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Novel Insights into the Mechanism of Action of FTY720 in a Transgenic Model of Allograft Rejection: Implications for Therapy of Chronic Rejection

FTY720 is a high-affinity agonist at the sphingosine 1-phosphate receptor 1 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 transgen...

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Published in:The Journal of immunology (1950) 2006-01, Vol.176 (1), p.36-42
Main Authors: Habicht, Antje, Clarkson, Michael R, Yang, Jun, Henderson, Joel, Brinkmann, Volker, Fernandes, Stacey, Jurewicz, Mollie, Yuan, Xueli, Sayegh, Mohamed H
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cited_by cdi_FETCH-LOGICAL-c403t-9b5ace66bf30bd9613a2f072dc7ba3e229d8e67287c986fcaa1c6bfe80fb7baa3
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container_title The Journal of immunology (1950)
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creator Habicht, Antje
Clarkson, Michael R
Yang, Jun
Henderson, Joel
Brinkmann, Volker
Fernandes, Stacey
Jurewicz, Mollie
Yuan, Xueli
Sayegh, Mohamed H
description FTY720 is a high-affinity agonist at the sphingosine 1-phosphate receptor 1 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.
doi_str_mv 10.4049/jimmunol.176.1.36
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ispartof The Journal of immunology (1950), 2006-01, Vol.176 (1), p.36-42
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subjects Adoptive Transfer
Animals
Apoptosis - drug effects
Apoptosis - immunology
CD4-Positive T-Lymphocytes - drug effects
CD4-Positive T-Lymphocytes - immunology
Chemotaxis, Leukocyte - drug effects
Chemotaxis, Leukocyte - immunology
Chronic Disease
Cytokines - drug effects
Cytokines - metabolism
Disease Models, Animal
Fingolimod Hydrochloride
Flow Cytometry
Graft Rejection - prevention & control
Heart Transplantation - immunology
Immunohistochemistry
Immunologic Memory - drug effects
Immunosuppressive Agents - pharmacology
Lymphocyte Activation - drug effects
Lymphocyte Activation - immunology
Mice
Mice, Transgenic
Propylene Glycols - pharmacology
Receptors, Antigen, T-Cell - genetics
Skin Transplantation - immunology
Sphingosine - analogs & derivatives
Transplantation, Homologous
title 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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