The discovery of immunologic tolerance.

The phenomenon of tolerance can be said to have begun with the seminal observations in 1945 by R. D. Owen that cattle dizygotic twins display red cell (chimerism--mosaicism as he called it--in adult life. Owen interpreted this extraordinary finding in terms of the much earlier discovery by F. R. Lillie that the placentae of cattle dizygotic twins undergo anastomosis early in fetal life, and he speculated that this would have permitted blood cells and their precursors to move from one twin to the other. Owen's discovery came out of the blue and it was ignored by immunologists until F. M. Burnet and F. Fenner highlighted it four years later in their influential monograph The Production of Antibodies, in which they predicted the existence of tolerance as a general phenomenon and developed their notion of "self-markers" to explain why the body does not react against self. Though it was Medawar's group that showed conclusively in 1953 that tolerance can be experimentally induced in fetal mice and in chick embryos, their entry into this field came from a totally different direction, an attempt to distinguish between mono- and dizygotic cattle twins by the exchange of skin grafts. This led to the seemingly paradoxic result that grafts exchanged between dizygotic twins were accepted (1951) and it was not until their cattle experiments had been virtually completed that they became aware of Owen's earlier discovery. Following the work of Billingham, Brent, and Medawar, and of Hasek, tolerance became incorporated into general immunologic theory and it helped to explain the fact that mammals do not normally suffer from injurious autoimmune manifestations. Ray Owen's discovery therefore has a secure place in the history of immunology.