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Presenter: Akira, Shimizu, , Japan
Authors:
Pathologic characteristics of transplanted GalT-KO pig xenografts in baboons.
Akira Shimizu1, 2, 3), Kazuhiko Yamada1) , David H. Sachs1), Robert B. Colvin3)
1) Department of Pathology, Nippon Medical School, Tokyo, Japan
2) Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
3) Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
Abstract
The use of α1,3-galactosyltransferase gene-knockout (GalT-KO) pig donors in discordant xenotransplantation has extended the survival of heart and kidney xenografts. Here we describe the pathology of previously reported GalT-KO pig hearts and kidneys transplanted into baboons treated with either chronic immunosuppression or a protocol designed to induce immune tolerance.
Baboons that received heterotopic heart xenografts from GalT-KO pigs were treated with chronic immunosuppression. No hyperacute rejection developed and one graft survived 6 months. However, all GalT-KO heart grafts underwent graft failure with acute humoral xenograft rejection (AHXR), acute cellular xenograft rejection (ACXR), and/or chronic rejection.
Baboons received life-surpporting kidney xenografts from GalT-KO pigs were treated with chronic immunosuppression or a tolerance protocol. All GalT-KO kidneys in the chronic immunosuppression group were rejected by AHXR and ACXR by day 34. In contrast, grafts in the immunotolerance group survived up to day 83 with normal graft function and no AHXR, ACXR or chronic rejection.
AHXR was pathologically characterized by multiple thrombi in vessels of various sizes in both heart and kidney grafts, and thrombotic microangiopathic glomerulopathy in the kidneys. IgM, IgG, C4d and C5b-9 deposition were noted with vascular endothelial cell death and procoagulant activation (increased expression of tissue factor and von Willebrand factor, with concomitant decreased espression of CD39). ACXR was characterized by the infiltration of T cells (including CD3 and TIA-1+ cytotoxic T cells), CD4+ cells, CD8+ cells, macrophages, and a small number of B and NK cells.
Therefore, despite the use of GalT-KO pigs in discordant xenotransplantation, acute and chronic antibody and cell-mediated rejection develops in grafts, maintained by chronic immunosupression. In contrast, the induction of immune tolerance may protect such grafts from AHXR, ACXR, and chronic rejection after xenotransplantation.
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