SYNERGISTIC EFFECT OF RAPAMYCIN AND CYCLOSPORINE-A IN THE TREATMENT OF EXPERIMENTAL AUTOIMMUNE UVEORETINITIS

Immunosuppressive drugs currently available for the treatment of autoi mmune diseases display a narrow therapeutic window between efficacy an d toxic side effects. The use of combinations of drugs that have a syn ergistic effect may expand this window and reduce the risk of toxicity . We evaluated the combination effect of rapamycin (Rapa) and cyclospo rin A (CsA) in an autoimmune disease model of the eye. The dose-effect relationship of Rapa with CsA was measured in vitro on the inhibition of proliferation of retinal S-Ag-primed lymphocytes. A median effect analysis was performed and a combination index (Cl) calculated for 50% inhibition of proliferation. Rapa and CsA were markedly synergistic o ver a wide dose range (lowest Cl = 0.31). Calculated dose reduction fa ctors indicated that Rapa could be reduced nine-fold and CsA reduced f ive-fold when these drugs were used in combination. These reduced dose s were tested in vivo for the treatment of experimental autoimmune uve oretinitis (EAU). Twelve of 15 rats treated with CsA, 2 mg/kg/day, dev eloped EAU with a median severity of 2.5. Fourteen of 15 rats treated with Rapa, 0.01 mg/kg/day, developed EAU with a median severity of 3.2 5. Complete inhibition of EAU was achieved in all 15 animals treated w ith the combination of Rapa and CsA (combined vs CsA alone, p < 0.0002 ; combined vs Rapa alone, p < 0.00001). The demonstrated synergistic r elationship between Rapa and CsA will allow the use of reduced doses o f each drug to achieve a therapeutic effect. The use of lower doses ma y reduce the toxicity of these drugs for the treatment of autoimmune u veitis.