Current and future prospects for xenotransplantation

Abstract

The transplantation of organs and tissues between animal species, orxenotransplantation, is the focus of a growing field of research, owingprimarily to the increasing shortage of allogeneic donor organs. The pigstands out as the most suitable donor animal for humans; however, xenografts(e.g. pig organs) used for human transplantation are normally destroyed by thehost within minutes by hyperacute xenograft rejection. An improvedunderstanding of the immune recognition and rejection of xenografts hasresulted in new therapies that can partially overcome hyperacute rejection(HAR), delayed xenograft rejection (DXR) or acute vascular xenograftrejection. Strategies to diminish immunogenicity following xenotransplantationcan be divided into two approaches: those directed at the recipient (e.g.antibodies or complement depletion or inhibition and tolerance induction) andthose directed at the donor (e.g. transgenic modifications to express humancomplement-regulatory proteins or removal or displacement of αGalepitopes). DXR is likely to be controlled by transgenic inhibition ofendothelial cell activation (e.g. inhibition of NF-κB). Transgenic pigsrequired for xenotransplantation will soon be generated at a greaterefficiency and precision using nuclear transfer and cloning when compared topronuclear injection. Of greater significance is that nuclear transfer offersthe ability to target gene insertion selectively to specific gene loci and todelete specific genes in the pig. Experimental pig-to-primate organxenotransplantation is currently under way, and results show increasedtransplant function from minutes to days and weeks. The final therapeuticregimen that allows survival of a discordant xenograft is likely to involve acombination of ‘modified’ functional genes in the donor organ, thedevelopment of immunological tolerance to pig antigens and administration ofnovel therapeutic agents, including immunosuppressants, that can controlnatural killer (NK) cell and monocyte mediated responses.