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 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.
Habicht
Antje
A
Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital, Boston, MA 02115, USA.
Clarkson
Michael R
MR
Yang
Jun
J
Henderson
Joel
J
Brinkmann
Volker
V
Fernandes
Stacey
S
Jurewicz
Mollie
M
Yuan
Xueli
X
Sayegh
Mohamed H
MH
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D002908:Chronic Disease; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology; D007150:Immunohistochemistry; D007156:Immunologic Memory / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D011409:Propylene Glycols / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D016038:Skin Transplantation / Q000276:immunology; D013110:Sphingosine / Q000031:analogs & derivatives; D014184:Transplantation, Homologous
D016207:Cytokines; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D011948:Receptors, Antigen, T-Cell; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine