Antibody-mediated rejection (AMR) is a barrier to successful long-term xenograft survival. We compared AMR in kidney xenotransplantation to sensitized kidney allotransplantation in a NHP model. With conventional CNI- based immunosuppressive maintenance, both groups showed limited graft survival with strong AMR features such as interstitial hemorrhage, thrombotic microangiopathy, peritubular capillaritis, and glomerulitis without T cell mediated rejection. The strong similarity between sensitized allo- and unsensitized xeno-rejection suggests a possible common mechanism of rejection in xeno- and sensitized allotransplantation. Currently pig to primate graft survival has markedly improved with interruption of the CD28/B7 and CD40/CD154 costimulation pathways. In theory, the same regimen should control the immune response against xenografts in allosensitized animals. Therefore, further investigation is warranted to evaluate the current successful costimulation blockade-based regimen that has shown great efficacy in xenotransplantation to determine if this strategy may apply as well to sensitized recipients.
Xenotransplantation is a conceptually attractive means of providing an adequate supply of organs for transplantation and may particularly benefit HLA-sensitized patients. Most HLA-sensitized patients are precluded from transplantation due to their poor outcome and their numbers on the organ transplant waiting lists are growing. Pharmacologic blockade of costimulation pathways has produced markedly prolonged pig-to-primate graft survival and has reproducibly provided proof of principle for clinical xenotransplantation. In theory, patients sensitized to other human HLA antigens are not sensitized to pig donors, and therefore preformed HLA antibody may not increase the risk of rejection of a xenotransplant. However, there is no existing preclinical data to support clinical xenotransplantation for sensitized patients. Our group has developed a preclinical allosensitized kidney transplantation model and will study strategies that will facilitate the design of a clinical xenotransplantation trial in a sensitized setting.
