title: Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD).
abstract: The immunomodulator FTY720 (FTY) has been shown to be beneficial in experimental models of organ transplantation and autoimmunity. We show that FTY significantly inhibited but did not prevent graft-versus-host disease (GVHD) in lethally irradiated or nonirradiated allogeneic recipients. Although most studies implicate prevention of lymphocyte egress from lymphoid organs as the primary mechanism of action, our data indicate that FTY effects on the host are more likely to be responsible for GVHD inhibition. FTY reduced splenic CD11c+ cells by 50%, and similarly reduced CD4+ and CD8+ T-cell responder frequencies in the spleen early after transplantation. Imaging of GFP+ effectors indicated that FTY modified donor effector T-cell migration to secondary lymphoid organs, but did not uniformly trap T cells in lymph nodes or prevent early effector migration to GVHD parenchymal target organs. Administration of FTY only prior to transplantation inhibited GVHD, indicating that the primary function of FTY may be targeted to host cells. FTY was additive with regulatory T cells for GVHD inhibition. FTY slightly impaired but did not abrogate a graft-versus-leukemia (GVL) effect against C1498, a myeloid leukemia. Our data further define the mechanisms of action and provide insight as to the potential clinical uses of FTY in allogeneic bone marrow transplant recipients.
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Taylor
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ehrhardt
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lees
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003131:Combined Modality Therapy; D000068876:Fingolimod Hydrochloride; D006086:Graft vs Host Disease / Q000401:mortality / Q000628:therapy*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D016219:Immunotherapy, Adoptive; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000637:transplantation*; D019172:Transplantation Conditioning / Q000379:methods
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine