Combined immunosuppressive therapy with cyclosporin A and azathioprine. A synergistic effect in three of four experimental models.

Cyclosporin A (Cy A) by itself is limited in its clinical application by its dose-related liver and kidney toxicity. Combining Cy A with prednisone allows lower doses of Cy A to be used, but the side effects of steroids are cumulative. Thus, we tested the effect of Cy A and various drug-dose combinations with azathioprine (AZA) in four different models. The one that gave the best results with the least toxicity was 1.25 mg of Cy A plus 15 mg of AZA for islet allotransplantation in rats across a minor histocompatibility barrier and for heterotopic heart allotransplantation in rats across a major histocompatibility barrier. In the latter, using the same strain of rats, no significant effect can be shown in rat pancreas allotransplantation. In canine renal allografts, only one dose combination (5 mg of Cy A plus 2.5 mg of AZA) was tested, but it was synergistic. Cy A may potentiate the myelosuppressive effect of AZA, and the dose may have to be adjusted to avoid this problem.