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.
OBJECTIVE
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).


METHODS
Intracellular proteins were analyzed by immunoprecipitation and Western blotting. Messenger RNA expression was studied by a polymerase chain reaction-based technique.


RESULTS
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.


CONCLUSIONS
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.
Suzuki
N
N
St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Kaneko
S
S
Ichino
M
M
Mihara
S
S
Wakisaka
S
S
Sakane
T
T
D000328:Adult; D001528:Behcet Syndrome / Q000188:drug therapy / Q000276:immunology*; D015153:Blotting, Western; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D005260:Female; D014644:Genetic Variation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011233:Precipitin Tests; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D016559:Tacrolimus / Q000627:therapeutic use*; D022021:Tacrolimus Binding Proteins
D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D009687:Nuclear Proteins; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus