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

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Abstract
Cyclosporin A (CS-A) is an unusual endecapeptide isolated from the fungi Cylindrocarpon lucidum Booth and Tri choderma polysporum1. It is a potent immunosuppressive drug that prevents rejection of kidney2–4 and heart5,6 allografts whilst having a low my elotoxicity7. Its mode of action is still unclear but its main target appears to be the T lymphocyte8. The mixed lymphocyte reaction (MLR) and cell-mediated lymphocytoxicity (CML) used here are generally regarded as in vitro correlates of allograft rejection9. 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.