Milestones on the path to clinical pig organ xenotransplantation.

Progress in pig organ xenotransplantation has been made largely through (1) genetic engineering of the organ-source pig to protect its tissues from the human innate immune response, and (2) development of an immunosuppressive regimen based on blockade of the CD40/CD154 costimulation pathway to prevent the adaptive immune response. In the 1980s, after transplantation into nonhuman primates (NHPs), wild-type (genetically unmodified) pig organs were rejected within minutes or hours. In the 1990s, organs from pigs expressing a human complement-regulatory protein (CD55) transplanted into NHPs receiving intensive conventional immunosuppressive therapy functioned for days or weeks. When costimulation blockade was introduced in 2000, the adaptive immune response was suppressed more readily. The identification of galactose-α1,3-galactose as the major antigen target for human and NHP anti-pig antibodies in 1991 allowed for deletion of expression of galactose-α1,3-galactose in 2003, extending pig graft survival for up to 6 months. Subsequent gene editing to overcome molecular incompatibilities between the pig and primate coagulation systems proved additionally beneficial. The identification of 2 further pig carbohydrate xenoantigens allowed the production of 'triple-knockout' pigs that are preferred for clinical organ transplantation. These combined advances enabled the first clinical pig heart transplant to be performed and opened the door to formal clinical trials.