Immunosuppressant FTY720 inhibits thymocyte emigration

FTY720 in Corneal Concordant Xenotransplantation

“…Controls were treated with saline only (n ϭ 6). Giemsa-stained blood smears verified the efficiency of FTY720-induced lymphopenia in peripheral blood in trial experiment as previously described (32,36,37). FTY720 was kindly provided by Novartis (Switzerland).…”

“…Previous studies suggest that FTY720 modifies patterns of T-cell migration and sequestration (32)(33)(34)(35)(36)41). However, we have also found that treatment with FTY induces profound reduction in T-cell expansion with macroscopically visible prevention of the normal increase in the size of the draining lymph nodes after transplantation and massively reduced cell numbers.…”

“…It inhibits lymphocyte emigration from the peripheral lymphoid organs and thymus (32)(33)(34)(35)(36), dramatically reducing the number of lymphocytes, especially T cells in the circulation (32,36,37), grafts (37,38) and tissues (30,39,40). Sequestration of lymphocytes in lymph nodes and Peyer's patches (41)-although less pronounced in mice (42)-is believed to be the dominant mode of action of FTY720, although long-term treatment also reduces the proliferative response of mouse lymphnode-derived T cells to alloantigens (42).…”

Tipping the gatekeeper: S1P regulation of endothelial barrier function

“…It is certainly unambiguous that S1P 1 is required for normal B and T cell development, with S1P 1 -null T and B cells showing elevated expression of CD69 [31], and thymocytes failing to emigrate from the thymic medulla. By contrast, the short-term or long-term administration of agonists in vivo [30,35,36], including non-downmodulating agonists such as SEW 2871, leads to CD69 downmodulation in single-positive medullary thymocytes. It has been argued that CD69 is an independent retention signal for lymphocytes [37,38], and also that S1P 1 modulation might be an essential upstream regulator of CD69 in controlling lymphocyte trafficking in response to interferon stimulation [39].…”

“…S1P 1 deletion was embryonic lethal [17], and the reconstitution of mice with S1P 1 null lymphocytes [31] and the selective deletion of S1P 1 [34] both defined a crucial role for S1P 1 in T and B cell development, with constitutive elevation of CD69 expression [31], itself a lymphocyte retention signal [37][38][39], and the failure of thymic egress. However, mechanistic effects of S1P agonists, including FTY720, and gene deletion were always subtly different, for example with FTY720 in long-term treatment inducing CD69 downmodulation in thymic medullary T cells [35,36]. Genetic approaches interrogate physiology through long-term and, in this case, absolute defects in gene expression.…”