AUGMENTATIVE INHIBITION OF LYMPHOCYTE-PROLIFERATION BY CYCLOSPORINE-ACOMBINED WITH THE RIMINOPHENAZINE COMPOUNDS CLOFAZIMINE AND B669

We have investigated the effects of cyclosporin A (CsA, 3-50 ng/ml) in combination with the riminophenazine agents clofazimine and B669 (60- 500 ng/ml) on the mitogen- and alloantigen-activated proliferative res ponses of human mononuclear leukocytes (MNL), as well as on the phosph olipase A(2) and Na+, K+-adenosine triphosphatase activities of these cells. When used in combination these agents caused inhibition of the proliferative responses of both mitogen- and alloantigen-activated MNL which was at least additive. Combinations of CsA with the riminophena zines also caused augmentative activation of PLA(2) and inhibition of Na+, K+-ATPase. The inhibitory effects of these agents, both individua lly and in combination, on the Na+, K+-ATPase and proliferative respon ses of MNL were neutralized by the membrane-stabilizing, lysophospholi pid complex-forming agent alpha-tocopherol (vitamin E, 20 mu g/ml). Th ese observations suggest that combinations of CsA with riminophenazine s cause interactive enhancement of the activity of PLA(2) in MNL leadi ng to lysophospholipid-mediated inactivation of Na+, K+-ATPase and con sequent inhibition of the proliferative responses of these cells. In t he therapeutic setting combinations of these agents may enable reducti on in the dose of CsA required to achieve meaningful immunosuppression with a consequent decrease in the risk of chemotherapy-related organ toxicity.