Pigs transgenic for hDAF were created by microinjection of human DNA into fertilized pig oocytes. Ten control hearts, eight heterozygous hDAF transgenic hearts and one homozygous hDAF transgenic heart, were transplanted heterotopically into the abdomen of non-immunosuppressed cynomolgus monkeys. Fifteen heterozygous transgenic and five control hearts were then transplanted heterotopically into the abdomen of immunosuppressed cynomolgus monkeys. Of the transgenic hearts ten were immunosuppressed with a high cyclophosphamide (CyP) regimen (group I) and five were immunosuppressed with a low CyP regimen (group 2). All control hearts were immunosuppressed with the high CyP regimen. The hDAF transgenic hearts in the high CyP group had a median beating time of 40 days (range 6-62 days) compared with 9 days (range 8-34 days) for those in the low CyP group. This difference was statistically significant (p <0.05). The control grafts had a median beating time of 55 minutes (range 2-180 minutes). The difference between the control grafts and the high CyP transgenics was statistically highly significant (p <0.001). The difference between the control grafts and the low CyP transgenics was also statistically significant (p <0.05). All control hearts were hyperacutely rejected. Only two hearts in the high CyP group were lost due to AVR, on days 6 and 62: all other hearts showed no evidence of rejection. All hDAF transgenic hearts in the low CyP group underwent AVR. These results confirm that HAR can be abrogated with the hDAF transgene in this pig-to-primate model and that prolonged survival can be achieved. Perioperative CyP would appear to be an essential component of this regimen, without which, graft loss due to antibody-mediated AVR is encountered. Finally, hDAF transgenic pig hearts were transplanted both heterotopically, and orthotopically into immunosuppressed baboons. No graft underwent HAR and survival of heterotopic pig-to-baboon heart xenografts for up to 21 days was achieved.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:663512 |
| Date | January 2000 |
| Creators | Waterworth, P. D. |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/23249 |
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