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Intestinal xenotransplantation from alpha 1,3-galactosyltransferase gene knockout and concurrent expression of membrane cofactor protein (MCP, CD46) transgenic pig to cynomolgus
Yousheng Li, Danhua Yao
OBJECTIVES
Gene-modified transgenic pig organs offers great potential to address the shortage of human organs for allotransplantation. However, there was no report of intestinal xenotransplantation from alpha 1,3-galactosyltransferase gene knockout and concurrent expression of membrane cofactor protein (MCP,CD46) transgenic (GTKO.hCD46Tg) pig to cynomolgus. We established an intestinal xenotransplantation model from pig to pathogen free cynomolgus and tried to find out the GTKO.hCD46Tg graft survival.
MATERIALS AND METHODS
We established a model of heterotopic intestinal xenotransplantation from wide-type pig to cynomolgus and defined it as control group. While in experimental group, GTKO.hCD46Tg pig was the graft donor. The procedure of segmental heterotopic intestinal xenotransplantation in both groups were performed by the same team of surgeons and assistants. Coagulation, hematologic and immunologic data on recipients and graft survival were collected.
RESULTS
The graft survived for 240 minutes (n=5, median survival 180 minutes and mean survival 155 minutes) in control group. GTKO.hCD46Tg intestine survived for up to 22.5 hours (n=5, median survival 560 minutes and mean survival 727 minutes. Postoperative coagulopathy in recipients appeared in both groups. Prothrombin time (PT), international normalized ratio (INR) and activated partial thrombin time (APTT) rose sharply during the first 30 minutes and reached the highest value in 30 minutes after reperfusion. However, in GTKO.hCD46Tg group, the value of PT, INR, APTT rose softly and the top value appeared at the 6th hour after reperfusion. The ratio of CD4 positive, CD8 positive T lymphocyte did not change significantly before and after transplantation.
CONCLUSIONS
Hyperacute rejection is not conquered in GTKO.hCD46Tg pig to cynomolgus intestinal xenotransplantation. However, the transgenic graft survival is significantly prolonged comparing to control group. Further therapeutic interventions, including candidate genetic modification of donor pigs, immunosuppression in recipients are required to overcome hyperacute rejection.