Medawar's Paradox and Immune Mechanisms of Fetomaternal Tolerance

Abstract

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.

Keywords: Medawar’s paradox; fetomaternal tolerance; immune tolerance; reproductive immunology.

Figure 1

Medawar’s model of allogeneic differences leading to skin graft rejection in rabbits. Medawar grafted skin from one rabbit (rabbit D-1) to another (rabbit R). All grafts were destroyed by days 12–15. Following this, skin grafting was performed from the D-1 rabbit as well as a different rabbit (rabbit D-2) to rabbit R. Cell division was inhibited and graft loss was observed at day 6 for this second grafting that was not observed with the D-2 to R graft. Through these experiments and others, Medawar established that the intensity of homograft rejection was mediated by 1) graft dosage (i.e. amount of skin grafted), 2) previous exposure to grafts from the same donor, and 3) genetic diversity of the rabbits.

Figure 2

The fetomaternal interface of the placenta is the primary site of maternal and fetal immune interaction. A) As a part of implantation, the fetal trophoblasts of the human placenta invade the maternal decidua to form chorionic villi, which are in direct contact with maternal blood and permit nutrient and oxygen exchange to nourish the growing fetus. Cell turnover is a hallmark of the chorionic villi as the undifferentiated cytotrophoblasts replenish the external fused syncytiotrophoblast layer and differentiate into extravillous trophoblasts, which are known to play key roles in driving maternal spiral artery remodeling and communicating with maternal cells throughout the pregnancy. B) The placenta acts as a semi-permeable membrane, fulfilling its primary function of extracting nutrients and oxygen from the maternal blood supply and permitting the return of waste. Apoptosis of the syncyctiotrophoblasts results in apoptotic bodies containing fetal genetic material to be returned to the maternal circulation as “cell-free DNA”. There is also a small amount of transfer of fetal cells to the maternal circulation as well as maternal cells to the fetus, known as microchimerism. C) Key crosstalk between fetus and mother involves several immune cells. Maternal APCs are trapped in decidua due to lack of lymphatic vessels, which prevents activation of maternal T cells and destruction of the fetus. Decidual macrophages and decidual NK cells are key regulatory cells at the interface. CD4+ T cell proliferation is downregulated and activated CD8+ T cells undergo apoptosis due to the presence of soluble non-classical MHC class I HLA-G, and regulatory T cells (T_regs) play a key role in establishing feto-maternal tolerance at the placental interface as well.