Sphingosine 1-phosphate receptor modulators: a new class of immunosuppressants.
In this review, we summarize how FTY720 came from the lab bench to the bedside by examining its structural similarities to natural occurring sphingosine analogues, the mechanism of action, and clinical applicability to not only transplantation but also autoimmune, oncological, and neurobiological fields. FTY720, a sphingosine 1-phosphate (S1P) analogue, promotes the survival of human and animal allografts by sequestering T lymphocytes within peripheral lymphoid tissue. The mechanism of sequestration is three-fold: (1) T lymphocytes are driven into peripheral lymph nodes in a chemokine dependent manner by FTY720; (2) FTY720 downregulates sphingosine 1-phosphate receptors (S1PRs) on the T lymphocyte surface, rendering it unable to migrate along a S1P gradient; and (3) FTY720 closes stromal gates on the abluminal side of the lymphatic endothelium. Future areas of investigation include developing S1P analogues that have specific agonist binding to S1PRs avoiding side effects seen in non-specific binding.
Yopp
Adam C
AC
Department of Gene and Cell Medicine, The Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
Ledgerwood
Levi G
LG
Ochando
Jordi C
JC
Bromberg
Jonathan S
JS
D000818:Animals; D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016377:Organ Transplantation; D011379:Prognosis; D011409:Propylene Glycols / Q000627:therapeutic use; D049349:Receptors, Lysosphingolipid / Q000187:drug effects* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine