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，而由于先前移植的肝细胞的作用耗尽，因此重复移植MHC抗原。在这项研究中，我们研究了抗CD4mAb的有效性，它已被证明在致敏大鼠中诱导移植耐受。移植到脾中的同种异体肝细胞在未经任何免疫抑制处理的几天内发生组织学排斥反应(F344对Lus；3-4天；F344对WKA；1-2天)。而环孢素A可延长小鼠肝细胞存活时间(F344比Lus；&Gt延长3周，F344比WKA延长3~4天)。另一方面，RIB-5/2(一种非耗竭的CD4mAb)对大鼠的存活没有影响。移植后的每一天。排斥肝细胞边缘不清，胞质稀少，核固缩或巨细胞形成，与未治疗大鼠相似。同一供体大鼠在RIB-5/2处理的第一次肝细胞移植后12天，二次肝细胞移植到脾内，没有明确的移植物存活。根据这些结果，RIB-5/2单独应用对同种异体肝细胞移植没有免疫抑制作用，在致敏期使用RIB-5/2可能不能诱导对致敏宿主的耐受。在同种异体肝细胞移植排斥反应中，CD_4~+T细胞和CD_8~+T细胞似乎是独立发挥作用的，因此不存在与“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.