Analysis of the mode of action of a novel immunosuppressant FTY720 in mice
Analysis of the mode of action of a novel immunosuppressant FTY720 in mice
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DOI：
10.1016/s0162-3109(99)00004-1
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发表时间：
1999-04-01
期刊：
影响因子：
--
通讯作者：
Miyasaka, M
中科院分区：
文献类型：
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作者：
Luo, ZJ;Tanaka, T;Miyasaka, M
加速淋巴细胞归巢和凋亡已被认为有助于FTY 720的有效免疫抑制作用，然而，其主要作用机制仍有待充分阐明。在这里，我们研究了FTY 720在小鼠中的作用模式。FTY 720以1 mg/kg的剂量单次给药时，显著降低了正常小鼠外周血淋巴细胞（PBL）的数量，但适度增加了淋巴结（LN）和派伊尔集合淋巴结（PP）中的淋巴细胞数量，如先前在大鼠中观察到的那样。然而，在缺乏LN和PP的aly/aly小鼠中也观察到PBL数量的急剧减少，表明这种现象不能用加速的淋巴细胞归巢到LN和PP来解释。此外，FTY 720的单次给药不抑制T细胞的增殖反应的发现表明PBL减少可以在不抑制淋巴细胞功能的情况下发生。然而，当以相同剂量给药2周时，FTY 720诱导了严重的全身淋巴细胞减少症，以及对正常小鼠淋巴细胞增殖反应的显著抑制。同样的治疗也延长了aly/aly小鼠的皮肤移植存活时间。我们的研究结果表明，FTY 720抑制体内免疫功能，主要是通过诱导全身淋巴细胞减少症，也通过抑制T细胞功能。(C)1999 Elsevier Science B. V.保留所有权利。
Accelerated lymphocyte homing and apoptosis have been suggested to contribute to potent immunosuppressive effects of FTY720, however, its main mechanism of action remains to be fully elucidated. Here, we examined the mode of action of FTY720 in mice. FTY720, when given at a single dose of 1 mg/kg, markedly decreased the number of peripheral blood lymphocytes (PBL) but moderately increased the lymphocyte numbers in lymph nodes (LN) and Peyer's patches (PP) in normal mice, as previously observed in rats. However, the sharp decrease in PBL numbers was also observed in aly/aly mice lacking LN and PP, indicating that this phenomenon is not explained by accelerated lymphocyte homing to LN and PP. in addition, the finding that a single administration of FTY720 did not suppress proliferative responses of T cells suggested that the PBL reduction could occur without inhibiting lymphocyte functions. However, when administered at the same dose for 2 weeks, FTY720 induced severe systemic lymphopenia, as well as marked suppression of lymphocyte proliferative responses in normal mice. The same treatment also prolonged skin allograft survival in aly/aly mice. Our results suggest that FTY720 suppresses in vivo immune functions mainly by inducing systemic lymphopenia and also by inhibiting T cell functions. (C) 1999 Elsevier Science B.V. All rights reserved.