The immunosuppressive mode of action of mizoribine

Mizoribine (MIZ) suppressed the mitogen response and mixed lymphocyte reaction (MLR) significantly at doses of 100 micrograms/ml and 10 micrograms/ml in a dose-response analysis. The 50% inhibition dose (ID50) was between 10 micrograms/ml and 1.0 microgram/ml, both in the mitogen response and MLR. In a kinetic study of the MLR, the degree of suppression with MIZ at a given dosage was essentially the same as the degree of suppression observed in the dose-response analysis when MIZ was added to MLR cultures from day 0 to day 4. In addition, MLR was more susceptible to the suppressive activity of MIZ at 100 micrograms/ml when MIZ was added near the peak of lymphocyte proliferation. This experiment also showed that MLR suppression induced by MIZ at 10 micrograms/ml was reversible and MLR activity had completely recovered 6-8 hr after its removal. MIZ had no inhibitory action on MLR-derived cytotoxic cells or the effector phase of cell mediated lymphocytotoxicity. These results clearly demonstrate that MIZ suppresses lymphoproliferation, but has no effect on the recognition phase or effector phase of cytotoxic lymphocytes.