The first baboon-to-human transplants.

A crisis followed the demonstration in 1962–1963 at the University of Colorado that azathioprine and prednisone, two immunosuppressants which were relatively ineffective individually, could in combination permit prolonged renal allograft and patient survival in the majority of human cases. This unexpected development came before other ingredients of an effective end-stage renal disease program were in place. Only a handful of dialysis facilities existed in the USA. Brain death pronouncement of cadaveric donors was 5 years away, and most kidney transplant candidates who did not have live volunteer donors died while waiting. Xenotransplantation appeared to offer a way out of the dilemma. Consequently, the enthusiasm ignited by Keith Reemtsma’s kidney xenotransplant trials of 1963 at Tulane University in New Orleans was both immediate and sustained. Although fierce rejection had destroyed a rhesus graft in a few days after its transplantation by Reemtsma, it was obvious that some of the chimpanzee grafts might function for long periods. In ploughing new ground, Reemtsma already had proved that kidneys from at least two non-human primate donor species would not be abruptly rejected. This observation was critical. By 1963, Roy Calne had observed immediate kidney rejection following transplantation between discordant species. It also had been learned in Colorado that hyperacute rejection similar to that observed by Calne was often triggered by isoagglutinins in human recipients of ABO-mis-matched kidney allografts. As a result of Reemtsma’s pioneer efforts, it could be concluded that rhesus and chimpanzee kidneys would be spared this fate. A few weeks after Reemtsma’s cases became public, Claude Hitchcock, Chief of Surgical Services, Hennapin County Hospital, Minneapolis, telephoned me with the information that a kidney from a third Old World primate species, the baboon, had also escaped hyperacute rejection. On 16 February 1963, Hitchcock had secretly engrafted a baboon kidney into a 65-year-old woman with an immediate diuresis. The graft suddenly stopped functioning after 4 days due to a hepatic arterial thrombosis, which he attributed to a flawed vascular anastomosis. Hitchcock was a baboon expert, having acquired a unique experience with this species during several preceding years in pioneer studies of auto- and allotransplantation of the lung, in collaboration with scientists attached to the large baboon colony at the Southwest Foundation for Research and Education, San Antonio, Texas. Fearful of public and professional criticism of his clinical kidney case (later reported in the Journal of the American Medical Association), Hitchcock had concealed its existence until Reemtsma’s initiatives were widely known. Regretting this decision, Hitchcock proposed a collaboration. It was appreciated that the threatened extinction as well as the anthropomorphic qualities of the chimpanzee would curtail the use of this animal as a donor. In contrast, the baboon had flourished in southern and central Africa and did not have such striking humanoid behavior. Because there was not yet a kidney transplant program in Minneapolis, the patients were to be treated at the University of Colorado, which had experience of nearly 50 renal allotransplantations under azathioprine/prednisone immune suppression. Preparation required several months and included on-site collaborations with experts in zoonoses (Dr S S Kalter [NIH] and his San Antonio associates) and primate specialists (e.g. J J Moor-Jankowski [NIH]), many of whom also had worked with Reemtsma. Reemtsma, himself, was an invaluable source of advice. His generosity eventually made possible Kendrick A Porter’s classical histopathologic comparison of rhesus, baboon, and chimpanzee kidney xenograft rejection by human recipients. Although we predicted from the Reemtsma/Hitchcock experience that the baboon kidneys would not be hyper-acutely rejected, the specter of more subtle antibody rejection hung heavily over the trials, prospectively and afterwards. It would be another year before hyperacute rejection associated with lymphocytotoxic antibodies was recognized in ABO-compatible allograft recipients1. Consequently, a study of such antigraft antibodies was not done. Instead, attention was focused by David Talmage’s immunology fellows (Charles Kirkpatrick and W E C Wilson) on the effect of hetero(xeno)specific hemagglutinins. The baboon xenografts functioned for a mean of 41 days when there was ABO compatibility (n = 3) versus 21 days when there was not (n = 3). Although this suggested an important ABO effect, there was serologic evidence that xenospecific hemagglutinins also bound to the transplanted kidneys in every case. It appeared from the clinical observations, and especially from Porter’s histopathologic analyses, that humoral xenograft rejection was uncontrollable with cell-directed immune suppression, even in the phylogenetically close baboon-to-human combination. Therefore, we concluded that, “until improved methods of management become available, further trials do not seem justified, and none are contemplated by us until that time”. The moratorium lasted more than 28 years until our two laboratory-based attempts at baboon-to-human liver transplantation of 1992–93. These also failed because of a less obvious humoral rejection, but with unmistakable complement activation despite complete freedom from cellular rejection out to 70 days. As in 1964, the rejection of ‘concordant’ xenografts was a ‘slow motion’ version of that seen with ‘discordant’ xenografts2. It was time for a new moratorium. The humoral component of xenograft rejection was discussed in our 1964 article as an Arthus reaction, the same term (or alternatively ‘Shwartzman reaction’) used to described hyperacute allograft rejection in patients who had preformed antigraft cytotoxic antibodies (classical pathway of complement activation) but also in exceptional patients who were antibody free (alternative pathway)3. Thus, it was recognized almost from the beginning that humoral rejection of allografts under specific circumstances and that of xenografts involved an acute inflammatory reaction that would not yield to conventional immune suppression. John Najarian, in commenting 30 years later on his own classical studies4, has pointed out how little progress has resulted from the cyclic ‘rediscovery’ of the pathogenesis of xenograft rejection, and of treatment strategies, using increasingly sophisticated technologies to delineate what was already quite obvious by the late 1960s. An exception to the futility was the recognition by Gus Dalmasso and Fritz Bach that the seminal problem of complement activation could be resolved by providing the target donor tissues with complement regulatory peptides of the recipient species. This objective was achieved when ‘humanized’ transgenic animals were produced by David White in England and by John Logan in the USA with the collaboration of Jeffrey Platt and other colleagues. With this progress in cracking the shell of the xenotransplant problem, what remains to be done is the induction of organ acceptance by the same chimerism-dependent mechanisms that have spawned successful allotransplantation5.