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

• 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
• Format: Article
• Language: English
• 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.176.1.36

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.