The mechanisms of graft failure in cardiac xenografts from α1,3-galactosyltransferase, gene-knockout (GalT-KO) pigs in babooons

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Heterotopic cardiac xenotransplantation from α1,3-galactosyltransferase gene-knockout (GalT-KO) swine to baboons has been performed. The pathology of the GalT-K0 cardiac xenografts was assessed to characterize the immunologic reaction to the xenograft in the absence of anti-Gal antibody-mediated rejection.Eight baboons received heterotopic cardiac xenografts from GalT-KO porcine donors. All baboons were treated with chronic immunosuppression. Histologic and immunohistochemical studies were performed on biopsy and graftectomy samples. No hyperacute rejection occurred. Three baboons were euthanized or died 16 to 56 days after transplantation. The other 5 grafts ceased beating between days 59 and 179 (median 78). All failing grafts exhibited thrombotic microangiopathy (TM) with platelet-rich fibrin thrombi in the microvasculature, myocardial ischemia and necrosis, and focal interstitial hemorrhage. TM developed in parallel with increases in immunoglobulin (IgM and IgG) and complement (C3, C4d, and C5b-9) deposition, as well as with subsequent increases in both TUNEL+ endothelial cell death and endothelial cell procoagulant activation (increased expression of tissue factor and von Willebrand factor, with concomitant decreased expression of CD39). CD3+T cell infiltration occurred in all grafts. Slowly progressive humoral rejection, likely associated with elicited nonGal antibodies, and possibly disordered thromboregulation represents a major remaining immunologic barrier to long-term xenograft survival, even when using GalT-KO swine donors. In addition, acute cellular xenograft rejection and chronic rejection also developed in grafts, maintained by chronic immunosupression.