Ellis Ramsay A, Brenner Michael J, Mackinnon Susan E, Myckatyn Terence M, Hunter Daniel A
Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
Microsurgery. 2003;23(3):276-82. doi: 10.1002/micr.10117.
The immunosuppressive agent FK-506 has a well-described neuroregenerative effect that is mediated by a mechanism independent of calcineurin inhibition. FK-506 levels that fall below the threshold for immunosuppression could therefore potentially enhance nerve regeneration while minimizing toxicity. The purpose of this study was to characterize the dose-dependent effects of FK506 on T-cell proliferation, and establish a subimmunosuppressive dosing regimen for FK-506 in mice. Forty BALB/cJ mice were randomized to four groups corresponding to 0, 0.25, 0.5, or 1.0 mg/kg/day doses of FK-506. Ten days postoperatively, animals were sacrificed, and mixed lymphocyte reaction assays were performed to quantify the immune response to nerve allografts. Mice receiving 0.25 and 0.5 mg/kg/day of FK-506 exhibited a robust T-cell proliferation response, with stimulation indices approaching those of untreated animals. Mice treated with 1.0 mg/kg/day of FK-506 demonstrated significantly decreased T-cell proliferation. These results establish 0.5 mg/kg/day as an upper limit for subimmunosuppressive FK-506 administration.
免疫抑制剂FK-506具有一种已被充分描述的神经再生效应，该效应由一种独立于钙调神经磷酸酶抑制作用的机制介导。因此，低于免疫抑制阈值的FK-506水平可能会在将毒性降至最低的同时增强神经再生。本研究的目的是确定FK506对T细胞增殖的剂量依赖性效应，并为小鼠建立一种低于免疫抑制剂量的FK-506给药方案。将40只BALB/cJ小鼠随机分为四组，分别对应0、0.25、0.5或1.0mg/kg/天剂量的FK-506。术后10天，处死动物，并进行混合淋巴细胞反应试验以量化对神经同种异体移植的免疫反应。接受0.25和0.5mg/kg/天FK-506的小鼠表现出强烈的T细胞增殖反应，刺激指数接近未治疗动物。用1.0mg/kg/天FK-506治疗的小鼠表现出T细胞增殖显著降低。这些结果确定0.5mg/kg/天为低于免疫抑制剂量的FK-506给药上限。
