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

Introduction. The effect of RAD, a new macrolide immunosuppressant, was examined 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 day of transplantation. The inbred strains Fisher and Lewis were used as donors and recipients, respectively. Five groups were involved: syngeneic control, allogeneic control, 2.5 mg/kg RAD, 40 mg/kg MMF, and double drug therapy 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 to 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, respectively, Combination therapy was superior to both monotherapies (100 +/- 15,8 days, P = 0,03), There was a significant reduction in the number of CD4(+), CD8(+), as well as CD45RA(+) cells in the RAD- and double drug-treated animals 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 RAD and MMF in murine corneal transplantation is that double drug therapy produces a highly synergistic effect in prevention of acute allograft rejection without a higher incidence of complications related to drug toxicity or overimmunosuppression.