Hepatocyte transplantation for enzyme deficiency disease in congenic rats.

Long-term effects of hepatocyte transplantation (HTX) in the treatment of enzyme deficiency disease were studied. Congenic enzyme-deficient (R/APfd-j/j) and non-enzyme-deficient (R/APfd) rats were used as recipients and donors, respectively. The R/APfd-j/j rat strain is congenitally deficient of bilirubin uridyldiphosphate (UDP)-glucuronyl transferase. R/APfd-j/j rats underwent HTX by intrasplenic injection of 10(7) isolated R/APfd hepatocytes (group 1A). Another group of R/APfd-j/j rats was treated similarly, but underwent splenectomy after 11 weeks (group 1B). Controls consisted of R/APfd-j/j rats grafted with 10(7) R/APfd-j/j hepatocytes (group 2), and R/APfd-j/j rats that underwent a sham operation (group 3). Total plasma bilirubin (TB) levels were significantly reduced in groups 1A and 1B during the experiment (both P less than 0.01). In the control groups TB reduction was not observed. Bile analyses at 30 weeks after HTX showed that in group 1A 13.7 +/- 2.7% of total biliary bilirubin was conjugated. In group 1B a significantly lower fraction was conjugated: 6.6 +/- 1.1% (P less than 0.05). Conjugated bilirubin was not found in bile of groups 2 and 3. Histology showed survival of hepatocytes in all spleens of rats of groups 1A, 1B and 2. It is concluded that congenic hepatocytes from R/APfd donors are not rejected after transplantation into the R/APfd-j/j rat, and maintain long-term function. Splenectomy does not abolish, but does reduce, the therapeutic effect significantly, indicating that part of the transplanted hepatocytes maintains function in the enzyme-deficient host liver. The congenic R/APfd-j/j and R/APfd rat strains represent a new animal model for research in metabolic deficiency disease.