THE INFLUENCE OF FK-506 AND LOW-CONCENTRATION CICLOSPORIN ON HUMAN LYMPHOCYTE-ACTIVATION ANTIGEN EXPRESSION AND BLASTOGENESIS - A FLOW CYTOMETRIC ANALYSIS

The influence of FK‐506 and ciclosporin (CsA), either alone or in combination, on PHA‐ and alloantigen‐induced human blood lymphocyte transformation was investigated. The concentrations of FK‐506 and CsA required to cause 50% inhibition of mitogen‐induced thymidine incorporation were 1.0 and 200 ng/ml respectively. Evidence of synergistic inhibition of DNA synthesis was obtained when doses of each drug below these concentrations were combined (FK‐506, ≤0.5 ng/ml; CsA ≤50 ng/ml). In contrast, FK‐506 and CsA failed to inhibit PHA‐induced increases in cell size and granularity determined by flow cytometric analysis at 1 and 3 days of culture. Moreover, no significant changes in the expression of the interleukin 2 receptor (IL‐2R; CD25), transferrin receptor (TR; CD7I) or HLA‐DR were observed in terms of percentage positive lymphocytes or mean cell surface membrane fluorescence intensity. In primary mixed lymphocyte cultures, 50% inhibition of thymidine incorporation was obtained with FK‐506 and CsA concentrations of approximately 0.25 and 25 ng/ml respectively. Evidence of synergy was obtained when lower doses of each drug were combined (FK‐506, ≤0.1 ng/ml; CsA ≤2 ng/ml). On their own, these concentrations of CsA were ineffective. In contrast to corresponding PHA‐stimulated cells, FK‐506‐treated alloactivated lymphocytes exhibited reductions in IL‐2R, TR and HLA‐DR antigen expression, which in the cases of IL‐2R and TR were further reduced by combination of FK‐506 with low‐concentration CsA. These data provide further evidence of the potential of combined low‐dosage FK‐506 and CsA for the control of human T‐cell activation and proliferation in response to allostimulation. Copyright © 1990, Wiley Blackwell. All rights reserved