Synergistic effect of rapamycin and cyclosporin A in the treatment of experimental autoimmune uveoretinitis.
Immunosuppressive drugs currently available for the treatment of autoimmune diseases display a narrow therapeutic window between efficacy and toxic side effects. The use of combinations of drugs that have a synergistic effect may expand this window and reduce the risk of toxicity. We evaluated the combination effect of rapamycin (Rapa) and cyclosporin 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 (CI) calculated for 50% inhibition of proliferation. Rapa and CsA were markedly synergistic over a wide dose range (lowest CI = 0.31). Calculated dose reduction factors indicated that Rapa could be reduced nine-fold and CsA reduced five-fold when these drugs were used in combination. These reduced doses were tested in vivo for the treatment of experimental autoimmune uveoretinitis (EAU). Twelve of 15 rats treated with CsA, 2 mg/kg/day, developed 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 3.25. Complete inhibition of EAU was achieved in all 15 animals treated with the combination of Rapa and CsA (combined vs CsA alone, p < 0.0002; combined vs Rapa alone, p < 0.00001). The demonstrated synergistic relationship between Rapa and CsA will allow the use of reduced doses of each drug to achieve a therapeutic effect. The use of lower doses may reduce the toxicity of these drugs for the treatment of autoimmune uveitis.
Martin
D F
DF
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892.
DeBarge
L R
LR
Nussenblatt
R B
RB
Chan
C C
CC
Roberge
F G
FG
D000818:Animals; D000941:Antigens / Q000276:immunology; D019393:Arrestin; D001327:Autoimmune Diseases / Q000188:drug therapy*; D016572:Cyclosporine / Q000627:therapeutic use*; D004357:Drug Synergism; D005136:Eye Proteins / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D011090:Polyenes / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D012173:Retinitis / Q000188:drug therapy* / Q000276:immunology; D020123:Sirolimus; D014605:Uveitis / Q000188:drug therapy* / Q000276:immunology
D000941:Antigens; D019393:Arrestin; D005136:Eye Proteins; D007166:Immunosuppressive Agents; D011090:Polyenes; D016572:Cyclosporine; D020123:Sirolimus