INTRASPLENIC HEPATOCYTE ALLOTRANSPLANTATION IN DALMATIAN DOGS WITH AND WITHOUT CYCLOSPORINE IMMUNOSUPPRESSION

Hepatocyte allotransplantation has been performed successfully in seve ral small animal models for the amelioration of inborn metabolic error s, Before a human clinical trial of hepatocyte allotransplantation can be attempted, preliminary experience in a large animal model is neede d, We transplanted isolated mongrel hepatocytes into the spleen of dal matians in the attempt to cure their inborn error of uric acid metabol ism. Of 10 dalmatian recipients, two that received 9-10 x 10(9) mongre l hepatocytes died early after surgery of acute portal hypertension an d hemorrhage, The eight long-term survivors received 5-6 x 10(9) hepat ocytes and were randomized either to no treatment or to oral cyclospor ine (CsA). Levels of CsA were adjusted to maintain trough levels betwe en 400 and 800 ng/ml, In the four nonimmunosuppressed dalmatians, a re producible average reduction in urinary uric acid excretion (UUAEx) of 23.7% was achieved; values returned to baseline within 14 days. In th e CsA-immunosuppressed dalmatians, the average decline in UUAEx was 30 %. The partial correction of the metabolic defect persisted for an ave rage of 25 days in three immunosuppressed dogs, whereas in one dog, th e partial correction lasted for over 90 days. No change in UUAEx was o bserved in two dalmatians that underwent sham laparotomy and intrasple nic injection of saline solution; CsA given alone to dalmatians did no t 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.