Corneal Xenotransplantation: Lessons From Allograft Immunobiology and Emerging Translational Strategies

ABSTRACT

Corneal transplantation is an effective sight‐restoring procedure, yet its global impact remains constrained by limited and uneven access to human donor tissue and by immune‐mediated graft failure, particularly in high‐risk recipients. Xenotransplantation offers a potentially scalable alternative, but successful clinical translation requires an understanding of how xenogeneic immune responses differ from, and build upon, the mechanisms governing corneal allograft rejection. This review critically examines the immunologic lessons from corneal allotransplantation that are most relevant to xenograft development and evaluates current evidence for porcine corneal xenotransplantation. We focus on the conditional nature of corneal immune privilege, antigen‐recognition pathways, and the relationship between donor tissue burden and immune exposure. Particular emphasis is placed on fresh cellular porcine corneal xenotransplantation and non‐human primate studies, which demonstrate that prolonged graft survival is achievable but remains dependent on control of T‐cell responses, antibody production, complement activation, and macrophage‐mediated injury. Porcine corneal xenoantigens, including α‐Gal and non‐Gal epitopes, further distinguish xenogeneic from allogeneic transplantation. Emerging strategies include genetically engineered donor pigs, targeted immunosuppression and costimulation blockade, tissue‐selective lamellar and endothelial xenografts, and decellularized or hybrid constructs designed to reduce xenogeneic antigenic burden. Collectively, current evidence suggests that clinical corneal xenotransplantation is unlikely to depend on a single strategy. Rather, durable and scalable graft survival will likely require an indication‐specific combination of donor modification, immune modulation, and graft design. Lessons from corneal allotransplantation therefore provide an important framework for determining which immune barriers can be reduced through tissue selection and which remain unique to the cross‐species setting.