Novel insights into the mechanism of action of FTY720 in a transgenic model of allograft rejection: Implications for therapy of chronic rejection
Novel insights into the mechanism of action of FTY720 in a transgenic model of allograft rejection: Implications for therapy of chronic rejection
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DOI：
10.4049/jimmunol.176.1.36
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发表时间：
2006-01-01
影响因子：
4.4
通讯作者：
Sayegh, MH
中科院分区：
文献类型：
--
作者：
Habicht, A;Clarkson, MR;Sayegh, MH
FTY720 是 1-磷酸鞘氨醇受体 I 的高亲和力激动剂，可防止淋巴细胞从淋巴组织中流出，并在多种实体器官移植动物模型中延长同种异体移植物的存活率。在本研究中，我们使用最近开发的 TCR 转基因 T 细胞过继转移模型来追踪 FTY720 给药环境下的同种异体 CD4(+) T 细胞扩增和运输特征、细胞因子分泌谱和体内表面表型。我们报告说，FTY720 给药对同种抗原驱动的 T 细胞激活、增殖、效应记忆功能的获得或 T 细胞凋亡没有影响。然而，FTY720 引起区域淋巴组织中同种异体抗原特异性效应记忆 T 细胞的可逆隔离，与同种异体移植物内 T 细胞浸润的减少以及随后同种异体移植物存活的延长相关。此外，在慢性同种异体移植排斥的心脏模型中延迟给予 FTY720 可减轻血管病变和组织纤维化的进展，这与 FTY720 中断激活的效应记忆 T 细胞运输的假设一致。这些数据对于实体器官移植中靶向 1-磷酸鞘氨醇受体 1 具有重要意义。
FTY720 is a high-affinity agonist at the sphingosine 1-phosphate receptor I that prevents lymphocyte egress from lymphoid tissue and prolongs allograft survival in several animal models of solid organ transplantation. In this study we used a recently developed adoptive transfer model of TCR transgenic T cells to track allospecific CD4(+) T cell expansion and trafficking characteristics, cytokine secretion profiles, and surface phenotype in vivo in the setting of FTY720 administration. We report that FTY720 administration had no effect on alloantigen-driven T cell activation, proliferation, acquisition of effector-memory function, or T cell apoptosis. However, FTY720 caused a reversible sequestration of alloantigen-specific effector-memory T cells in regional lymphoid tissue associated with a decrease in T cell infiltration within the allograft and a subsequent prolongation in allograft survival. Furthermore, delayed administration of FTY720 in a cardiac model of chronic allograft rejection attenuated the progression of vasculopathy and tissue fibrosis consistent with the hypothesis that FTY720 interrupts the trafficking of activated effector-memory T cells. These data have important implications for targeting the sphingosine 1-phosphate receptor 1 in solid organ transplantation.