Axel Kornerup Hansen & Kirsten Dahl
Centre of Bioethics and Risk Assessment, Division of Laboratory Animal Science and Welfare, Department of Pharmacology and Pathobiology, Royal Veterinary and Agricultural University, Copenhagen, Denmark
Due to the shortage of human organs for allotransplantation essential efforts aimed at development of a transgenic donor for animal-human xenotransplantation have been performed over the last decade. However, transplantation between two different species may give rise to two types of graft rejection. Between so-called discordant species a hyperacute rejection (HAR) occurs within minutes or hours. In so-called concordant species this type of rejection does not occur, but over days a delayed xenograft rejection (DXG) will occur. Man is concordant with old world primates, but due to several reasons, such as breeding difficulties, risk of retroviral epidemics, concerns for the use of endangered species, etc., the discordant pig is considered the donor of choice. HAR is primarily caused by initiation of the complement cascade. The antigen known to be activating the classical pathway is the a-gal epitope, which is found in primates but not in most other mammals. In species, in which the antigen is absent, circulating antibodies are found; a phenomenon, which is thought to be caused by the presence of the epitope in cell wall structures of bacteria of the normal flora. To remove this epitope from the xenograft the a-galactosyl-transferase enzyme locus has to be knock-outed. This was done in mice several years ago by two groups and also recently in pigs by a US as well as a British company. Three types of transgenes may also be attractive to insert in a xenograft donor. One approach may be to insert the gene coding for the H-transferase, which fucosylates N-acetyl-lactosamine in competition with the a-galactosyl-transferase. Another approach would be to insert genes coding for the enzyme, a1,3-galatosidase, which resynthesises the a-gal epitope into a compound not attacked by natural antibodies. None of these seem to be rather applicable in practice. However, a third and so far more successful approach is to insert genes for complement-regulatory factors (CRF), which identify the tissue as homologue to the complement system and, therefore, binds parts of the proteins involved in the complement cascade, thereby disabling both the classical and the alternative pathway. Knock-out of the a-gal epitope is likely to reveal the importance of other HAR-related xenoantigens (Cooper 1998). Therefore, the most applicable xenograft donor will probably be a multiple knock-out pig with some CRF genes inserted in its genome. Even if these problems are solved, a key issue related to the risk of the epidemic propagation of porcine endogen retroviruses in humans still needs to be solved. These have been shown to be able to propagate in human cells in vitro but not in primate cells in vivo. Therefore, the main ethical question in the discussion on xenotransplantation seems to be whether the risk of retroviral xenozoonotic epidemics in the majority can be considered that minor, that xenotransplantation can be used as a means of treating life-threatening disease in a minority.
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