ABSTRACT
AIMS: To evaluate the efficacy and safety of topically applied mycophenolate mofetil (MMF) for the prophylaxis of corneal graft rejection in an experimental keratoplasty model. METHODS: A total of 12 female Lewis rats received 3.5-mm MHC I/II-incompatible corneal grafts from DA donors. Recipients were randomly assigned to receive either topical MMF + beta-cyclodextrin therapy (1%), beta-cyclodextrin therapy alone or to remain untreated. Therapy was applied every 2 h (over 24 h) during the first 3 postoperative days, then twice hourly during daytime. Grafts were graded every day based on a rejection score including the parameters transplant clarity and edema. RESULTS: The mean survival time (MST) of the grafts in the MMF-treated group was 12 days, the MST in the vehicle-treated group was 14.3 days and the MST in the untreated group was 13.3 days. So, the survival curves of the 3 treatment groups did not differ significantly. CONCLUSION: Topical MMF is ineffective for prophylaxis of corneal graft rejection.
Subject(s)
Corneal Transplantation , Graft Rejection/drug therapy , Graft Survival/drug effects , Immunosuppressive Agents/pharmacology , Mycophenolic Acid/analogs & derivatives , Administration, Topical , Animals , Disease Models, Animal , Female , Graft Rejection/prevention & control , Immunosuppressive Agents/chemistry , Mycophenolic Acid/chemistry , Mycophenolic Acid/pharmacology , Ophthalmic Solutions , Rats , Rats, Inbred Lew , Transplantation, Homologous , Treatment Failure , beta-Cyclodextrins/pharmacologyABSTRACT
BACKGROUND: New insights into the molecular mechanisms of corticosteroid-mediated actions have revealed new substances, such as selective glucocorticoid receptor agonists (SEGRA), for the treatment of inflammatory diseases. We set out to evaluate the effect of a SEGRA compound following topical application on the course of experimental orthotopic corneal grafts. METHODS: A total of 42 female Lewis rats received 3.5-mm MHC I/II-incompatible corneal grafts from DA donors. Recipients were randomly assigned to receive either no therapy, 0.25% cyclodextrin-encapsulated SEGRA compound in a new microemulsion formulation or carrier system only. All treatments started on the day of surgery and were given five times daily for 35 days. Grafts were graded every day and a rejection score was generated based on cornea clarity and edema. In addition, intragraft mRNA expression of CD3, IFN-gamma, TNF-alpha, IL-10 and IL-4 was analyzed using real-time RT-PCR analysis at day 7 after transplantation before rejection occurred in additional control animals. RESULTS: Topical application of a SEGRA compound was highly effective in prolonging the mean survival time of corneal grafts (42.2+/-4.0 days) compared with untreated controls (11.7+/-1.2 days, p=0.00003) or animals that received the vehicle only (15.0+/-1.5 days, p=0.114). In addition, real-time RT-PCR analysis of SEGRA-treated grafts revealed lower mRNA expression of intragraft cytokines; the difference was significant for IL-4 (p<0.05). CONCLUSIONS: Our results indicate that topical application of a SEGRA compound significantly prolongs corneal graft survival in an experimental keratoplasty model. It further suggests that SEGRA can be a potentially useful drug to suppress the immune response.