Xenografts from Livestock

Abstract

The world-wide shortage of organs for allotransplantation has recently led to renewed interest in the field of xenotransplantation. As the pig shares a number of anatomical and physiological similarities with man and because it can easily be bred in large numbers, it is considered as a possible source of xenografts for human transplantation. However, such discordant xenotransplantation would result in hyperacute rejection of the transplanted organ. This hyperacute rejection process is a result of the activation of the recipients complement, which leads to loss of vascular integrity, haemorrhage and thrombosis in the transplanted organ. In this chapter we describe the main strategies that are currently being employed to overcome the problem of hyperacute rejection. One such strategy is the production of transgenic pigs expressing human regulators of complement activation such as decay accelerating factor (DAF), membrane cofactor protein (MCP) or CD59. Analysis of the different organs from pigs transgenic for human DAF showed that the transgene was expressed in all the organs analysed. Transplantation of the hearts from transgenic pigs into cynomologus monkeys resulted in a median graft survival time of 40 days. In contrast, normal pig hearts were hyperacutely rejected within 6 hours. These results demonstrate that expression of human DAF in the transgenic pigs protects them from hyperacute rejection and indicates that organs from these pigs may be suitable for clinical xenotransplantation. An alternative strategy that is also discussed in this chapter is the modulation of the expression of the epitopes that are recognised by the xenoreactive antibodies involved in the initiation of hyperacute rejection.