Oral efficacy of the new immunomodulator FTY720 in cynomolgus monkey kidney allotransplantation, given alone or in combination with cyclosporine or RAD

Abstract

FTY720 is an effective immunosuppressant in prevention of acute kidney allograft rejection in cynomolgus monkeys and synergizes with cyclosporine and/or RAD in yielding rejection-free allograft survival.

The Sphingosine 1-Phosphate Receptor Agonist FTY720 Differentially Affects the Sequestration of CD4+/CD25+ T-Regulatory Cells and Enhances Their Functional Activity

“…ϩ T cells and 30% of CD8 T cells were refractory to depletion by the drug (24). The current view is that these cells represent long-lived effector memory T cells because in contrast to naive and central memory T cells they lack the lymph node homing receptors CCR7 and CD62L and reside in nonlymphoid tissues (33)(34)(35).…”

“…However, multiple studies have demonstrated that the depletion of lymphocytes from the circulation is not complete, suggesting the presence of a T cell subpopulation that is resistant to FTY720 (23,24). Because little is known about the effect of FTY720 on the sequestration of CD4 ϩ /CD25 ϩ T-regulatory cells, the distribution of this lymphocyte subpopulation in blood and spleen after treatment with FTY720 was investigated.…”

FTY720 suppresses CD4+CD44highCD62L− effector memory T cell-mediated colitis

“…therapy; migration; I cell 2-AMINO-2-[2-(4-OCTYLPHENYL)ETHYL]-1,3-PROPANEDIOL HYDROCHLO-RIDE (FTY720) is a chemical derivative of myriocin (thermozymocidin), a substance found in the fungi Myriococcum albomyces and Isaria sinclairii (1,2,5,6). FTY720 is a potent immunomodulator that has been shown to prevent graft rejection in various animal allotransplantation models (23,24), autoimmune disease animal models (11,16,20), and viral infection animal models (17,21). Good synergy with cyclosporine and sirolimus has been reported (3,28,30).…”

“…In nohuman primates treated with FTY720 for over 100 days, however, ϳ10% of peripheral blood CD4 ϩ T cells were refractory to depletion by FTY720 (23). It is likely that these cells represent long-lived T EM cells.…”

FTY720 Prevents Anti-CD4 mAb-Induced Tolerance but Cannot Reverse Established Tolerance in a Rat Kidney Transplantation Model

“…Several studies demonstrated the reduced inflammatory cellular infiltration of allogeneic grafts under the cover of FTY720 treatment (8,9). FTY720 synergistically acts in combination with calcineurin inhibitors or rapamycin, preventing more efficiently acute rejection and development of chronic graft dysfunction (10,11). Based on these data, the beneficial effects of FTY720 in combination with several immunosuppressive protocols are now under clinical investigation.…”