Xenotransplantation - Nuffield Council on Bioethics

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Animal-to-Human Transplants : the ethics of xenotransplantation 3.30 A slightly different approach is to modify pigs so that they no longer have the pig antigens that mark them as different from human beings. The most important pig antigen is the sugar molecule galactosyl -1,3-galactose (here called -gal). 32 This is recognised by the human antibodies which trigger hyperacute rejection. One strategy would be to remove the pig gene which produces -gal so it was no longer present on the pig’s cells. Deleting a gene from an animal requires embryonic stem cells which can be grown in the laboratory. This allows the appropriate gene to be deleted from the cells, after which the cells are placed into developing embryos. The resulting offspring will contain some tissue that developed from the embryonic stem cells and which does not contain the gene. Suitable pig embryonic stem cells are not yet available, although this approach has been used successfully in mice. 3.31 Since genes cannot be deleted from pigs at the moment, a different strategy has to be used in order to reduce the levels of -gal pig antigen. This involves making transgenic pigs containing a human gene which has the effect of reducing the levels of -gal antigen. The transgenic pigs contain the human -1,2-fucosyltransferase gene. This gene makes the pigs produce a different antigen and a competition is set up: in producing the new antigen, the pigs produce less of the -gal antigen that causes hyperacute rejection. 33 3.32 It would, in principle, be possible to breed animals containing two or more different transgenes. For example, if an animal with the DAF transgene were mated with an animal with the -1,2-fucosyltransferase transgene, some of the offspring would have both transgenes. The hope would be that the presence of two complement regulating proteins might allow more effective complement inhibition if the organs were transplanted into human beings. Other methods for reducing hyperacute rejection 3.33 A different approach is to try and make the human recipient tolerant of the xenografted organ or tissue so that an immune response is not induced. There is evidence that if an animal receives a bone marrow transplant from an animal of a different, but closely related, species, the recipient can subsequently receive other transplants from the same source animal without mounting a strong immune response. 34 Attempts to transplant pig bone marrow into primates have not yet been successful. In principle, however, it might prove easier to transplant pig bone marrow than pig organs since, like other tissue, it is not susceptible to hyperacute rejection (paragraph 3.24), although graft versus host disease can be a problem 32 Platt J L and Parker W (1995) Another step towards xenotransplantation. Nature Medicine, 1:1248-50. 33 Sandrin M S et al. (1995) Enzymatic remodelling of the carbohydrate surface of a xenogenic cell substantially reduces human antibody binding and complement-mediated cytolysis. Nature Medicine, 1:1261-7. 34 Sachs D H et al. (1995) Tolerance and xenograft survival. Nature Medicine, 1:969. 34
<strong>Xenotransplantation</strong> : progress and prospects (paragraph 3.21). The eventual aim would be to give people bone marrow transplants from a source animal. Once tolerance was induced, other organs could be transplanted. 3.34 A number of other methods have been used to try and prevent, or reduce, hyperacute rejection. 35 One approach is to remove the antibodies that recognise pig antigens from the blood of the human recipient. In principle this could be done by passing the person’s blood through a filter that contains the pig antigen. The antibodies would stick to the antigen in the filter and thus be removed from the blood. This would allow a xenograft to take place. The human recipient would eventually make more antibodies but it is possible that the pig tissue would not be destroyed at that stage. Another approach is to treat the pig organ with fragments of antibody before transplantation which cover up the antigens and stop the body’s antibodies sticking to them. Finally, it is possible to try and treat the recipient with substances that inhibit the complement system. 36 Cobra venom factor acts as a complement inhibitor. Alternatively, one of the body’s natural complement inhibitors, soluble complement receptor type 1, can be made artificially and used to try and prevent hyperacute rejection. It is not yet clear whether these methods will be useful for clinical xenotransplantation. Other obstacles to xenotransplantation using pig organs 3.35 Thus, a number of methods for preventing, or reducing, hyperacute rejection are being developed. If hyperacute rejection can indeed be controlled, there will be other elements of the immune system to overcome. 37 Since most discordant xenografts are destroyed by hyperacute rejection, little is known about these other elements but they may have a significant role in organ rejection. First, there is likely to be an additional antibody response, less vigorous than hyperacute rejection and similar to the antibody response seen in human organ transplantation. Second, there will be a cell-mediated response, in which T-cells attack the xenograft. T-cells, however, must interact with the cells they are attacking. Since the cells of a pig xenograft are very different to human cells, the T-cells may not be able to interact with them very effectively and so it is possible that the cell-mediated response to a xenograft may be less severe, in some respects, than the response to a human transplant. Finally, xenografts, like human transplants, may be susceptible to chronic rejection. This slow process happens over months or years, and leads to damage to the blood vessels of the transplant. Even in human organ transplantation, this process is not 35 Reviewed in Rowe P M (January 1996) <strong>Xenotransplantation</strong>: from animal facility to the clinic? Molecular Medicine Today, pp 10-15, and Fabre J W (1995) Nudging xenotransplantation towards humans. Nature Medicine, 1:403-4. 36 Ryan U S (1995) Complement inhibitory therapeutics and xenotransplantation. Nature Medicine, 1:967-8. 37 Bachs F H et al. (1995) Barriers to xenotransplantation. Nature Medicine, 1:869-73. 35
Page 1 and 2: NUFFIELD COUNCIL ON BIOETHICS Anima
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Page 6 and 7: Preface Preface Since the N
Page 8 and 9: Table of contents Table of contents
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Page 29 and 30: Alternatives to xenotransplantation
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Xenotransplantation - Nuffield Council on Bioethics

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