Effect of αGal on corneal xenotransplantation in a mouse model

Background: It has been reported that hyperacute rejection (HAR) does not occur after pig-to-nonhuman corneal xenotransplantation. However, considering that immune privilege is already disrupted in most human corneal recipients, and the expression of alpha Gal can be gradually reduced after pig-to-rat corneal transplantation, the long-term survival of corneal grafts from wild-type pigs cannot be guaranteed. Accordingly, we aimed to investigate the effect of alpha Gal on the change in anti-Gal antibodies, using sensitized alpha 1,3-galactosyl-transferase gene-knockout (GTKO) mice recipients. Methods: C57BL/6 (B6) and GTKO mice were divided into 5 groups and underwent orthotopically full thickness cormeal transplantation as follows (n=4 for each group): (1) group 1: B6 to B6; (2) group 2: fresh porcine posterior corneal lamella to B6; (3) fresh porcine posterior corneal lamella to GTKO; (4) group 4: decellularized porcine posterior corneal lamella to GTKO, and (5) group 5: B6 to GTKO. Before transplantation, all GTKO recipients were sensitized using intraperitoneal injections of rabbit blood cells. Median survival times (MST) for the corneal grafts of the different groups were compared and plasma concentrations of IgG/IgM anti-Gal antibodies were evaluated at 1 week, 2 weeks and 3 weeks post-transplantation. Results: There were no differences in MSTs between groups. Although there was no HAR of fresh porcine posterior corneal grafts even in sensitized GTKO recipients, alpha Gal expression was induced in the transplanted fresh porcine corneal grafts and plasma concentration of IgG anti-Gal antibody was gradually increased in fresh porcine corneagrafted GTKO recipients. On the contrary, alpha Gal expression did not increase in the grafts and plasma concentration of anti-Gal antibodies did not change after transplantation using decellularized porcine corneas. Conclusions: Our findings suggest that alpha Gal may affect the long-term survival of porcine corneal xenografts via antibody-mediated rejection, although alpha Gal does not have an effect on acute rejection and decellularized porcine corneas may enable the long-term survival of porcine corneal xenografts.