New drugs in prevention of experimental corneal graft rejection
Immune mediated graft rejection remains a major complication of penetrating keratoplasty (PKP), requiring more effective preventive measures. Purpose: We investigated the efficacy of selective glucocorticoid receptor agonist (SEGRA), everolimus and spironolactone on the prevention of allograft rejection in a MHC class I/II mismatch rat corneal transplant model. Methods: A total of 133 female Lewis rats underwent PKP. Syngeneic corneal grafting in 20 rats served as control for technical failure.
... All other 113 Lewis rats received allogeneic corneal grafts from Dark Agouti donors and were randomly assigned to receive the agent of interest, vehicle or remained untreated. ME- CD-SEGRA (0.25% SEGRA-containing microemulsion) and everolimus microemulsion (0.05 and 0.025%) were applied as topical treatment five times daily, while spironolactone suspension was given orally, 100 mg/kg/day. Therapy was applied daily for 35 days in SEGRA group and until the day of rejection in everolimus and spironolactone treated rats for graft survival analysis. Detection of immunological parameters was performed by testing mRNA expression of cytokines (IL-4, IL-10, IFN-γ, TNF-α) and T-cell markers (CD3, CD25) at predestinated time points. Results: Topical application of ME-CD-SEGRA significantly prolonged mean survival time (MST) 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). ME-CD-SEGRA decreased intragraft mRNA expression of all tested cytokines and T-cell marker, in particularly significant for IL-4 compared to untreated controls (p < 0.05). Local administration of 0.05 or 0.025% everolimus was effective in prolonging the MST of corneal grafts (21 ± 6.57 days and 16.4 ± 2.3 days, respectively) compared to the vehicle group (13.3 ± 1.7 days, for both p < 0.001). At the same time, increased mRNA expression of IL-10 (p = 0.015) was detected in everolimus treated grafts. Spironolactone also significantly prolon [...]