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Anatomy of an Error

It has been a particular pleasure to see the life-changing impact of the hand, face, and other composite allografts. Over the past decade, a rapidly growing number of this novel type of transplants have been performed worldwide with highly encouraging functional and immunological outcomes. Recipients of these grafts represent a new generation of transplant recipient pioneers. The uniqueness of their grafts, which include donor bone and its marrow, could help further elucidate the mechanisms by which transplanted organs and tissues are accepted. In turn, novel strategies to facilitate these mechanisms may be developed. The title of my talk today could be improved. A more explanatory title would be “The missing half of the Billingham-Brent-Medawar discoveries." This informational void caused a pervasive early error that precluded the orderly development of transplantation immunology and limited clinical progress almost exclusively to the development of more potent immunosuppressive drugs. To understand how an error of this magnitude could have occurred, it is necessary to go back to the birth of modern day transplantation. The midwife was the English Zoologist, Peter Medawar. The seed from which all else derived was Medawar’s demonstration in 1943 that skin graft rejection is an immunologic event. In the next 10 years, efforts to weaken the immune response with irradiation or steroids had little or no effect on experimental graft survival. During the same period, however, a study by Medawar’s team of the natural tolerance in freemartin cattle revealed a chink in the immunologic armor. In freemartin cattle, fusion of their placentas allowed mixture of the 2 animal circulations during gestation. After birth and throughout life, the animals shared each others blood cells (blood chimerism). Moreover, the cattle were tolerant to each others tissues and organs. Inspired by the freemartin findings, Medawar and his colleagues demonstrated in 1953 that similar chimerism-associated tolerance could be deliberately produced. In their experimental model, splenic or bone marrow leukocytes were infused from adult mouse donors into newborn mouse recipients whose immune system was not developed enough to reject the cells. With leukocyte engraftment, the neonatal recipients had lifetime tolerance to skin (or other tissues) from the original leukocyte donor, but not to tissues from any other donor. These chimeric mice were analogs of future patients treated with bone marrow transplantation for immune deficiency diseases. In 1956, Main and Prehn at the NIH extended these observations to adult mouse recipients whose fully competent immune system had been weakened with high dose total body irradiation before the cell infusion. These mouse chimeras were analogs of today’s cytoablated human bone marrow recipients. Stable donor leukocyte chimerism in both mouse models was achievable only when the donors and recipients had a good histocompatibility match. Otherwise, the donor leukocytes were either rejected, or they turned the tables and rejected the immunologically defenseless recipient—graft versus host disease (GVHD). Because human histocompatibility antigens were yet to be discovered, clinical bone marrow transplantation for the treatment of hematologic disorders and other indications was delayed until 1968. As in the mice, donor-specific tolerance was associated with the leukocyte chimerism. GVHD was the most common and specific complication that could be avoided or minimized only with a perfect HLA match. This was a beautiful story. The escalation of the mouse tolerance models to humans with parallel developments in histocompatibility research was heralded as a perfect example of bench-to-bedside research. In contrast, kidney transplantation with survival of at least one year was precociously accomplished in 7 patients between 1959 and 1962 without a preceding animal model: 2 in Boston and 5 in Paris. The first success was a fraternal twin recipient treated by the Boston plastic surgeon and future Nobel laureate, Joe Murray. All of the first 6 patients were irradiated before transplantation but had limited therapy afterwards because drug immunosuppression was not yet available. The exceptional seventh patient (also a Brigham patient of Murray) was not irradiated but was treated daily with azathioprine throughout the 17 months of graft function. Although the 7 successes were isolated exceptions in more than 300 failures, they were hailed as a collective breakthrough. However, the accomplishments were inexplicable. Engraftment had been achieved without donor leukocyte infusion, without HLA matching, and with no hint of GVHD. If there was any connection with Medawar’s mouse