The sphingosine-1-phosphate receptor agonist FTY720 modulates dendritic cell trafficking In vivo
The sphingosine-1-phosphate receptor agonist FTY720 modulates dendritic cell trafficking In vivo
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DOI：
10.1111/j.1600-6143.2005.01085.x
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发表时间：
2005-11-01
影响因子：
8.8
通讯作者：
Thomson, AW
中科院分区：
文献类型：
--
作者：
Lan, YY;De Creus, A;Thomson, AW
前药FTY 720正在进行预防同种异体移植排斥反应的III期临床试验。磷酸化后，FTY 720靶向淋巴细胞上的G蛋白偶联鞘氨醇-1-磷酸受体1（S1 PR 1），从而抑制它们从淋巴器官中流出并再循环到炎症部位。尚未评价对树突状细胞（DC）运输的潜在影响。在这里，我们证明了所有五种S1 PR亚型（S1 PR 1 -5）的表达鼠DC。给C57 BL/10小鼠施用FTY 720在24 h内显著减少循环T和B淋巴细胞，但不减少血源性DC，其显著增强达96 h，而淋巴结和脾脏中的DC减少。在FTY 720处理的动物中，血液中过继转移的荧光染料标记的同基因或同种异体DC的数量显著增加，而供体来源的DC和脾脏内宿主幼稚T细胞的同种异体刺激活性降低。施用选择性S1 PR 1激动剂SEW 2871显著增强循环DC数量。流式细胞仪分析显示，FTY 720可下调DC表面CD 11b、CD 31/PECAM-1、CD 54/ICAM-1和CCR 7的表达。FTY 720-P处理的未成熟DC向CCR 7配体CCL 19的跨内皮迁移减少。这些新的数据表明，FTY 720对DC运输的调节可能有助于其免疫抑制作用。
The pro-drug FTY720 is undergoing phase III clinical trials for prevention of allograft rejection. After phosphorylation, FTY720 targets the G protein-coupled -sphingosine-1-phosphate receptor 1 (S1PR1) on lymphocytes, thereby inhibiting their egress from lymphoid organs and their recirculation to inflammatory sites. Potential effects on dendritic cell (DC) trafficking have not been evaluated. Here, we demonstrate the expression of all five S1PR subtypes (S1PR1-5) by murine DCs. Administration of FTY720 to C57BL/10 mice markedly reduced circulating T and B lymphocytes within 24 h, but not blood-borne DCs, which were enhanced significantly for up to 96 h, while DCs in lymph nodes and spleen were reduced. Numbers of adoptively transferred, fluorochrome-labeled syngeneic or allogeneic DCs in blood were increased significantly in FTY720-treated animals, while donor-derived DCs and allostimulatory activity for host naive T cells within the spleen were reduced. Administration of the selective S1PR1 agonist SEW2871 significantly enhanced circulating DC numbers. Flow analysis revealed that CD11b, CD31/PECAM-1, CD54/ICAM-1 and CCR7 expression on blood-borne DCs was downregulated following FTY720 administration. Transendothelial migration of FTY720-P-treated immature DCs to the CCR7 ligand CCL19 was reduced. These novel data suggest that modulation of DC trafficking by FTY720 may contribute to its immunosuppressive effects.