Immunological and physiological observations in baboons with life‐supporting genetically engineered pig kidney grafts

Abstract

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.