Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts.
BACKGROUND
Genetically engineered pigs could provide a source of kidneys for clinical transplantation. The two longest kidney graft survivals reported to date have been 136 and 310 days, but graft survival >30 days has been unusual until recently.


METHODS
Donor pigs (n=4) were on an α1,3-galactosyltransferase gene-knockout (GTKO)/human complement regulatory protein (CD46) background (GTKO/CD46). In addition, the pigs were transgenic for at least one human coagulation regulatory protein. Two baboons received a kidney from a six-gene pig (GroupA) and two from a three-gene pig (GroupB). Immunosuppressive therapy was identical in all four cases and consisted of anti-thymoglobulin (ATG)+anti-CD20mAb (induction) and anti-CD40mAb+rapamycin+corticosteroids (maintenance). Anti-TNF-α and anti-IL-6R mAbs were administered to reduce the inflammatory response. Baboons were followed by clinical/laboratory monitoring of immune/coagulation/inflammatory/physiological parameters. At biopsy or euthanasia, the grafts were examined by microscopy.


RESULTS
The two GroupA baboons remained healthy with normal renal function >7 and >8 months, respectively, but then developed infectious complications. However, no features of a consumptive coagulopathy, eg, thrombocytopenia and reduction of fibrinogen, or of a protein-losing nephropathy were observed. There was no evidence of an elicited anti-pig antibody response, and histology of biopsies taken at approximately 4, 6, and 7 months and at necropsy showed no significant abnormalities. In contrast, both GroupB baboons developed features of a consumptive coagulopathy and required euthanasia on day 12.


CONCLUSIONS
The combination of (i) a graft from a specific six-gene genetically modified pig, (ii) an effective immunosuppressive regimen, and (iii) anti-inflammatory therapy prevented immune injury, a protein-losing nephropathy, and coagulation dysfunction for >7 months. Although the number of experiments is very limited, our impression is that expression of human endothelial protein C receptor (±CD55) in the graft is important if coagulation dysregulation is to be avoided.
['Iwase|Hayato|H|', 'Hara|Hidetaka|H|', 'Ezzelarab|Mohamed|M|', 'Li|Tao|T|', 'Zhang|Zhongqiang|Z|', 'Gao|Bingsi|B|', 'Liu|Hong|H|', 'Long|Cassandra|C|', 'Wang|Yi|Y|', 'Cassano|Amy|A|', 'Klein|Edwin|E|', 'Phelps|Carol|C|', 'Ayares|David|D|', 'Humar|Abhinav|A|', 'Wijkstrom|Martin|M|', 'Cooper|David K C|DKC|0000-0002-8899-9431']
D000818:Animals D030801:Animals, Genetically Modified D006084:Graft Rejection D006085:Graft Survival D006801:Humans D007166:Immunosuppressive Agents D007668:Kidney D016030:Kidney Transplantation D010215:Papio D013552:Swine D014183:Transplantation, Heterologous D019737:Transplants D014409:Tumor Necrosis Factor-alpha
genetically engineered pig kidney anti-IL-6R antagonist costimulation blockade xenotransplantation