FTY720: from bench to bedside

FTY720, a synthetic myriocin analogue derived from culture filtrates of Isaria sinclairii, is a novel immunosuppressant that in experimental animals and nonhuman primates produces lymphocytopenia and prolongs allograft survival in dose-dependent fashion. FTY720 exerts synergistic interactions not only with calcineurin antagonists, but also with proliferation signal inhibitors. These interactions offer the possibility of reducing exposure to and mitigating toxicity of existing drugs. The mechanism of drug action is not entirely clear. FTY720 appears to undergo phosphorylation by sphingosine phosphokinase 2, rendering it capable of interacting with the specific G protein-linked receptors for its structural homologue-sphingosine-1-phosphate. However, it is not clear how this interaction leads to emigration of lymphocytes from the peripheral blood and sequestration in secondary lymphoid structures. Present theories suggest that the drug prevents emigration rather than directing the onset of sequestration. Thus, the drug is the archetype of a new class of agents that alter lymphocyte homing patterns: the adhesion-migration paradigm. These modalities reduce interstitial infiltration of grafts and attenuate their release from lymph nodes. Since FTY720 seems to spare nonspecific elements of host resistance, it may not only represent a useful addition to the immunosuppressive armamentarium but also address the not infrequent complications of infections associated with existing therapies.