Inhibitory Effects of FK506 in Combination with Cyclosporine A on Human Lymphocyte Alloproliferative Responses

Abstract

FK506 (FK) is a novel immunosuppressive drug isolated from Streptomyces tsukubaensis. Its in vitro effect on lymphocyte proliferation is several hundred-fold greater than that of Cyclosporine A (CsA). Studies were conducted on the inhibitory effect of combinations of FK and CsA on lymphocyte proliferation in vitro. The secondary proliferative response (PLT) of alloreactive T cells was significantly inhibited by a combination of 0.06 ng/ml of FK and 1 ng/ml of CsA. At these low concentrations, these drugs were ineffective. The synergistic effect between FK and CsA was also demonstrated through sequential exposure of alloreactive lymphocytes to FK followed by CsA. Pretreatment of IL2-expanded alloreactive cells with FK yielded cell cultures whose PLT activity was considerably more sensitive to low doses of CsA than control cells or CsA-pretreated cells. These findings provide evidence for a synergism between the immunosuppressive effects of FK and CsA. The combination of low-dose FK plus CsA immunosuppression may benefit organ transplant outcome.