A cquired transplantation tolerance without immunosuppression was described l\.by Billingham, Brent and Medawar J·2 more than four decades ago follow ing the injection of immune competent adult spleen cells into immunologi cally immature mice in utero or perinatally. The engrafted donor cells flour ished, perpetuated themselves and were thought in effect to have endowed the recipient with the donor immune system. This explanation of tolerance by immunologic replacement was strengthened by Main and Prehn3.4 who dem onstrated the same outcome in irradiated adult mice, whose cytoablated hematolymphopoietic cells were reconstituted with donor bone marrow. The anticipated clinical application of tolerance induction for transplanta tion was temporarily derailed in 1957 when Billingham and Brent showed in mice5•6 and Simonsen in chickens7 that graft-versus-host (runt) disease (GVHD) was a danger in these immunologically unbalanced systems in rough pro portion to the degree of MHC disparity. In spite of the same limitations as with the radiation chimera models, a strategy for clinical bone marrow trans plantation could be assembled directly from the Main-Prehn experiments, with similar results. Stable drug free chimerism could be induced in irradiated ani mals using MHC matched donor marrow, but otherwise there was an intoler able incidence of GVHD. Translation of these experiments into successful clinical bone marrow trans plantation in 19688•9 was supremely gratifying because it had been so logical as Nobel Laureate Thomas has summarized. 1o However, the achievement ef fectively detached from a scientific base, surgeons who by this time had re corded thousands of successful whole organ transplantations under continuous immunosuppression-without host preconditioning, dependence on MHC match ing or problems with GVHD. The avalanche of whole organ cases had begun in 1962 when azathioprine was combined with prednisone. I J A characteristic cycle was identified in which rejection could be reversed surprisingly easily with prednisone. More importantly, the need later on for maintenance immu nosuppression frequently declined. The same sequence has been seen since with all other organs transplanted and with all of the immunosuppressive regi mens. Something had changed in the host, the graft or both. But what?
