Antibody Mediated Rejection in Pig-To-Nonhuman Primate Xenotransplantation Models

Abstract

Antibody-mediated mechanisms are central to the rejection that occurs when pig organs are transplanted into primates. In this article, the histopathological features of the humoral rejection process in these species combinations, namely hyperacute rejection and acute humoral xenograft rejection, will be illustrated. The profile of the natural and elicited antibodies involved will also be discussed. It has now been demonstrated that the natural immune response to a porcine xenograft is primarily directed to Galalpha1-3Gal (alphaGal) specificities, whilst the elicited immune response is directed to both alphaGal and non-alphaGal antigens. The principal characteristics of anti-alphaGal, anti-non-alphaGal and polyreactive antibodies will be described, together with the identification of the molecules recognised by natural and elicited xenoreactive antibodies. The role of the humoral immune response in the rejection of porcine islets in the primate is still uncertain and the current views on the subject will be discussed. Finally, a concise but comprehensive review of the different strategies that have been attempted to prevent the onset of antibody-mediated rejection is presented. These strategies encompass approaches aimed at interfering with the binding of xenoreactive antibodies with their targets, the use of conventional or novel immunosuppressants and splenectomy. It is undeniable that significant progress has been recently achieved in understanding the humoral rejection process of pig organs transplanted into primates. It is expected that a more comprehensive elucidation of the mechanisms underlying accommodation and tolerance may, in the not too distant future, further extend survival of pig organs transplanted into primates.

An Update on Xenotransplantation

“…Several lines of evidence support the importance of both anti-aGal and anti-non-aGal antibodies in the establishment of AHXR (as reviewed by Cozzi et al, 2005). In particular, the relevance of anti-non-aGal immunoglobulins has recently been demonstrated in a study by Kuwaki and colleagues (Kuwaki et al, 2005) where AHXR was observed in 5/8 cases of heterotopic aGalT j/j pig heart transplantation to baboons.…”

“…The removal of XNA has been achieved by ex vivo serum perfusion, plasmapheresis, and XNA neutralisation, (reviewed in Cozzi et al, 2005). Similarly, advancements in cloning strategies in large animal models have recently allowed the development of genetically modified pigs lacking the galactosyltransferase gene (aGalT j/j ), and hence aGal epitopes (Lai et al, 2002).…”

Reduced Fibrin Deposition and Intravascular Thrombosis in hDAF Transgenic Pig Hearts Perfused With Tirofiban

“…The pathogenic mechanism of early (hyperacute rejection) and delayed humoral xenograft rejection (acute vascular rejection, also called acute humoral xenograft rejection) includes a distortion of endothelial shape caused by the binding of antibodies to the endothelium and activation of the complement cascade (3). Activation and change of the endothelial cell lining mediates the change from an anticoagulant to a procoagulant state, and allows the immediate interaction of circulating platelets with the matrix underlying the endothelial cells, resulting in platelet activation and aggregation (4,5).…”

Xenotransplantation Literature Update May–June, 2005

“…During the period, May to June 2005, six reviews on xenotransplantation were published [1][2][3][4][5][6]. Vodicka et al [1] discussed the use of the miniature pig as a model in biomedical research.…”

“…Cozzi et al [5] summarized the role of antibodies in the rejection process of pig-to-non-human primate xenografts. The authors discussed the pathophysiology of hyperacute xenograft rejection and acute humoral xenograft rejection, and illustrated different strategies that had been attempted to prevent the onset of antibody-mediated rejection.…”