The immunology of pig-to-primate xenotransplantation

• Main Author: Cozzi, E.
• Published: University of Cambridge 2001
• Subjects: 616.079
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598114

This thesis describes the analysis of transgenic pigs expressing the human regulatory protein decay-accelerating factor (HDAF). The first part of this research was aimed at proving the success of the genetic manipulation undertaken, by demonstrating the existence of HDAF in these transgenic pigs. These studies, conducted on PBMC from founder animals, provided evidence that both lymphocytes and monocytes from most transgenic pigs analysed express the HDAF protein. As altered expression and function of human proteins in transgenic pigs had previously been reported, the HDAF was further characterised by immunoprecipitation and epitope mapping. Together these experiments demonstrated the integrity of HDAF expressed by these transgenic pigs. To test the efficacy of the transgene, HDAF transgenic pig hearts were heterotopically transplanted into cynomolgus monkeys. None of these organs underwent HAR demonstrating the capacity of HDAF to protect the xenograft from complement mediated damage. HDAF transgenic pig kidneys were also transplanted into immunosuppressed and splenectomised cynomolgus monkeys. This led to a prolongation in the survival time of primates receiving a life-supporting porcine renal xenograft. The final part of this thesis provides insight into the xenogeneic antibody repertoire believed to be responsible for the vascular rejection of these transgenic organs. In conclusion, the detailed characterisation of the recently developed HDAF transgenic pig lines has led to the identification of pigs whose organs are not hyperacutely rejected when transplanted into primates. Together with growing insight into the humoral mechanisms responsible for the onset of delayed graft rejection, these studies have led to the longest survival reported to date for recipients of life-supporting pig-to-primate renal transplants.