Current standard drugs used to prevent organ graft rejection all interfere with discrete sites in the T-cell/B-cell activation cascade. They can be classified as inhibitors of cytokine transcription (CsA, FK506), inhibitors of nucleotide synthesis (azathioprine, mycophenolate mofetil, mizoribine, leflunomide), inhibitors of growth factor signal transduction (rapamycin, leflunomide), and inhibitors of differentiation (15-deoxyspergualin)(1). The beneficial effects of these therapeutics in disease relate to their broad immunosuppressive potential; however, generalized immunosuppression may reduce defense against infection and malignancies.

As described below, the novel immunomodulator FTY720 protects allografts including islets with remarkable potency, apparently without inducing generalized immunosuppression (2, 3). FTY720 is a structural analog of myriocin (Fig. 1), a metabolite of the ascomycete Isaria sinclairii (4–7). However, unlike myriocin, FTY720 does not bind the serine-palmitoyl transferase and does not inhibit the sphingolipid pathway (8). Although much research has yet to be done to completely unravel the mechanism of action of FTY720, recent data suggest that the drug acts as an agonist and increases the intrinsic mobility of lymphocytes, thereby accelerating chemokine-dependent lymphocyte homing to secondary lymphoid tissues (9) and reducing the recruitment of effector lymphocytes into grafted organs and peripheral lesions (10, 11). The high efficacy of the drug in animal models (3) combined with the good tolerability in Phase I and II clinical trials (12–14) may relate to the compound’s novel mode of action that has not been observed with any other immunosuppressive agent.