In vivo mechanisms for the inhibition of T lymphocyte activation by long-term therapy with tacrolimus (FK-506): experience in patients with Behçet's disease
Abstract
To examine the in vivo mechanisms of suppression of T lymphocyte function in patients with Behçet's disease (BD) undergoing long-term treatment with tacrolimus (FK-506). Intracellular proteins were analyzed by immunoprecipitation and Western blotting. Messenger RNA expression was studied by a polymerase chain reaction-based technique. Interleukin-2 production was suppressed in patients treated with tacrolimus. This suppression was found to be due to inhibition of interactions between activated calcineurin (Cn) and nuclear factor of activated T cells (NF-AT), inhibition of cleavage of the autoinhibitory domain of the CnA subunit, and inhibition of heterodimer formation by CnA and CnB subunits, resulting in the absence of NF-AT in nuclei of the T cells. We found that T lymphocytes in some BD patients treated with tacrolimus had reduced amounts of FK-506 binding protein (FKBP) in their cytoplasm. Tacrolimus reduces the Cn activity of T cells in vivo by the cumulative effects of several distinct mechanisms. It is plausible that reduced amounts of FKBP may be associated with diminished clinical efficacy in some BD patients receiving prolonged treatment with tacrolimus.
References
Equilibria and kinetics of lac repressor-operator interactions by polyacrylamide gel electrophoresis
Heat shock protein peptides reactive in patients with Behçet's disease are uveitogenic in Lewis rats
Citations
Related Concepts
Related Feeds
Ataxia telangiectasia (MDS)
Ataxia telangiectasia is a rare neurodegenerative diseases caused by defects in the ATM gene, which is involved in DNA damage recognition and repair pathways. Here is the latest research on this autosomal recessive disease.