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Blocking porcine sialoadhesin improves extracorporeal porcine liver xenoperfusion

Joshua Waldman¹, Thomas Vogel², Peter Friend², Michael Rees¹

¹Urology, University of Toledo Medical Center, Toledo, MI, United States; ²Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom

Background: Patients in fulminant hepatic failure (FHF) currently do not have a temporary means of support while awaiting liver transplantation. A potential therapeutic approach for patients in FHF is the use of extracorporeal perfusion with porcine livers as a form of “liver dialysis”. During a 72 hour extracorporeal perfusion of porcine livers with human blood, porcine Kupffer cells (KC) bind to and phagocytose human red blood cells (hRBC) causing the hematocrit to decrease to 2.5% of the original value. Our laboratory has identified sialoadhesin (Sn) on the surface of porcine KC as the lectin responsible for binding N-acetylneuraminic acid (Neu5Ac) on the surface of the hRBC. In order for extracorporeal porcine liver perfusion to be used as a therapy for patients in liver failure, all forms of anti-human rejection must be resolved. We evaluated whether targeting Sn prevents the recognition and subsequent destruction of hRBCs seen during extracorporeal porcine liver xenoperfusion.

Methods: Six wild type pig livers were perfused with isolated hRBCs for 72 hours. In one group, three livers were treated with an anti-Sn antibody. As a control group, three livers were treated with an antibody of the same isotype but with no known specificity for Sn.

Results: We have shown that the addition of an anti-Sn antibody to an extracorporeal porcine liver xenoperfusion model significantly reduces the loss of hRBC over a 72 hour period (p <0.01). Sustained liver function was demonstrated by continued bile production and other markers.

Conclusions: This study suggests that the destruction of human erythrocytes in an extracorporeal porcine liver xenoperfusion model is, in part, mediated by Sn expressed on the surface of porcine KC. Furthermore, this data illustrates that the addition of anti-Sn antibody to the circulation of a pig-to-human xenoperfusion may inhibit the destruction of human erythrocytes by porcine Kupffer cells.