The Impact of Immunosuppressive Drugs on the Analysis of T-Cell Activation

Author(s): Paula Rovira, Laurent Mascarell, Paolo Truffa Bachi.

Journal Name: Current Medicinal Chemistry

Volume 7 , Issue 7 , 2000

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Abstract:

The discovery of the immunosuppressive properties of cyclosporin A (CSA) and its successful utilisation in organ transplantation was a milestone in clinics. CSA has revolutionised transplantation both in term of efficiency and quality-of-life of the patient. In addition, the analysis of the mode of action of CSA has been rewarding in the understanding the mecha-nisms leading to T lymphocytes activation. CSA binds to a family of cytosolic receptors, the cyclophilins, a highly conserved family of proteins. Once this complex is formed, a third protein, the calcineurin, is recruited. The calcineurin, a calcium-dependent phosphatase, loose its activity when complexed. Dephosphorylation of NFAT, a substrate of calcineurin is a mandatory step for its translocation to the nucleus where NFAT acts as a transactivator involved in the regulation of the genes encoding many cytokines. CSA preventing NFAT dephosphorylation blocks cytokine production this in turn allowing for a better engrafting. The resolution of the tertiary structure of CSA alone or complexed with cyclophilin and calcineurin has important implication in the modelling of new drugs devoid of its side effects. Indeed, the high incidence of cancer is one of the main problems linked to CSA utilisation. Recent data suggest that CSA may promote cancer inducing the transcription of the gene encoding transforming growth factor b. Other molecules sharing with CSA its immunosuppressive activity were later described. Some of them, as FK506, have the some mode of action; others, as rapamycin, mycophenolate mofetil or leflunomide, act at different steps of T cell activation.

Keywords: immunosuppressive durgs, T cell activation, cyclosporin A CSA, dephosphorylation, rapamycin, cyclophilins, CSA receptors, calcineurin, t lymphocyte activation, IL2 gene expression, CSA FK506 sensitive, apoptosis, thymic selection, tridimensional structure, immunosuppressor immunophilin complex, mycobhenolate mofetil MM

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Article Details

VOLUME: 7
ISSUE: 7
Year: 2000
Page: [673 - 692]
Pages: 20
DOI: 10.2174/0929867003374778
Price: $58

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