INDUCTION AND MAINTENANCE OF IMMUNOLOGICAL TOLERANCE IN REPEATED HEPATOCYTE TRANSPLANTATIONS FOR THE CONGENITAL HEPATIC ENZYME DEFICIENCY DISEASES

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Major problem facing hepatocytes transplantation now is host sensitization to MHC antigens which were transplanted repeatedly because of a depletion of effects of previously transplanted hepatocytes. In this study, we investigated the usefulness of anti CD4 mAb, which had been proven to induce transplantation toleranse in sensitized rats.Allogeneic hepatocytes transplanted into the spleen were histologically rejected within several days when untreated with any immunosuppression (F344 to LEWS; 3-4 days, F344 to WKA; 1-2 days). However, administration of ciclosporine A achieved prolongation of hepatocytes survival (F344 to LEWS; > 3weeks, F344 to WKA; 3 〜 4days). On the other hand, no survival effect was obtained in the rats, which were treated with RIB-5/2 (a nondepleting CD4 mAb.) every day after the transplantation. Rejected hepatocytes showed unclear margin with a scanty cytoplasm and nuclear pyknosis or giant cell formation histologically, similar to that of untreated rats.Secondary hepatocytes transplantation from the same donor strain into the spleen 12 days after the first hepatocytes transplantation under the treatment with RIB-5/2, demonstrated no definite graft survival.According to these results, RIB-5/2 alone does not have immunosuppresed effects to the allogeneic hepatocytes transplantation, and probably can not induce toleranse to sensitized hosts in spite of the usage of this agent during the sensitization period. It seems that CD4^+ T cells and CD8^+ T cells independently work in hepatocellular allograft rejection, leading to no immune events associated with "infectious" toleranse.