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https://hdl.handle.net/2440/17537
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Type: | Journal article |
Title: | The sphingosime-1-phosphate receptor agonist FTY720 modulates dendritic cell trafficking in vivo |
Author: | Lan, Y. De Creus, A. Colvin, B. Abe, M. Brinkmann, V. Coates, P. Thompson, A. |
Citation: | American Journal of Transplantation, 2005; 5(11):2649-2659 |
Publisher: | Blackwell Munksgaard |
Issue Date: | 2005 |
ISSN: | 1600-6143 1600-6143 |
Statement of Responsibility: | Yuk Yuen Lan, An De Creus, Bridget L. Colvin, Masanori Abe, Volker Brinkmann, P. Toby H. Coates and Angus W. Thomson |
Abstract: | 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 naïve 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. |
Keywords: | B-Lymphocytes Dendritic Cells T-Lymphocytes Animals Mice, Inbred C3H Mice, Inbred C57BL Mice Sphingosine Propylene Glycols Oxadiazoles Thiophenes Cell Adhesion Molecules Receptors, Lysosphingolipid DNA Primers Immunosuppressive Agents Lymphocyte Depletion Polymerase Chain Reaction Apoptosis Cell Differentiation Fingolimod Hydrochloride |
DOI: | 10.1111/j.1600-6143.2005.01085.x |
Published version: | http://dx.doi.org/10.1111/j.1600-6143.2005.01085.x |
Appears in Collections: | Aurora harvest 6 Medicine publications |
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