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Comparison of Gal and non-Gal mediated cardiac xenograft rejection

Christopher McGregor^1,2, Henry Tazelaar², Guerard Byrne^1,2

¹Cardiothoracic Surgery, University College London, London, United Kingdom; ²Surgery, Mayo Clinic, Rochester, MN, United States

Background: The histopathology of delayed xenograft rejection (DXR) for cardiac xenografts can vary depending on donor genetics and immune suppression. This study compares the pathology of DXR in Gal-positive and Gal knockout cardiac xenografts after pig-to-baboon heterotopic cardiac xenotransplantation when the induced anti-Gal antibody response is unregulated, blocked or absent.

Methods: Three transplant groups were compared. Group 1 (n = 11) and group 2 (n = 8) recipients received Gal-positive, CD46 pig hearts. Group 1 was treated with an [alpha]Gal polymer and Group 2 received immunoapheresis to block anti-Gal antibody. Group 3 (n = 5) received Gal knockout cardiac xenografts with no anti-Gal therapy. Perioperative and interim biopsies were examined and antibody responses were determined.

Results: No hyperacute rejection was seen and histologic findings were similar across the groups. All groups showed vascular antibody deposition in perioperative and interim biopsies and in explant samples. A prominent antibody response was detected only in Group 2. Complement activation was evident by C3d deposition but deposition of C5b and C5b-9 was limited. Earliest evidence of myocardial injury was consistent myocyte vacuolization in the absence of microvascular thrombosis or coagulative necrosis which developed later. Histology of explanted hearts exhibited mainly microvascular thrombosis and coagulative necrosis with little evidence of interstitial hemorrhage or edema.

Conclusions: Under these conditions the histology of DXR, progressing from early vascular antibody deposition, complement activation, and myocyte vacuolization to increasing levels of microvascular thrombosis and terminal myocyte coagulative necrosis, was similar for anti-Gal and non-Gal mediated rejection. Myocyte vacuolization without microvascular thrombosis was a consistent early feature of DXR. Non-ischemic myocyte vacuolization may result as a secondary effects of chronic endothelial cell activation and deserves further investigation.