Primary xenogeneic porcine alpha-1,3-galactosyltransferase knockout skin grafts do not cause sensitization of allogeneic humoral responses in a non-human primate model

Alexander Albritton^1,3, Angelo Leto Barone^1,2, Josef Kurtz^1,3, Christopher Mallard¹, David Sachs¹, Curtis Cetrulo^1,2

¹Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School; ²Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School; ³Emmanuel College; Boston, MA, USA

Methods:  Baboons received primary xenogeneic and allogeneic split thickness skin grafts followed by secondary xeno and allo skin grafts from the same donors, with no immunosuppression.  The development of specific anti-allo and anti-xeno IgM and IgG antibodies was assessed in the serum of the recipients by flow cytometry.

Results: In a recipient that received primary allo, xeno (Gal+) and xeno (GalT-KO) skin grafts, the Gal+ graft was rejected in a hyperacute manner, while both allo and GalT-KO grafts were rejected on day 10. Secondary allo and GalT-KO skin grafts were both rejected in an accelerated fashion, demonstrating presensitization to both allo and xeno antigens. To assess whether an anti-xeno non-Gal antibody response can accelerate rejection of an allograft, we transplanted a GalT-KO skin graft onto a naïve baboon and followed it, after rejection, with an allogeneic skin graft.  Anti-non-Gal antibodies were detected after rejection of the GalT-KO skin, but there was no evidence for cross-reactivity against alloantigens, and the subsequent allograft was rejected in a time frame (day 10) consistent with a non-sensitized response.  

Conclusions: Rejection of primary GalT-KO xenogeneic skin grafts leads to an anti-non-Gal humoral response with no evidence for cross-sensitization to alloantigens.  These data suggest that GalT-KO skin grafts could provide an early first line clinical approach for severe burns that would not preclude subsequent use of allografts.