Submitted May 14, 2007
Accepted June 22, 2007
Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD)
Patricia A Taylor, Michael J Ehrhardt, Christopher J Lees, Jakub Tolar, Brenda J Weigel, Angela Panoskaltsis-Mortari, Jonathan S Serody, Volker Brinkmann, and Bruce R. Blazar*
University of Minnesota Cancer Center & Dept of Pediatrics, Division of BMT, University of Minnesota, Minneapolis, MN, United States
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, United States
Transplantation and Immunology, Novartis Institutes for BioMedical Research, Basel, Switzerland
* Corresponding author; email: blaza001{at}umn.edu.
The immunomodulator, FTY720, has been shown to be beneficial in experimental models of organ transplantation and autoimmunity. We show that FTY significantly inhibited but did not prevent GVHD in lethally irradiated or non-irradiated 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 nor 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 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 BMT recipients.
