IN-VIVO MECHANISMS FOR THE INHIBITION OF T-LYMPHOCYTE ACTIVATION BY LONG-TERM THERAPY WITH TACROLIMUS (FK-506) - EXPERIENCE IN PATIENTS WITH BEHCETS-DISEASE

Objective. To examine the in vivo mechanisms of suppression of T lymph ocyte function in patients with Behcet's disease (ED) undergoing long- term treatment with tacrolimus (FK-506). Methods. Intracellular protei ns were analysed by immunoprecipitation and Western blotting, Messenge r RNA expression was studied by a polymerase chain reaction-based tech nique. Results. Interleukin-2 production was suppressed in patients tr eated with tacrolimus. This suppression was found to be due to inhibit ion of interactions between activated calcineurin (Cn) and nuclear fac tor of activated T cells (NF-AT), inhibition of cleavage of the autoin hibitory domain of the CnA subunit, and inhibition of heterodimer form ation by CnA and CnB subunits, resulting in the absence of NF-AT in nu clei of the T cells, We found that T lymphocytes in some ED patients t reated with tacrolimus had reduced amounts of FK-506 binding protein ( FKBP) in their cytoplasm. Conclusion. Tacrolimus reduces the Cn activi ty of T cells in vivo by the cumulative effects of several distinct me chanisms, It is plausible that reduced amounts of FKBP may be associat ed with diminished clinical efficacy in some ED patients receiving pro longed treatment with tacrolimus.