Molecular mechanisms of immunosuppression.
The immunosuppressive drug cyclosporin A (CsA, Sandimmun, SIM) is currently being evaluated in a variety of autoimmune disorders with some remarkable successes. Despite the wide empiric application of CsA, the precise mechanism of action of this drug remains elusive. To identify the molecular mode of action of CsA in the process of T cell activation, we have compared the biological profile of cyclophilin-binding cyclosporin analogues (CBCA), which lack immunosuppressive properties, with CsA. We have found that CsA binding to its intracellular receptor (cyclophilin) is required but not sufficient for immunosuppression. Moreover, inhibition of the peptidyl-prolyl cis-trans isomerase activity of cyclophilin does not seem to be relevant for the inhibitory effects of CsA. In analogy to the immunosuppressants FK506 and rapamycin, a specific structure at the 'effector' domain of the CsA molecule different from the immunophilin 'binding' domain determines the biological activity. Overall, a significant understanding of the structure-activity relationship of CsA has emerged. This will have a major impact on the identification of the precise mechanism of action of CsA and its side effects in the process of immunosuppression.
Baumann
G
G
Preclinical Research, Sandoz Pharma Ltd, Basel, Switzerland.
Zenke
G
G
Wenger
R
R
Hiestand
P
P
Quesniaux
V
V
Andersen
E
E
Schreier
M H
MH
D000591:Amino Acid Isomerases / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology; D016572:Cyclosporine / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D009492:Neurospora crassa; D019696:Peptidylprolyl Isomerase; D011090:Polyenes / Q000276:immunology / Q000494:pharmacology; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus; D016559:Tacrolimus / Q000276:immunology / Q000494:pharmacology
D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011090:Polyenes; D016572:Cyclosporine; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D020123:Sirolimus; D016559:Tacrolimus