Effect of cyclosporine, cyclosporine metabolite 17, and other cyclosporine-related compounds on T lymphocyte clones derived from rejected human kidney grafts. I. Inhibition of proliferation.

The effect of cyclosporine and metabolite 17 (M17) as well as other CsA-related compounds (CsG, dihydro-CsC, dihydro-CsD, CsH, B5.49, and H7.94) was tested on T lymphocyte clone proliferation. In these experiments, antigen and interleukin 2 (IL-2) dependent long-term T lymphocyte clones derived from a rejected human kidney graft infiltrate were used. They were specifically committed (proliferation and cytotoxicity) for the donor Epstein-Barr virus (EBV)-transformed cells. CsA strongly inhibited clone T cell proliferation induced by the antigen. Inhibition of antigen-driven proliferation was reversed by pure recombinant IL-2 (rec-IL-2) only when low amounts of CsA (less than 25 ng/ml) were used, whereas this lymphokine was ineffective at higher but still pharmacological CsA concentrations (50-500 ng/ml). Increasing rec-IL-2 concentrations did not modify this finding. In addition, CsA, did not inhibit the growth signal(s) induced by rec-IL-2/IL-2 receptor interactions when R-IL-2 is pre-expressed on clone cells. M17 was far less effective in inhibiting antigen-induced clone cell proliferation (50% inhibition at 16 ng/ml versus 500 ng/ml with, respectively, CsA and M17) but was nevertheless inhibitory. This observation, if extended to other metabolites, could be important for interpretation of the relevance of "CsA" concentration through radio-immunoassay monitoring of recipients' blood. Although CsA appeared to display the major inhibitory effect, dihydro-CsC and CsG, as well as B5.49 and H7.94 CsA-related compounds, also exhibited strong activity. Dihydro-CsD was less inhibitory, and CsH had no effect.