The Shared Trail of Organ, Limb, and Face Transplantation

TRANSPLANTATION OF A LIMB or face has been a logical extension of organ transplantation. The feasibility of transplanting organ allografts2 was demonstrated for the first time with kidneys in 1959. During the preceding 15 years, it had been established that rejection of skin allografts in experimental animals (1) and humans (2) is an immunologic response and that analogous events cause destruction of canine (3,4) and human kidney allografts. The only exception was with identical twins, between whom tissues and organs (isografts) can be freely exchanged (5,6).Before 1959, most of the human kidney allografts were transplanted to non-immunosuppressed recipients.3 The kidneys were obtained from recently deceased persons (e.g., in France after guillotine execution) or in the United States from surgical patients from whom a kidney was removed for a variety of non-transplant objectives (7-12), and from a mother in France who was the first recorded living organ donor (for her son) (13).No matter what the source of the renal allografts, the pace of the rejection was much the same and was complete in a few days or weeks. Efforts up to 1959 to prevent the rejection of renal allografts by weakening the recipient immune response with irradiation or drug immunosuppression had failed to produce kidney allograft survival in humans or in any animal model for as long as 30 days. Consequently, the successful kidney alloengraftments accomplished in humans between 1959 and 1963 (table 1) were surprising to almost all immunologists, physicians, and surgeons.In retrospect, however, there had been clues suggesting the theoretical possibility of organ alloengraftment, beginning with observations in cattle. In these bovine fraternal twins, the placentas are fused during uterine gestation, allowing fetal cross-circulation (fig. 1, inset I).4 In 1945, it had been reported by Ray Owen (APS 1984) that each member of a freemartin pair contained the other's blood cells after birth and throughout life (persistent blood chimerism) (14).The blood chimerism subsequently was incorporated by the Australian Macfarlane Burnet (APS I960) in the clonal selection theory of immunity that became the cornerstone of modern immunology (15). As part of his hypothesis, Burnet predicted that the cattle twins would be able by virtue of their chimerism to freely exchange all tissues. In 1952, Peter Medawar (APS 1961) and his English team validated this prediction with skin graft experiments in both same-sex and cross-sex cattle twin pairs (16), and then proceeded in 1953 to demonstrate that similar non-responsiveness (acquired immunologic tolerance) could be deliberately produced in mice.In the mouse experiments, Medawar and his associates, Rupert Billingham and Leslie Brent, transplanted allogeneic spleen cells from adult donors into immunologically immature animals (17,18) (fig. 2, outer rim). This was the forerunner model of bone marrow cell transplantation for humans afflicted with immune deficiency diseases (fig.l, inset 2a). In a second model, Main and Prehn (19) in Bethesda reduced the immune responsiveness of adult recipient mice by total body irradiation prior to the transplantation of bone marrow cells (fig. 2, center). This model ultimately evolved into clinical bone marrow transplantation for a wide range of hematologic and other indications (fig. 1, inset 2b). Under both circumstances depicted in figure 2, the mouse recipients engrafted with donor leukocytes could accept other tissues from the same donor. Thus, the strong association of acquired donor-specific tolerance with donor leukocyte chimerism was formally established.A three-step strategy derived from the mouse experiments that could permit organ engraftment in patients was promptly envisioned by surgeons (20,21). It consisted of weakening the recipient's immune system with total body irradiation as had been done by Main and Prehn, infusion of donor lymphopoietic (e. …