|[Frontiers in Bioscience 1, d248-265, September 1, 1996]|
XENOTRANSPLANTATION - STATE OF THE ART|
Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
Received 07/16/96; Accepted 08/12/96; On-line 09/01/96
Most work in this area has been directed at the use of pharmacologic immunosuppressive agents and, to a lesser extent, total lymphoid irradiation (TLI). In early studies, heavy pharmacologic immunosuppressive therapy was shown to extend African green monkey heterotopic heart survival in baboons for several weeks, though there was a relatively high morbidity and mortality from infection in the recipient animals (12). African green monkey livers have been demonstrated to function for >12 months in baboons (13,35,36), despite a relatively high incidence of cellular rejection episodes.
TLI has similarly been shown to extend kidney or heart survival in concordant species combinations, particularly in association with pharmacologic agents (37-41).
Survival of orthotopically transplanted concordant heart xenografts was investigated by Kawauchi et al. (42), who performed the procedure using rhesus monkeys as donors and juvenile baboons as recipients. In six control experiments in which no immunosuppressive therapy was given, the recipients survived for a mean of eight days and all died of classic cellular rejection. In five baboons that underwent splenectomy and were treated with perioperative antilymphocyte globulin and long-term maintenance FK506 (tacrolimus) (with intravenous methotrexate, methylprednisolone, or both as rescue therapy in cases of severe rejection), mean survival was extended to 48 days. Two baboons died from rejection and three from cytomegalovirus infection.
Seven additional baboons received the same immunosuppression but with an added intravenous (i.v.) dose of methotrexate given twice weekly. Mean survival in this group was 127 days, and one baboon was still alive after 286 days. Four died from infection, one from pulmonary embolism, and one from renal failure. Only two of the baboons that died showed mild rejection at autopsy.
Although the authors concluded that FK506 coupled with low-dose maintenance methotrexate and splenectomy can produce prolonged host survival in this model, the quantity of immunosuppression given was clearly considerable and resulted in death from infection in a large number of recipient animals. If this degree of immunosuppression were required to provide long-term survival of concordant xenografts in humans, it would likely lead to a high incidence of recipient morbidity or mortality from infection.
With the current immunosuppressive agents available to us, it seems unlikely that even concordant donor organs will survive for very prolonged periods of time (years) in human recipients. If standard immunosuppressive therapy is given, there will be a risk of organ failure through recurrent or severe acute rejection and/or graft arteriosclerosis (chronic rejection). Function for some months is likely to be achieved, but the amount of immunosuppressive therapy required is likely to be excessive and will almost certainly lead to infectious complications.
Some of the newer immunosuppressive agents may well prove to be more efficacious in prolonging concordant xenograft survival. In particular, leflunomide (43,44), brequinar sodium (45,46), and 15-deoxyspergualin (47-51) have shown encouraging results in some experimental models, although there remain few data on studies in large animals, particularly in primates. There is some prospect, however, that a combination of the immunosuppressive agents that will become available to us within the next few years may well enable concordant xenotransplantation to be carried out successfully, particularly as a bridge to allotransplantation in cases of cardiac or liver failure.
Concordant xenotransplantation in humans will be limited, however, by the relative paucity of the number of suitable donor animals that will become available and, in particular, on the size of such animals. The baboon does not grow to a size sufficient to provide organs such as hearts for adult humans, although there may be a role for it in bridging infants and children to cardiac allotransplantation. Baboons are known to carry certain infectious agents, particularly viruses, that may be hazardous if transferred to humans (52-55). In addition, there will likely be a significant public objection to the use of non-human primates in large numbers for purposes of transplantation. Increasingly, therefore, the attention of those interested in this field has been directed towards discordant xenotransplantation.