The Placenta, Fetomaternal Tolerance and Beyond: A Tribute to Sir Peter Medawar on the 60th Anniversary of his Nobel Prize

BARRIENTOS, GABRIELA; BLOIS, SANDRA M; SHARMA, SURENDRA; SOLANO, MARIA EMILIA; SIMPSON, ELIZABETH

Frontiers Media SA

Año: 2022 p. 301

978-2-88976-980-3

The work of biologist Sir Peter Medawar represents a milestone in Immunology, which awarded him the 1960 Nobel Prize in Physiology or Medicine “for the discovery of acquired immunological tolerance” and provided evidence for physicians and surgeons to pursue the idea of transplantation to treat end stage organ failure. However, while developing his thesis he became puzzled by an immunological problem, now recognized as Medawar’s Paradox: how is pregnancy possible? Pregnancy resembles organ transplantation, yet the fetus survives and is nourished in the mother’s womb despite its paternal hence ‘foreign’ or non-self antigens. As Medawar himself stated, “The immunological problem of pregnancy may be formulated thus: how does the pregnant mother contrive to nourish within itself, for many weeks or months, a foetus that is an antigenically foreign body?”. Thus, he proposed three hypotheses to explain tolerance of the fetal allograft: (1) anatomical separation between mother and fetus by the placenta, (2) immaturity of fetal antigens, impairing their ability to elicit a maternal immune response, and (3) immunological inertness of the maternal immune system during pregnancy. Besides their importance for transplantation, Medawar’s groundbreaking studies gave rise to Reproductive Immunology as a distinct area of research within Reproductive Medicine.Nowadays, Medawar’s paradox has been modified as we explore species variation in the anatomy of the placenta between mother and foetus, the timing of gene expression during foetal development and try to elucidate how the maternal immune system promotes successful pregnancy outcomes, rather than preventing them. Sixty years have passed since the Nobel Prize and while his original hypotheses about mechanism have been modified, many aspects of fetomaternal immune tolerance remain puzzling questions. What signals trigger immune rejection in some pregnancies but not others? Does the placenta drive the specialization of maternal immune cells once they have entered the maternal-fetal interface? What are the functions of maternal immune cell subsets throughout gestation?Despite the continuous research efforts in answering these questions, clinical reproductive immunology has remained disproportionally stagnated over the last two decades. The main reason appears to stem from an insufficient acknowledgement of the centrality of maternal immune tolerance in determining successful outcomes. For instance, while the past few years have delivered a plethora of studies in animal models addressing the question of maternal immune adaptations to pregnancy, results from basic research appear to be frustrated in their potential application to clinical practice or made difficult by species variation.In an attempt to shed light into the above-mentioned questions, this Research Topic aims to present state-of-the-art works covering basic and clinical aspects of Reproductive Immunology. We particularly welcome Review articles and appealing subjects include (but are not limited to):• Classical and novel mediators of maternal fetal immune crosstalk: hormones, cytokines, microRNAs, extracellular vesicles• Cellular and molecular mechanisms involved in trophoblast - immune cell crosstalk• Modulation of host-microbial interactions in pregnant women and their influence on pregnancy outcome• Dysregulation of fetomaternal tolerance and its consequences on pregnancy outcomes and offspring health in later life• Application of -omics approaches to the study of fetomaternal immune interactions and their potential for diagnosis and treatment of adverse outcomes.