Effects of cyclosporin A on the metabolism of unstimulated and mitogen-activated lymphocytes.

The immunosuppressive drug cyclosporin A (CS-A) reduces the magnitude of T-lymphocyte activation by all mitogenic lectins tested. However, in all cases a proportion of the activation observed is resistant even to very high concentrations of the drug. This proportion depends on the mitogen used, the responses to concanavalin A (Con A) and soybean agglutinin (SBA) being much more strongly inhibited than the responses to phytohaemagglutinin (PHA) or pokeweed mitogen (PWM). The differential effects of CS-A on lymphocyte activation by these mitogens could not be accounted for by the magnitude of the mitogenic response, the mitogen concentration used or the dependence of the responses on the presence of accessory cells, and they were maintained when several different procedures were used to assess the degree of activation. CS-A effectively inhibited inhibited lymphocyte activation. CS-A effectively inhibited lymphocyte activation only when added prior to, or very shortly after, the mitogen. Its ability to inhibit the response to PHA was lost more rapidly than that of Con A. The rate of protein synthesis by unstimulated lymphocytes was also affected by CS-A over the concentration range required to inhibit activation by mitogens. Although this effect was smaller than the inhibition of mitogen activation, it was highly significant and reproducible, and could not be accounted for by inhibition of spontaneous activation occurring in the unstimulated cultures.