Livng-donor liver transplantation combined with donor-derived bone maroow hematopoietic cells as a treatment for advanced hepatocellular carcinoma

我们建立了小鼠骨髓移植（BMT）模型。BMT的预处理用抗肿瘤剂环磷酰胺（环磷酰胺）进行。BALB/c和C57 BL/6小鼠分别作为受体和供体。将供体来源的骨髓细胞以200 mg/kg的剂量给予后移植到受体中。因此，用BALB/c小鼠源性肿瘤细胞系colon 26建立荷瘤小鼠模型，以评价BMT的移植物抗肿瘤效应。将结肠26细胞皮下注射到受体，并在预处理后移植供体来源的骨髓细胞或脾细胞。异基因骨髓移植具有明显的抗肿瘤作用。然而，许多受者死于系统性GVHD。因此，我们试图开发一种新的方案来控制异基因大鼠模型中的GVHD，在该模型中可以容易地进行嵌合体的连续血液监测。发现降低剂量的顺铂（150 mg/kg）诱导骨髓嵌合体，而没有GVHD。此外，即使在200 mg/kg剂量下，FK 506的短暂使用也可抑制GVHD。通过该方案，在心脏移植模型和MLR中建立了供体特异性耐受。由于该方案具有抗肿瘤作用，且不需要长期免疫抑制，因此有可能应用于晚期肝癌的肝移植。

We established a bone marrow transplantation (BMT) model in mice. Preconditioning for BMT was performed with an anti-tumor agent, cyclophosphamide (CYP). BALB/c and C57BL/6 mice were used as recipients and donors. Donor-derived bone marrow cells were transplanted to the recipient after administration of CYP at a dose of 200mg/kg. Consequently, tumor-bearing mouse model was established with a BALB/c mouse-derived tumor cell line, colon 26 to evaluate graft-versus-tumor effect by BMT. Cells of colon 26 was injected subcutaneously to the recipient, and donor-derived bone marrow cells or splenocytes were transplanted alter CYP preconditioning. Allogeneic BMT exerted significant anti-tumor effect. However, many recipients died of systemic GVHD. Then we tried to develop new protocols to control GVHD in an allogeneic rat models in which serial blood monitoring of chimerism can be performed easily. A reduced dose of CYP (150mg/kg) was found to induce bone marrow chimerism without GVHD. Additionally transient use of FK506 inhibited GVHD even with a dose of 200mg/kg CYP. With this protocol donor-specific tolerance was established in a heart transplantation model and MLR. Because this protocol have anti-tumor effect and does not require chronic immunosuppression, it may be applied to liver transplantation for advanced hepatocellular carcinoma.