Medawar’s Paradox and Immune Mechanisms of Fetomaternal Tolerance

Brazilian-born British biologist Dr. Peter Medawar played an integral role in developing the concepts of immunologic rejection and tolerance, which led to him receiving the Nobel Prize “for the discovery of acquired immunologic tolerance” and eventually made organ transplantation a reality. However, at the time of his early work in tolerance, a paradox to his theories was brought to his attention; how was pregnancy possible? Pregnancy resembles organ transplantation in that the fetus, possessing paternal antigens, is a semi-allogeneic graft that can survive without immunosuppression for 9 months. To answer this question, Medawar proposed three hypotheses of how a mother supports her fetus in utero, now known as “Medawar’s Paradox.” The mechanisms that govern fetomaternal tolerance are still incompletely understood but may provide critical insight into how to achieve immune tolerance in organ transplantation. Here, we review current understanding of the immune factors responsible for fetomaternal tolerance during pregnancy and discuss the potential implications for advances in transplantation science.