Akita K, Ogawa M, Mandel T E
Transplantation Unit, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Cell Transplant. 1994 Jan-Feb;3(1):61-73. doi: 10.1177/096368979400300110.
Varying doses of FK506, and a cell-depleting anti-CD4 monoclonal antibody, GK1.5, were tested as either monotherapy or in combination for their effect on the survival of renal subcapsular xenografts of organ-cultured fetal pig pancreas in three strains of mice. Subcutaneous injections of FK506 at 4.0 mg/kg/day for 28 d prevented graft rejection to day 35 posttransplantation (i.e., 7 days after cessation of treatment in NOD/Lt, and CBA mice) while BALB/c mice had intact grafts at 28 days. Lower doses were less effective and immunosuppression was less effective in NOD mice than in the other strains. Even 2.0 mg/kg/day of FK506 prevented rejection in CBA mice until day 35, but not in NOD/Lt mice. GK1.5 alone did not prevent rejection in NOD/Lt mice but when a low dose of FK506 (2.0 mg/day) was added, the grafts were present, essentially intact, at 35 days. There were no obvious toxic effects of FK506 in NOD/Lt and CBA mice. With FK506 treatment there was no significant difference in absolute numbers of total leucocytes or lymphocytes in peripheral blood and spleen, but there was a decrease in thymus cellularity. Flow cytometric analysis of lymphocyte subsets in blood and spleen also showed no significant differences, but in the thymus the percentage of immature CD4/CD8 "double positive" cells increased while the more mature CD3"high", and CD4 or CD8 "single-positive" cells decreased. Thus, prolonged discordant xenograft survival in mice is possible and the use of two agents that act on different parts of the immune system allows a reduction in the dose of FK506 to safe levels.
在三种品系的小鼠中，测试了不同剂量的FK506和一种细胞清除性抗CD4单克隆抗体GK1.5作为单一疗法或联合疗法对器官培养的胎猪胰腺肾被膜下异种移植物存活的影响。以4.0mg/kg/天的剂量皮下注射FK506，持续28天，可防止移植后35天（即NOD/Lt和CBA小鼠停止治疗7天后）的移植物排斥反应，而BALB/c小鼠在28天时移植物仍完好无损。较低剂量的效果较差，并且在NOD小鼠中免疫抑制效果不如其他品系。即使是2.0mg/kg/天的FK506也能防止CBA小鼠在35天前发生排斥反应，但对NOD/Lt小鼠无效。单独使用GK1.5不能防止NOD/Lt小鼠的排斥反应，但当添加低剂量的FK506（2.0mg/天）时，移植物在35天时仍基本完好。FK506对NOD/Lt和CBA小鼠没有明显的毒性作用。用FK506治疗后，外周血和脾脏中白细胞或淋巴细胞的绝对数量没有显著差异，但胸腺细胞数量减少。对血液和脾脏中淋巴细胞亚群的流式细胞术分析也没有显示出显著差异，但在胸腺中，未成熟的CD4/CD8“双阳性”细胞百分比增加，而更成熟的CD3“高表达”以及CD4或CD8“单阳性”细胞减少。因此，小鼠中延长的非协调性异种移植物存活是可能的，并且使用作用于免疫系统不同部位的两种药物可将FK506的剂量降低到安全水平。
