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The interaction of two commonly used immunosuppressive agents, azathioprine (AZA) and prednisolone sodium succinate (PSS), with three mitogens, Concanavalin A (Con A), phytohemagglutinin (PHA), and pokeweed mitogen (PWM) was studied. Using the endpoint of 50% inhibition of 3H-thymidine incorporation (ID50) as an indicator of cellular replication, the affect of suboptimal and optimal concentrations of mitogen on the immunosuppressive action of AZA or PSS on human lymphocyte replication in vitro was determined by isobolic analysis. The AZA ID50 for optimal concentrations of Con A (60 mcm/cc) was 242 +/- 21 ngm/cc (mean +/- SEM, n = 8), and at a suboptimal concentration of Con A (20 mcg/cc) it was 233 +/- 42, i.e., the AZA ID50 was independent of the concentration of Con A. This same independent interaction was found for PHA and PWM. However, at the optimal concentration of Con A (60 mcg/cc) the PSS ID50 of 523 +/- 55 ngm/cc was significantly higher (p less than 0.001) than the PSS ID at the suboptimal concentration of Con A (20 mcg/cc) which was 234 +/- 24 ngm/cc. A similar antagonistic interaction was found between PSS and either PHA or PWM. These findings emphasize the importance of accurately defining the testing parameters when assessing a drug's effect on lymphocyte proliferation. The data, along with other studies, support the hypothesis that drugs which directly interfere with DNA synthesis will not be affected by the strength of the signal for cellular replication, whereas those that modulate cellular replication are affected by the strength for lymphocyte replication.