The thymus is required for the ability of FTY720 to prolong skin allograft survival across different histocompatibility MHC barriers

Abstract

The immunosuppressive effect of FTY720 is associated with the reversible sequestration of lymphocytes from the blood and the spleen into secondary lymphoid organs and reduced egress of mature thymocytes from the thymus. This work was designed to dissect the differential effect of FTY720 on CD4 and CD8 T cell-mediated mechanisms of skin graft rejection in the presence (euthymic) or absence (thymectomized) of thymic output. To that end, untreated and FTY720-treated euthymic (Euthy) and thymectomized (ATX) mice received skin allografts across a full, class II or class I major histocompatibility complex (MHC) mismatched (MM) barriers and graft survival was monitored. We demonstrate that a short course of FTY720 treatment significantly augments the survival of full, class I and class II MHC MM skin grafts compared to the nontreated controls. Interestingly, FTY720-treated Euthy recipients showed a significantly prolonged skin allograft survival compared to FTY720-treated ATX mice. These results together show that FTY720 impairs both CD4 and CD8 T cell-mediated mechanisms of rejection and, more importantly, the presence of the thymus is necessary for the ability of FTY720 to modulate skin allograft rejection across different histocompatibility MHC barriers.