The Pathobiology of Pig-to-Primate Xeno.: A Historical Review

The immunologic barriers to successful xenotransplantation are related to the presence of natural anti-pig antibodies in humans and nonhuman primates that bind to antigens expressed on the transplanted pig organ (the most important of which is galactose-α1,3-galactose [Gal]) and activate the complement cascade, which results in rapid destruction of the graft, a process known as hyperacute rejection. High levels of elicited anti-pig IgG may develop if the adaptive immune response is not prevented by adequate immunosuppressive therapy, resulting in activation and injury of the vascular endothelium. The transplantation of organs and cells from pigs that do not express the important Gal antigen (α1,3-galactosyltransferase gene-knockout [GTKO] pigs) and express one or more human complement-regulatory proteins (hCRP, e.g., CD46, CD55), when combined with an effective costimulation blockade-based immunosuppressive regimen, prevents early antibody-mediated and cellular rejection. However, low levels of anti-nonGal antibody and innate immune cells and/or platelets may initiate the development of a thrombotic microangiopathy in the graft that may be associated with a consumptive coagulopathy in the recipient. This pathogenic process is accentuated by the dysregulation of the coagulation–anticoagulation systems between pigs and primates. The expression on GTKO/hCRP pigs of a human coagulation-regulatory protein, e.g., thrombomodulin, is increasingly being associated with prolonged pig graft survival in nonhuman primates.