INDIVIDUAL-DIFFERENCES IN THE IN-VITRO RE SPONSE TO CYCLOSPORINE-A (CSA) - POSSIBLE HETEROGENEITY IN THE INVOLVEMENT OF THE CD28-B7 BB1 PATHWAY/

Differences in the response of graft recipients to the immunosuppressi ve effect of cyclosporin A (CsA) represent a major factor of allograft acceptance. Response to CsA was investigated in vitro in 59 healthy s ubjects by measuring the inhibition of lymphocyte proliferation and in terleukine-2 (IL-2) production. Marked differences were found comparin g individuals : 61% of the subjects responded with half inhibitory dos es ID50 < 200 ng/ml (responder group), 20% with ID50 within 200-400 ng /ml (intermediate responder) and 19% were non responder with ID50 > 40 0 ng/ml and sometimes over 1000 ng/ml, To explain these differences, t he CD28-B7, co-stimulatory pathway for T-cell activation was explored since it is the only CsA-resistant pathway known so far. Both responde r and non responder individuals showed increased proliferative respons e and IL-2 secretion by co-stimulation with CD3 and CD28, resulting in increased ID50 by a similar factor. The percentage of CD28(+) cells w ithin T-lymphocytes varied markedly among subjects (48.5 +/- 28.9% of the CD8(+) cells). However we could not correlate the inter-individual variation of sensitivity to CsA to the size of the CD8(+)CD28(+) T ce ll subset nor to divergent response to CD3 and CD28 co-stimulation.