Physiology
The existence of potential physiological incompatibilities between donor and recipient in the context of xenotransplantation are an important consideration. Currently, because of their comparable organ size, rapid growth rate, large litters, the possibility of genetic manipulation and fewer ethical concerns than other species, pigs are considered to be the most appropriate organ source. Whilst physiological incompatibilities between pigs and primates are recognised, to date these do not appear to represent an insurmountable challenge to the long-term survival of porcine renal or cardiac xenografts. Such incompatibilities include molecular differences between the complement and coagulation systems of pigs and primates. Some have also hypothesised that anaemia, often observed in renal pig-to-primate xenotransplantation, could be related to the inability of porcine erythropoietin adequately to stimulate primate haematopoietic precursors, although conclusive evidence is still lacking.
As far as coagulation is concerned, it is of note that porcine von Willebrand Factor interacts with human platelet receptors with high affinity, possibly resulting in elevated pro-coagulant activity. Porcine tissue factor pathway inhibitor (TFPI) is not able to neutralize human factor Xa, and is therefore unable to inhibit the direct activation of human prothrombin to thrombin. In addition, although porcine thrombomodulin has been shown to bind human thrombin and Protein C, the human thrombin-porcine thrombomodulin complex is a poor activator of Protein C. The insufficient production of activated Protein C contributes to enhanced levels of thrombin favouring the initiation of clotting. Approaches such as the use of platelet fibrinogen receptor antagonist (GPIIbIIIa), P-selectin inhibitor and soluble ATP diphosphohydrolase (ATPDase/CD39, the major vascular nucleoside triphosphate diphosphohydrolase, whose activity generates the anti-thrombotic and anti-inflammatory mediator adenosine) may provide some benefit in prolonging the survival of xenografted organs in primates but have yet to be tested (as reviewed by Robson et al.).
Furthermore, transgenic modulation of the clotting cascade by de novo expression or induction of anticoagulants, or elimination of pro-coagulant molecules on xenogenic vascular endothelium, may represent an additional potential therapeutic strategy. In this context, several target gene candidates for transgenic expression (e.g. CD39, TFPI, thrombomodulin, hirudin, CD73), or knock-out (e.g. Tissue Factor, PAR3, PAR4, Fgl-2) in pig tissues have been identified. Encouraging results, although only obtained in vitro and in small animal models, have provided a basis for the future genetic manipulation of porcine organs, able to overcome thrombotic events that compromise xenograft survival.
Notwithstanding the physiological differences reported and the advantages that transgenesis may provide, studies in non-human primates suggest that porcine heart and kidney are able to work in primates and sustain their life for up to several months. During such a time, the organs support normal levels of activity, with the recipients exhibiting normal social behaviour. Together, these observations suggest that an adequate control of the immune response such as that achieved by Lin et al. could mitigate the functional significance of the physiological differences reported, further extending the survival of transplanted pig organs in the primate.
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