Xenotransplantation: postponed by a millennium?

Abstract

In the late 1980s, a persistent shortage of human donor organs and the availability of new molecular techniques sparked a renewed interest in transplantation of organs and tissues across the species barrier. In spite of the considerable phylogenetic distance to humans, the pig was chosen for its size, breeding pattern and general availability as the most suitable xenogeneic donor species. The following years saw substantial financial and intellectual investments in xenotransplantation, which resulted in the development of genetically modified animals that were thought to be suitable for use in clinical trials. Although these clinical trials are yet to be implemented, the issues that drove the initial enthusiasm, notably the shortage of human donors, have become even more acute in recent years, strengthening the need for alternative sources of organs for transplantation. However, serious reservations remain about the use of xenotransplantation. If we assume, and this is a major assumption in the present climate, that the ethical concerns related to the use of animals as a source of donor organs will be met by society, three major problems remain to be overcome before xenotransplantation can become a viable treatment: (i) immunological acceptance of the xenograft; (ii) functional compatibility of organs between species; and (iii) concerns that transmission of novel infectious agents will occur between species.1 The transplantation of vascularized xenografts including heart, kidney or liver into unmodified hosts invariably leads to hyperacute xenograft rejection.2 This process occurs rapidly and does not require de novo protein synthesis, because it is mediated by pre‐existing xenoreactive natural antibodies (XNA) that bind to specific terminal carbohydrate epitopes termed Gal‐ α ‐1,3Gal that are synthesized by a specific form of the enzyme galactosyltransferase. Gal‐ α ‐1,3Gal is expressed on pig cells but not on human cells, as man (in common with other higher primates) …