Molecular mechanisms of immunosuppression by cyclosporine, FK506, and rapamycin.
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.
Cardenas
M E
ME
Department of Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Zhu
D
D
Heitman
J
J
D000818:Animals; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018797:Cell Cycle Proteins; D016572:Cyclosporine / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D011090:Polyenes / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins
D019703:Calcineurin; D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016572:Cyclosporine; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus; D022021:Tacrolimus Binding Proteins; C546842:MTOR protein, human