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

肝细胞移植目前面临的主要问题是宿主对MHC抗原的致敏性，由于先前移植的肝细胞的作用耗尽而反复移植。在这项研究中，我们研究了抗CD4单抗的有效性，它已被证明可以诱导致敏大鼠的移植耐受。同种异体肝细胞移植到脾脏后，未经任何免疫抑制（F344对LEWS； 3-4天；F344对WKA； 1-2天），在几天内发生组织学排斥反应。然而，给予环孢素A可延长肝细胞生存期（F344至LEWS； bbbb3周；F344至WKA； 3 ~ 4天）。另一方面，移植后每天用RIB-5/2（一种非耗竭CD4单抗）治疗的大鼠没有获得生存效果。排斥肝细胞边界不清，细胞质稀少，组织学上核固缩或巨细胞形成，与未治疗大鼠相似。在第一次肝细胞移植12天后，在RIB-5/2治疗下，将同一供体的肝细胞移植到脾脏中，没有明确的移植物存活。由此可见，单独使用RIB-5/2对同种异体肝细胞移植没有免疫抑制作用，可能在致敏期即使使用RIB-5/2也不能诱导致敏宿主耐受。CD4^+ T细胞和CD8^+ T细胞似乎在肝细胞异体移植排斥反应中独立起作用，导致没有与“感染性”耐受相关的免疫事件。

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.