INTRASPLENIC HEPATOCYTE ALLOTRANSPLANTATION IN DALMATIAN DOGS WITH AND WITHOUT CYCLOSPORINE IMMUNOSUPPRESSION1

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Abstract
Hepatocyte allotransplantation has been performed successfully in several small animal models for the amelioration of inborn metabolic errors. Before a human clinical trial of hepatocyte allotransplantation can be attempted, preliminary experience in a large animal model is needed. We transplanted isolated mongrel hepatocytes into the spleen of dalmatians in the attempt to cure their inborn error of uric acid metabolism. Of 10 dalmatian recipients, two that received 9-10 x 10(9) mongrel hepatocytes died early after surgery of acute portal hypertension and hemorrhage. The eight long-term survivors received 5-6 x 10(9) hepatocytes and were randomized either to no treatment or to oral cyclosporine (CsA). Levels of CsA were adjusted to maintain trough levels between 400 and 800 ng/ml. In the four nonimmunosuppressed dalmatians, a reproducible average reduction in urinary uric acid excretion (UUAEx) of 23.7% was achieved; values returned to baseline within 14 days. In the CsA-immunosuppressed dalmatians, the average decline in UUAEx was 30%. The partial correction of the metabolic defect persisted for an average of 25 days in three immunosuppressed dogs, whereas in one dog, the partial correction lasted for over 90 days. No change in UUAEx was observed in two dalmatians that underwent sham laparotomy and intrasplenic injection of saline solution; CsA given alone to dalmatians did not modify UUAEx. We conclude that the dalmatian dog is a valuable large animal model for studies of the role of hepatocyte transplantation in the cure of inborn hepatic metabolic errors.