Coadministration of the new macrolide immunosuppressant RAD and mycophenolate mofetil in experimental corneal transplantation

Introduction. The effect of RAD, a new macrolide immunosuppressant, was exa mined as mono- and combination therapy with mycophenolate mofetil (MMF) in prevention of acute allograft rejection in murine corneal transplantation. Methods. Both drugs were administered orally for 18 days beginning at the d ay of transplantation. The inbred strains Fisher and Lewis were used as don ors and recipients, respectively. Five groups were involved: syngeneic cont rol, allogeneic control, 2.5 mg/kg RAD, 40 mg/kg MMF, and double drug thera py with 1.5 mg/kg RAD and 20 mg/kg MMF. Results, The median transplant survival time in the allogeneic combination was 12 (+/-0,3) days. Monotherapy with 2.5 mg/kg RAD and 40 mg/kg MMF led t o a statistically significant prolongation of transplant survival to 25.5 ( +/-12.5, P = 0,0001) days and 19.5 (+/- 13.9, P = 0,0053) days, respectivel y, Combination therapy was superior to both monotherapies (100 +/- 15,8 day s, P = 0,03), There was a significant reduction in the number of CD4(+), CD 8(+), as well as CD45RA(+) cells in the RAD- and double drug-treated animal s when compared with the allogeneic control, This significant reduction in graft-infiltrating lymphocytes has not been found in the MMF monotherapy. Conclusions. The unique finding of this first study on the combination of R AD and MMF in murine corneal transplantation is that double drug therapy pr oduces a highly synergistic effect in prevention of acute allograft rejecti on without a higher incidence of complications related to drug toxicity or overimmunosuppression.