98th Annual Meeting DOG 2000

V 109

Highly efficient il-2-inhibitor-free immunomodulation with RAD and mmf in experimental corneal transplantation: a way to immunologic tolerance?

A. Reis, H. Spelsberg, M. Megahed1, C. Braunstein2, E. Godehardt3, R. Sundmacher

Introduction: Activation of lymphocytes is crucial for inducing immunologic tolerance. Immunosuppressive agents like cyclosporin A and tacrolimus, which act at a very early stage of the immunologic cascade prevent the induction of tolerance in several experimental models. RAD (40-0 (2-hydroxyethyl)-rapamycin) a new, highly active macrolid immunosuppressant and mycophenolate mofetil (MMF) do not interfere with the activation of lymphocytes and hence do not prevent the development of immunologic tolerance. The aim of this study was to evaluate the effect of RAD as mono and combination therapy with MMF in the prevention of acute allograft rejection following 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, RAD 2.5 mg/kg, MMF 40 mg/kg, and double drug therapy with RAD 1.5 mg/kg and MMF 20 mg/kg.

Results: The average transplant survival rate in the allogeneic combination was 12.3 days (± 0.3). Monotherapy with RAD 2.5 mg/kg and MMF 40 mg/kg led to a statistically significant prolongation of transplant survival to 37.7 (± 12.5, p<0.05) days and 31.2 (± 13.9, p<0.05) days, respectively. Combination therapy was superior to both monotherapies (84.2 ±15.8 days, p<0.05). There was a significant reduction in the number of CD4+, CD8+ as well as CD45+ cells in the RAD and even more pronounced in the double drug treated animals when compared to the allogeneic control. This significant reduction in graft-infiltrating lymphocytes could not be found in the MMF monotherapy.

Conclusions: We have been able to show a significant synergistic effect of RAD and MMF in prevention of acute rejection following corneal transplantation. As this therapeutic protocol allows activation of lymphocytes and hence induction of tolerance, it is especially attractive for patients following high-risk keratoplasty with a short course of postoperative immunosuppression.

Eye Clinic, 1Department of Dermatology, 2Department of Pathology and 3Department of Cardiac and Thoracic Surgery, Heinrich Heine University, Duesseldorf