The emergence of xenotransplantation

The field of transplantation is faced with a growing shortage of human organs as the list of potential recipients continues to increase. Those currently listed can already expect long waits; some die waiting. Xenotransplantation is a potential solution to this widening donor-recipient disparity. Consequently, in recent years, there have been several clinical attempts using organs from nonhuman primates and pigs. The results with nonhuman primates as donors have been encouraging, but it is unlikely that these species will provide a long-term solution to the organ shortage. Most recent xenotransplantation research has therefore shifted to more phylogenetically disparate species, such as pigs, as potential donors. The major barrier to transplantation between members of disparate species combinations has been hyperacute rejection (HAR). The elements of humoral immunity involved in this rejection process include (1) naturally occurring antibodies directed against carbohydrate and other antigens expressed on pig endothelium, and (2) the complement system, which is activated by binding of natural antibodies to their targets. Several elegant strategies to prevent HAR are being developed. The creation of transgenic pigs, whose cells express human regulators of complement activation, is one such strategy. Another promising approach has been to remove antidonor antibodies from the recipient by absorption with some recently characterized carbohydrate epitopes of porcine endothelial xenoantigens. Recent experimental work indicates that HAR can successfully be prevented by inhibition or depletion of complement. A delayed type of xenograft rejection, characterized by endothelial cell antibody deposition and cellular infiltration, occurs over the next three to four days. The likely mechanisms involved in delayed xenograft rejection include antibody-dependent cell-mediated cytotoxicity and the phenomenon of endothelial cell activation.