Acquired immunological tolerance

Early in the Second World War the Medical Research Council asked Peter Medawar, an Oxford zoologist, why skin taken from one person would not form a permanent graft on another. He studied rejected grafts in burns patients and in rabbits. A graft from another individual healed in at first, then was rejected after about two weeks, and a second graft from the same donor was rejected faster. Medawar showed that rejection was an immune reaction.

In 1945 Ray Owen reported that adult cattle twins from separate eggs carried red cells of both twins. Their placentas join early in fetal life, and he suggested that blood cells and their precursors had passed from one twin to the other. Immunologists took little notice until 1949, when Frank Macfarlane Burnet, director of the Walter and Eliza Hall Institute in Melbourne, and Frank Fenner cited it in their monograph The Production of Antibodies. They proposed that the body carries self-markers and predicted that tolerance would prove a general phenomenon. Burnet reasoned that the ability to recognize self was acquired in fetal life, so a foreign substance introduced at the right time should later be treated as self.

Medawar reached the question from another direction. After he moved to Birmingham in 1947, he and Rupert Billingham used skin grafts to try to tell identical cattle twins from non-identical ones. Grafts between non-identical twins were accepted too, while grafts from unrelated animals were rejected. The cattle work was almost finished before the team learned of Owen's paper.

At University College London, where Medawar moved in 1951, he, Billingham and Leslie Brent injected cells from one inbred mouse strain into late-stage embryos of another. When the mice were grafted as young adults with skin from the donor strain, many kept the grafts indefinitely, yet they rejected skin from a third strain. The 1953 Nature report rested on a small number of mice, with similar findings in chicks, and a full account followed in 1956. The Czech immunologist Milan Hašek had reported red cell chimerism and weakened immune responses in birds joined to a partner's circulation as embryos.

The method could not be used on human fetuses, and in mice the ability to induce tolerance declined with age. Kidney transplantation moved forward instead with drugs that suppressed rejection. Burnet and Medawar shared the 1960 Nobel Prize in Physiology or Medicine for the discovery of acquired immunological tolerance.