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

Arthritis and Rheumatism
N SuzukiT Sakane

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.

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Citations

Mar 3, 2015·American Journal of Therapeutics·Nivin HaroonZeenat Yousuf Bhat
Feb 23, 2013·American Journal of Therapeutics·Sharad SathyanAlan S Perlman
Jul 5, 2001·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·A I RussellD O Haskard
Feb 22, 2013·Expert Opinion on Pharmacotherapy·Robert M BeardsleyPhoebe Lin
Apr 13, 1999·The Journal of Clinical Endocrinology and Metabolism·S MiharaT Sakane
Nov 4, 2000·Expert Opinion on Investigational Drugs·T Sakane, M Takeno
Mar 14, 2008·Clinical and Experimental Immunology·K NaraN Suzuki
Jan 5, 2002·Expert Opinion on Investigational Drugs·Susan Lightman, Howesen Kok
Jun 22, 2005·Survey of Ophthalmology·Cem Evereklioglu

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