Molecular mechanisms of immunosuppression by cyclosporine,... : Current Opinion in Nephrology and Hypertension (original) (raw)
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Departments of *Genetics and † Pharmacology, and ‡ Howard Hughes Medical Institute Duke University Medical Center, Durham, North Carolina, USA
Joseph Heitman, Department of Genetics, Box 3546 322, Carl Bldg, Research Drive, Duke University Medical Center, Durham, NC 27710, USA.
Abstract
The immunosuppressant cyclosporine A revolutionized treatment of graft rejection. Two newer agents, FK506 and rapamycin, show great clinical potential. These drugs suppress the immune system by forming protein-drug complexes that interact with and inhibit key components of the signal transduction pathways required for T-cell activation. The target of the cyclophilin A-cyclosporine A and FKBP12-FK506 complexes is calcineurin, a protein phosphatase required for signaling via the T-cell receptor. Cyclosporine A and FK506 nephrotoxicity may reflect renal-specific functions of calcineurin. The target of the FKBP12-rapamycin complex is TOR, a lipid and protein kinase homolog that is likely to be required for T-cell proliferation in response to interleukin-2. The identification of cyclosporine A, FK506, and rapamycin targets reveals much concerning T-cell signaling and provides the means to design novel immunosuppressants with reduced toxicity.
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