Sanne Hoeks

Chapter 1 10 HISTORICAL PERSPECTIVE A successful pregnancy is a unique result of immune regulatory mechanisms in both the pregnant mother and her offspring. However, survival is not the only successful outcome parameter. The nine months in utero might be seen as one of the most critical periods in a person’s life, shaping future capacities and health trajectories. 4 Two milestone publications set the stage for this theory: one on acquired immunological tolerance by Medawar (1963) and one on fetal programming by Barker (1989). In 1963 Medawar demonstrated that in utero inoculation of donor strain cells will lead to acceptance of tissue grafts later in life (Fig 1). 5 This effect was specific for the inoculated strain as grafts from other strains were rejected. 6 These experiments proved that the immune system is not pre-programmed to distinguish between self and non-self but is shaped to a tolerant state as a result of exposure to self-molecules during early development. 7 This concept was called acquired immunological tolerance and newer research now suggests that his observations are applicable in a lot of other domains, amongst which are reproductive technology, inflammatory diseases, neonatal infections and vaccination strategies further underscoring the translational implications of this research. 8 In 1989, Barker initiated the Developmental Origins of Health and Disease (DOHaD) hypothesis (Fig 2, A ) with his report on the fetal environment in utero as a significant determinant of risk for adult-onset diseases. 9, 10 In studying coronary artery disease rates in the early twentieth century, it became apparent that birth weight was inversely correlated with increased early death secondary to coronary heart disease (Fig 2, B ). Furthermore, rates of growth in the first two years of life has been associated with adult onset hypertension and type 2 diabetes. 11 Medawar’s immune tolerance concept and Barkers DOHAD hypothesis stress that the immune system in early life is functionally distinct and responsive to programming that persists into adulthood. During the perinatal period the immune system is shaped for an entire lifespan, “a foundation for a life time”.