FTY720 causes lymphocytes to get trapped in nodes (bracket).

Rosen/AAAS

Organ rejection in transplant patients can be prevented using the drug FTY720, but the drug's mechanism of action has been unknown. Now, Suzanne Mandala, Hugh Rosen, and colleagues (Merck Research Laboratories, Rahway, NJ) show that it acts by retaining lymphocytes in lymph nodes, preventing their circulation through the bloodstream.

B and T lymphocytes are either retained in lymph nodes in order to contact antigens and antigen-presenting cells or sent back out into the bloodstream for circulation. Circulating lymphocytes may enter tissues, where they mediate protective activities or cause tissue damage. Most immunosuppressive drugs work by inhibiting lymphocyte function: they either kill the cells directly, inhibit their production, or block signals downstream of antigen recognition. But FTY720 works in a novel manner.

Rosen's group found that a phosphate ester metabolite of FTY720 mimics the natural lipid sphingosine-1-phosphate (S1P) and binds several forms of S1P receptors. Activation of the receptors causes the sequestration of lymphocytes at nodes and a corresponding decrease in circulating lymphocytes. “This is the first indication that S1P and its receptors regulate lymphocyte trafficking and that, if manipulated pharmacologically, [they] can give rise to immunosuppression,” says Rosen. Unlike S1P, the side effects of which include low blood pressure, FTY720 is better tolerated in clinical use. The reasons behind this distinction are yet unclear, but may involve the failure of FTY720 to bind all S1P receptors. ▪

Reference:

Mandala, S., et al. 2002. Science. 10.1126/science.1070238