2011 - CTS-IXA


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Parallel Session 12- Preclinical Models - Vascular and cellular organs (Xeno Track)

22.333 - Nonhuman primates may fail to serve as an adequate model for studying extracorporeal porcine liver perfusion

Presenter: Joshua, Waldman, Toledo, United States
Authors: Joshua Waldman1, Linda Goding2, Michael Rees1

333

Nonhuman primates may fail to serve as an adequate model for studying extracorporeal porcine liver perfusion

Joshua Waldman1, Linda Goding2, Michael Rees1

1Urology, University of Toledo Medical Center, Toledo, MI; 2NIAID, National Institutes of Health, Bethesda, MD; United States

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 these patients is the use of extracorporeal liver perfusion (ECLP) with a porcine liver to serve as a form of “liver dialysis”. Previously, our laboratory has shown that during a 72 hour extracorporeal perfusion with human blood, porcine Kupffer cells (KC) bind to and phagocytose human red blood cells (hRBCs) causing the hematocrit to fall to 2.5% of the original value. Furthermore, we have identified N-acetylneuraminic acid (Neu5Ac) on the surface of the hRBC as the ligand being bound and sialoadhesin on the surface of the porcine KC as the lectin receptor mediating erythrocyte removal. The FDA has stated that in order for ECLP with a porcine liver to advance to the clinic as a potential therapy for patients in FHF, data from preclinical studies performed in nonhuman primates (NHP) must first demonstrates the efficacy of this therapy. Given that no primate other than humans express Neu5Ac to the exclusion of Neu5Gc, we evaluated whether porcine ECLP of NHP would provide adequate evaluation of the loss of erythrocytes that might be expected in a clinical trial.

Methods: We evaluated the ability of porcine macrophages to recognize erythrocytes from various NHPs including those classically used in pre-clinical xenotransplantation studies.

Results: The ability of porcine macrophages to recognize hRBCs is significantly greater than their ability to recognize RBCs from all NHPs tested (p <0.001, see Table that shows binding as a percent of human RBC binding to porcine macrophages).

Conclusions: This study suggests that the mechanism of erythrocyte loss seen in pig liver/human blood xenoperfusion is not replicated by nonhuman primate erythrocytes. Therefore, NHP may not be an adequate model for studying extracorporeal porcine liver xenoperfusion.


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