“Acquired tolerance” may be defined as an induced state of specific 120% reactivity towardsa substance that is normally antigenic-a nonreactivity, moreover, that is due to a primary failure of the machinery of the immunological response.* The prolongation of the life of homografts that may be brought about by the administration of cortisone or trypan blue or by X irradiation should not, therefore, be ascribed to “tolerance,” for such treatments are not immunologically specific in their effects. They lower the resistance of the host to homografts from all donors. Our definition also excludes the acceptance by F1 hybrid mice of homografts transplanted to them from members of either of their parental inbred strains, for the tissues of the parents are not antigenic towards their hybrid progeny, whose “tolerance,” though specific, is therefore in no sense actively induced.

Although there are grounds for believing that the principles weshall formulate now apply to heteroplastic as well as to homoplastic grafts, and to cancerous tissues as well as to normal, we shall be concerned at present only with homografts of normal cells; nor do we wish to recapitulate, except in briefest outline, findings that have already been published elsewhere (Billingham, Brent, and Medawar, 1953). What we have done, in effect, is to reproduce experimentally in chickens, rabbits, and mice a state of affairs that occurs naturally in the lifetime of most twin cattle of dizygotic origin (Owen, 1945) and very rarely in twin human beings (Dunsford, Bowley, Hutchison, Thompson, Sanger, and Race, 1953). Twin cattle are normally synchorial, and cells circulating in the blood stream of the one have free access to the other through the anastomoses of the fetal vessels. Owen showed that twin cattle are born with, and may long retain, red blood cells of dual origin. In other words, each calf contains its own red blood cells mixed with a certain, sometimes high, proportion of red cells belonging to the zygote heritage of its twin. Since erythrocytes are end cells with a determinate span of life, Owen infers that the twins exchange red-cell precursors in fetal life and so become, and usually remain, chimeras. The experiments of Weiss and Andres (1952) provide strong support for this interpretation: they have not only shown (as Rawles and Eastlick had shown beforehand) that pigmentary melanocytes introduced into embryos of nonpigmented or differently colored breeds may survive beyond hatching, but, by using the intravenous route of inoculation, they have also shown that cells injected into the blood stream may eventually leave the blood vessels and take up their proper positions in the body.