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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 Rejection¹

Antje Habicht^2,*, Michael R. Clarkson^2,*, Jun Yang^*, Joel Henderson, Volker Brinkmann, Stacey Fernandes^*, Mollie Jurewicz^*, Xueli Yuan^* and Mohamed H. Sayegh^3,*

^* Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Boston, MA 02115; Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02130; and Transplantation Research, Novartis Institutes for Biomedical Research, Basel, Switzerland

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.

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