Introduction: Before initiating clinical trials of pig kidney or heart xenotransplantation, important questions need to be addressed. (i) Will a patient with a high level of anti-HLA antibodies be at increased risk of rejecting a pig organ graft? (ii) Will a pig organ graft successfully bridge a patient to allotransplantation without an increased risk of rejecting the allograft.

Methods: The literature was reviewed regarding relevant reports of in vitro and in vivo studies in nonhuman primates (NHPs) and humans but not in other species. In most studies, serum anti-pig antibodies were detected using pig RBCs or PBMCs, and their effect was confirmed by a complement-dependent cytotoxicity assay. Allotransplantation after pig xenotransplantation/sensitization studies were limited to (i) pig-to-NHP models, (ii) human subjects exposed to pig antigens during ex vivo pig organ perfusion before allotransplantation, and (iii) immunosuppressed patients with renal allografts who received fetal pig islet-like cells.

Results: Studies in HLA-sensitized subjects: Ten studies reported that cross-reactivity between the anti-HLA immune response and pig antigens are, or maybe, detrimental to the survival of a xenograft, and four studies reported no detrimental effect. The data suggest that approximately 11% of highly HLA-sensitized wait-listed patients demonstrate cross-reactive antibodies, representing only 2% of all wait-listed patients. In a GTKO.CD55 pig-to-monkey kidney transplant model, prior allosensitization resulted in reduced xenograft survival, though survival was improved when TKO pig kidneys expressing multiple human proteins were transplanted.
Studies of allotransplantation after sensitization to pig antigens: NHPs exposed to pig antigens (n=72) did not become sensitized to alloantigens and did not show an increased incidence of allograft rejection. Humans (n=14) exposed to pig antigens by ex vivo perfusion of pig organs before allotransplantation showed no definitive features of early allograft rejection. Patients (n=10) with Type 1 diabetes with functioning renal allografts who received wild-type fetal pig islet-like cells developed xenoreactive antibodies against Gal antigens without any increase in panel-reactive antibodies or detrimental effect on allograft function.  
Conclusions: (i) All patients for whom xenotransplantation is being considered should be tested to ensure that they do not have antibodies against pig RBCs and/or PBMCs. This is particularly important in those with high anti-HLA antibody levels (a high cPRA). (ii) Although based on limited evidence to date, there is little or no evidence that previous sensitization to pig xenoantigens will be detrimental to subsequent allotransplantation.