2010 - TTS International Congress


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Late Breaking I

96.6 - Nonhuman Primates May Fail to Serve as an Adequate Model for Studying Extracorporeal Porcine Liver Perfusions

Presenter: Joshua, Waldman, Toledo, United States
Authors: Waldman J., Rees M.

NONHUMAN PRIMATES MAY FAIL TO SERVE AS AN ADEQUATE MODEL FOR STUDYING EXTRACORPOREAL PORCINE LIVER PERFUSIONS

LATE BREAKING I

J.P. Waldman1, M. Rees2
1Urology, e University of Toledo Medical College of Medicine, Toledo/OH/UNITED STATES OF AMERICA, 2Urology, UNIV TOLEDO MED CENTER, TOLEDO/OH/UNITED STATES OF AMERICA

Body: Introduction: Patients in fulminate hepatic failure (FHF) currently do not have a temporary means of support while awaiting a liver transplant. In contrast, patients with end stage kidney disease can live for years on dialysis. A potential therapeutic approach for patients with FHF is the use of extracorporeal liver perfusion (ECLP) with porcine livers as a form of “liver dialysis.” During a 72 hour extracorporeal perfusion of porcine livers with human blood, porcine Kupffer cells bind to and phagocytose human red blood cells (hRBCs) causing the hematocrit to decrease to 2.5% of the original value. Our laboratory has identified N-acetylneuraminic acid (Neu5Ac) on human RBCs as the ligand being bound and sialoadhesin on porcine Kupffer cells as the lectin receptor. Before allowing clinical trials of porcine liver ECLP, the FDA is requiring additional preclinical data in which primates with FHF are successfully supported using porcine liver ECLP (personal communication, FDA Xenoadvisory Committee meeting, 2009). Given that primate other than humans express minimal amounts of Neu5Ac, we evaluated whether porcine macrophages bound the RBC from several species of Old World Primates. Methods: The ability of porcine macrophages to bind human erythrocytes was quantified using a binding assay. Herein, porcine alveolar macrophages (PAM) adhered to a well in a 96-well plate and tested for their ability to bind human and nonhuman primate erythrocytes. PAM were used as a more readily accessible Kupffer cell-like macrophage source. Results: We have shown that 1) pretreatment of PAM with antibodies specific for porcine sialoadhesin inhibits PAM binding of human erythrocytes; 2) PAM bind nonhuman primate RBCs significantly less than they bind human RBCs (p < 0.001, see Table that shows binding as a percent of human RBC binding to PAM).

RBC Species Isotype Control mAb a-sialoadhesin mAb vs. human p-value
Human 100 + 13 12 + 9
Baboon 9 + 2 7 + 4 0.001
Gibbon 17 + 5 10 + 2 0.0005
DeBrazza 16+ 8 6 + 4 0.0003

Conclusion: This study suggests that a nonhuman primate may not be an adequate model for studying extracorporeal porcine liver perfusions, due to the fact that porcine macrophages do not bind nonhuman primate RBCs. We believe that this lack of binding is caused by the relative paucity of Neu5Ac on all mammalian cells except humans. Only humans have homologously lost the enzyme necessary to convert Neu5Ac to N-glycolylneuraminic acid (Neu5Gc) so that humans preferentially express Neu5Ac as opposed to Neu5Gc. We believe the diminished expression of Neu5Ac on all primates other than humans makes it unlikely that nonhuman primates will serve as an adequate model to study erythrocyte binding during extracorporeal liver perfusion.

Disclosure: All authors have declared no conflicts of interest.


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