GalT-KO pig lungs are highly susceptible to acute vascular rejection in baboons, which may be mitigated by transgenic expression of hCD47 on porcine blood vessels.

Abstract

Despite recent progress in survival times of xenografts in non-human primates, there are no reports of survival beyond 5days of histologically well-aerated porcine lung grafts in baboons. Here, we report our initial results of pig-to-baboon xeno-lung transplantation (XLTx). Eleven baboons received genetically modified porcine left lungs from either GalT-KO alone (n=3), GalT-KO/humanCD47(hCD47)/hCD55 (n=3), GalT-KO/hD47/hCD46 (n=4), or GalT-KO/hCD39/hCD46/hCD55/TBM/EPCR (n=1) swine. The first 2 XLTx procedures were performed under a non-survival protocol that allowed a 72-hour follow-up of the recipients with general anesthesia, while the remaining 9 underwent a survival protocol with the intention of weaning from ventilation. Lung graft survivals in the 2 non-survival animals were 48 and >72hours, while survivals in the other 9 were 25 and 28hours, at 5, 5, 6, 7, >7, 9, and 10days. One baboon with graft survival >7days, whose entire lung graft remained well aerated, was euthanized on POD 7 due to malfunction of femoral catheters. hCD47 expression of donor lungs was detected in both alveoli and vessels only in the 3 grafts surviving >7, 9, and 10days. All other grafts lacked hCD47 expression in endothelial cells and were completely rejected with diffuse hemorrhagic changes and antibody/complement deposition detected in association with early graft loss. To our knowledge, this is the first evidence of histologically viable porcine lung grafts beyond 7days in baboons. Our results indicate that GalT-KO pig lungs are highly susceptible to acute humoral rejection and that this may be mitigated by transgenic expression of hCD47.