CORRECTION OF CONGENITAL HYPERBILIRUBINEMIA IN HOMOZYGOUS GUNN-RATS BY XENOTRANSPLANTATION OF HAMSTER LIVERS

The homozygous Gunn(j/j) rat is an animal model for crigler-Najjar syn drome in which the lack of the enzyme uridine diphosphoglucoronate-glu curonosyltransferase (UDP-GT) results in congenital unconjugated nonhe molytic hyperbilirubinemia., Because the binding of bilirubin to album in in plasma varies from species to species, xenotransplantation (XTx) of fiver afforded in this model the opportunity to study the interact ions between xenoproteins of the donor and bilirubin of the recipient. For this purpose, orthotopic liver transplantation (OLTx) was perform ed 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/da y x 15 days, IM) and cyclophosphamide (8 mg/kg/day x 7 days, IF) were administered to animals receiving hamster xenografts (Group III, n=11) . While untreated animals (Group I) died within 7 days (6.8+/-0.2 days ) post-transplantation (Tx), the use however of IS resulted in prolong ed (30.2+/-6.8 days) survival of xenogeneic recipients (Group III) who eventually succumbed to rejection, A precipitous decline in total ser um 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 observati on that sustained itself only in the latter group during the course of their follow-up, The decrease in TBili was also associated with a con temporaneous 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 xenoprote ins and enzymes involved in the process of membrane transport and gluc uronidation 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 follow-up.