| Fig. 1. Number of kidney transplants and patients waiting to receive a transplant in Austria, Belgium, Germany and Netherlands (data from Eurotranplant) |
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Engineering tissues for transplantation
Topics
There is currently a problem of supply of human organs for transplantation and the problem is especially acute for rare HLA haplotypes. This is illustrated in Fig. 1 below which summarizes the data for several European countries. This and the availability of potent immunosuppressive drugs has prompted renewed interest in the prospect of using xenogeneic grafts in clinical practice. Most of the research effort in this field has involved pig tissues and organs. These, are typically rejected within minutes if grafted to a non-human primate because of natural antibodies against a small carbohydrate antigen (Gala1-3Galb1) synthesized by an a1,3-galactosyltransferase (Fig. 2 below).
| Fig. 1. Number of kidney transplants and patients waiting to receive a transplant in Austria, Belgium, Germany and Netherlands (data from Eurotranplant) |
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In a second approach attempts have been made to control the complement reaction triggered by the binding of natural antibodies to Gala1-3Galb1 by expressing in the pigs human complement regulatory proteins, such as the decay accelerating factor (DAF) and the membrane cofactor protein (MCP) (Fig. 3). These experiments have shown that that the hyperacute reaction can be largely controlled using tissues from transgenic pigs expressing human complement inhibitors and graft survivals in excess of several months have been obtained by D White and colleagues. In conclusion, genetic manipulation, together with the use of immunosuppressive therapy, holds considerable prospect for the utilization of xenografts in medicine. Further research is needed, however, in order to extend graft survivial further and in order to address concerns wbout the risk of transferring zoonosis as a result of xenotransplantation. This concern is legitimate and following the first report of the growth of a porcine endogenous retrovirus in human cells, several investigators have called for a moratorium. Thus it is conceivable that the major obstacles to clinical applications of xenotransplants may now reside with the risk transfer of pathogens from pigs to humans rather than with the inability to control rejection by a combination of genetics and pharmacological means.
| Fig. 3. The classic and alternative complement pathways and the sites of activity of the decay accelerating factor (DAF), membrane cofactor protein (MCP) and CD59 |
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| Fig. 4. Survival of pig to baboon heart transplant. Control vs DAF transgenic pigs (from Bhatti FNK et al., 1999) |
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