Genetic modification of pigs as organ donors for xenotransplantation

Transgenic pigs are promising donor organisms for xenotransplantation as they share many anatomical and physiological characteristics with humans. The most profound barrier to pig-to-primate xenotransplantation is the rejection of the grafted organ by a cascade of immune mechanisms commonly referred to as hyperacute rejection (HAR), acute humoral xenograft rejection (AHXR), immune cell-mediated rejection, and chronic rejection. Various strategies for the genetic modification of pigs facilitate tailoring them to be donors for organ transplantation. Genetically modified pigs lacking alpha-1,3-Gal epitopes, the major xenoantigens triggering HAR of pig-to-primate xenografts, are considered to be the basis for further genetic modifications that can address other rejection mechanisms and incompatibilities between the porcine and primate blood coagulation systems. These modifications include expression of human complement regulatory proteins, CD39, endothelial protein C receptor, heme oxygenase 1, thrombomodulin, tissue factor pathway inhibitor as well as modulators of the cellular immune system such as human TNF alpha-related apoptosis inducing ligand, HLA-E/beta-2-microglobulin, and CTLA-4Ig. In addition, transgenic strategies have been developed to reduce the potential risk of infections by endogenous porcine retroviruses. The protective efficacy of all these strategies is strictly dependent on a sufficiently high expression level of the respective factors with the required spatial distribution. This review provides an overview of the transgenic approaches that have been used to generate donor pigs for xenotransplantation, as well as their biological effects in in vitro tests and in preclinical transplantation studies. A future challenge will be to combine the most important and efficient genetic modifications in multi-transgenic pigs for clinical xenotransplantation.