FTY720 enhances the activation-induced apoptosis of donor T cells and modulates graft-versus-host disease
FTY720 enhances the activation-induced apoptosis of donor T cells and modulates graft-versus-host disease
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DOI：
10.1002/eji.200636123
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发表时间：
2007-01-01
影响因子：
5.4
通讯作者：
Teshima, Takanori
中科院分区：
文献类型：
--
作者：
Hashimoto, Daigo;Asakura, Shoji;Teshima, Takanori
FTY 720是一种新型的免疫抑制剂，由于T细胞被隔离到LN中而改善实体器官和骨髓移植（BMT）后的结果。我们测试了这样的假设，即通过FTY 720隔离LN中的供体T细胞将增强它们与宿主APC的相互作用，从而引起同种异体反应性T细胞的更大程度的活化诱导的凋亡，从而导致移植物-vs.宿主病（GVHD）。短期应用FTY 720可提高异基因骨髓移植后受体的存活率。FTY 720处理促进了供体T细胞库的快速收缩，这与供体T细胞的凋亡程度增加有关。供体T细胞对宿主同种异体抗原的反应性在宿主LN中减弱，并且从FTY 720治疗的异基因BMT受体的LN中分离的供体T细胞的过继转移在继发性受体中诱导的GVHD比从对照转移的严重程度低。半胱天冬酶依赖性细胞凋亡参与了这一机制，因为FTY 720诱导的保护被废除时，泛半胱天冬酶抑制剂的管理。因此，这些发现表明FTY 720调节同种异体T细胞反应的新机制的存在：即通过诱导LN中同种异体反应性T细胞的活化诱导的凋亡。
FTY720 is a novel immunosuppressant that improves the outcomes after solid organ and bone marrow transplantation (BMT) due to the sequestration of T cells into LN. We tested the hypothesis that the sequestration of donor T cells in LN by FTY720 would enhance their interaction with host APC, thus causing a greater degree of activation-induced apoptosis of alloreactive T cells, and thereby resulting in a reduction of graft-vs.-host disease (GVHD). The short-term administration of FTY720 improved the recipient survival after allogeneic BMT. FTY720 treatment facilitated a rapid contraction of the donor T cell pool in association with an increased degree of apoptosis of donor T cells. The donor T cell reactivity to host alloantigens was diminished in host's LN and adoptive transfer of donor T cells isolated from LN of FTY720-treated recipients of allogeneic BMT induced less severe GVHD in secondary recipients than the transfer from controls. Caspase-dependent apoptosis was involved in this mechanism because FTY720-induced protection was abrogated when a pan-caspase inhibitor was administered. These findings thus demonstrate the presence of a novel mechanism by which FTY720 modulates the allogeneic T cell responses: namely, by the induction of activation-induced apoptosis of alloreactive T cells in LN.