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The clinical investigator

, Volume 70, Issue 9, pp 773–779 | Cite as

Progress towards a molecular understanding of cyclosporin A-mediated immunosuppression

  • A. Schumacher
  • A. Nordheim
Guest Lecture, “Gesellschaft für Nephrologie”, 23rd Congress

Summary

Immunosuppressive drugs like cyclosporin A (CsA), FK506 and rapamycin exert their immunosuppressive potential primarily by interfering with the activation and proliferation of T cells. These substances bind to intracellular receptor proteins, called immunophilins. Immunophilins are ubiquitous and abundant proteins, found in all prokaryotic and eukaryotic cells investigated, as well as in many subcellular compartments. Immunophilins display an inherent enzymatic activity, the prolyl-peptidyl cis-trans isomerase (PPIase). The eukaryotic PPIases are inhibited upon the binding of immunosuppressants. In addition, the complex of immunophilins and CsA or FK506 acquires a new activity, namely the binding and inhibition of the cytoplasmic Ca2+-binding phosphatase calcineurin. This inhibition is postulated to prevent the proper assembly and nuclear positioning of the transcription factor NF-AT (nuclear factor of activated T cells). The correct DNA binding of NF-AT to regulatory elements of the interleukin 2 (IL-2) promoter normally contributes to the transcriptional activation of this gene. Thus, immunosuppressive drugs prevent T-cell activation by interfering with Ca2+-dependent signal transduction pathways which regulate gene activities.

Key words

Cyclophilin FK506 Signal transduction Gene regulation Calcineurin 

Abbreviations

CsA

cyclosporin A

IL-2a

interleukin 2

PPIase

prolyl-peptidyl cis-trans isomerase

NF-AT

nuclear factor of activated T cells

FKBPs

FK506- and rapamycinbinding proteins

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Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • A. Schumacher
    • 1
  • A. Nordheim
    • 1
  1. 1.Medizinische Hochschule HannoverInstitut für MolekularbiologieHannover 61Germany

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