make use of either foreign MHC antigens or non-self antigens, situations more similar to graft rejection than autoimmunity. Ideally, one would like to develop an in vivo model in which tolerance induction, graft rejection and autoimmunity can be studied. While models exist in which these phenomena can be studied separately, few models yet exist in which graft rejection and the breakdown of peripheral tolerance can be compared and contrasted. The ability to compare immune responses in an allotypic versus a syngeneic model may allow us to discern differences between the types of immunologic responses, and consequently gain insight into the regulation not only of graft rejection, but also of the breakdown of peripheral tolerance in autoimmunity. Mammalian pregnancy represents a natural in vivo model of graft tolerance, in that the placenta is a fetal tissue bearing paternal antigens, yet it does not elicit a deleterious immune response. It has been proposed that the lack of major MHC antigens on trophoblast accounts for this immunologic privilege. We have tested this hypothesis in a transgenic mouse model by forcing the expression of classical Class I MHC on trophoblast. We find that the mothers experience immunologically mediated spontaneous abortion in both allogeneic and syngeneic pregnancies. These observations suggest that this model represents both an example of classic allotypic graft rejection in the case of an allogeneic mother, and of the breakdown or lack of peripheral tolerance to trophoblast antigens in the syngeneic mother. We believe that a study of this model to determine how or if tolerance to trophoblast antigens develops, and studies to determine the nature of the immunological responses leading to abortion will provide insights not only to the development and maintenance of peripheral tolerance, but also to understanding immunoregulation at the maternal-fetal interface.
