The Potential Role of Expression of HLA‐E and HLA‐G in Organ Xenotransplantation

ABSTRACT

Xenotransplantation offers a promising solution to the shortage of human organs for transplantation but requires overcoming numerous immune responses—particularly those mediated by the innate immune system through natural killer (NK) cells and macrophages. This review examines advances demonstrating that the expression of human leukocyte antigen E (HLA‐E) on porcine cells contributes to reduce cellular xenograft rejection. HLA‐E expression partially inhibits both direct NK cell cytotoxicity and antibody‐dependent cellular cytotoxicity (ADCC), while also attenuating macrophage‐mediated lysis. Furthermore, perfusion of transgenic porcine organs expressing HLA‐E with human blood resulted in significantly less tissue damage compared to wild‐type counterparts, thereby confirming the protective effect of HLA‐E against innate immunity. Inhibition of NK cell activation can be further enhanced by co‐expression of HLA‐G and HLA‐E. These findings confirm the potential of HLA‐E and HLA‐G expression as a complementary strategy in the design of immune‐compatible porcine organs for clinical xenotransplantation.