Rapid loss of sensitivity of mitogen-induced lymphocyte activation to inhibition by cyclosporin A.

The ability of the immunosuppressive drug cyclosporin A (CS-A) to inhibit the activation of lymphocytes by phytohaemagglutinin (PHA) and concanavalin A (Con A) is progressively lost over the 8-hr period following mitogen addition. This process is dependent on the presence of Ca2+ in the culture medium and is complete at a time when activation still requires the continued presence of the mitogen. While inhibition by CS-A is reduced to some extent by lymphokines produced by mitogen-activated cultures, the initial loss of sensitivity to CS-A is too complete and too rapid to be accounted for in this way. We conclude that CS-A inhibits an early Ca2+-dependent step in mitogen-induced activation that is not in itself sufficient to commit the cells to initiate proliferation, but is required for later steps in the activation process, including lymphokine production.