Correction of congenital hyperbilirubinemia in homozygous Gunn rats by xenotransplantation of hamster livers

Abstract

The homozygous Gunn j/j rat is an animal model for Crigler-Najjarsyndrome in which the lack of the enzyme uridine diphosphoglucoronate-glucuronosyltransferase (UDP-GT) results in congenital unconjugated nonhemolytic hyperbilirubinemia. Because the binding of bilirubin to albumin in plasma varies from species to species, xenotransplantation (XTx) of liver afforded in this model the opportunity to study the interactions between xenoproteins of the donor and bilirubin of the recipient. For this purpose, orthotopic liver transplantation (OLTx) was performed from hamster to adult Gunn j/j rats. No immunosuppression (IS) was given to controls. (Group I, n=5) and to OLTx recipients of syngeneic (Gunn j/j rat) grafts (Group II, n=5), whereas tacrolimus (1 mg/kg/ day × 15 days, IM) and cyclophosphamide (8 mg/kg/day × 7 days, IP) were administered to animals receiving hamster xenografts (Group III, n=l1). While untreated animals (Group I) died within 7 days (6.8±0.2 days) post-transplantation (Tx), the use however of IS resulted in prolonged (30.2±6.8 days) survival of xenogeneic recipients (Group III) who eventually succumbed to rejection. A precipitous decline in total serum bilirubin (TBili) from pre-operative levels of 5.3±1.0 mg/dL to 0.5±0.2 mg/dL was noted in both Group I and III animals, an observation that sustained itself only in the latter group during the course of their follow-up. The decrease in TBili was also associated with a contemporaneous increase in biliary concentration of conjugated bilirubin. No noticeable reversal of hyperbilirubinemia was however observed in OLTx recipients of syngeneic grafts (Group II). Taken together, these data suggest that hamster albumin and hepatocyte-associated xenoproteins and enzymes involved in the process of membrane transport and glucuronidation of bilirubin, functioned efficaciously after OLTx in Gunn j/j , rats, resulting in the reversal of the inborn error of metabolism for the duration of followup.

Prospects for Xenotransplantation of the Liver

“…24,25 The major limitation to hepatocyte xenotransplantation may be the incompatibility of secreted donor proteins with proteins of the recipient. 26…”