Suppression of in vitro lymphocyte reactivity by cyclosporin A: existence of a population of drug-resistant cytotoxic lymphocytes.

Cyclosporin A (CS-A) is an unusual endecapeptide isolated from the fungi Cylindrocarpon lucidum Booth and Trichoderma polysporum. It is a potent immunosuppressive drug that prevents rejection of kidney and heart allografts whilst having a low myelotoxicity. Its mode of action is still unclear but its main target appears to be the T lymphocyte. The mixed lymphocyte reaction (MLR) and cell-mediated lymphocytoxicity (CML) used here are generally regarded as in vitro correlates of allograft rejection. Our data show that CS-A is a powerful inhibitor of MLR reactivity, regardless of whether the cells were obtained from normal or presensitized donors; that the CML of lymph node cells is likewise totally inhibited if the drug is added early during cell culture; and that, by contrast, the cytotoxic response of spleen cells from presensitized but not from normal mice is only partially inhibited, even with a tenfold increase in dose. It is therefore suggested that there exists a population of cytotoxic spleen cells that is relatively resistant to the action of this drug.