gms | German Medical Science

Background: Mast cells (MCs) are prominent inflammatory cells in choroid. MCs are effector cells of innate immunity that we have previously demonstrated are elevated in number and in degranulation in geographic atrophy (GA) (Bhutto et al, BJO 2016). Furthermore, MC tryptase released during degranulation is present in Bruchs membrane in GA subjects (McLeod et al, IOVS 2018). This enzyme could lead to degradation of Bruchs membrane and thinning of choroid. The goal of this study was to develop an animal model to evaluate the role of MC activation and degranulation (DG) in causing RPE degeneration and retinal and choroidal thinning, hallmarks of GA.

Methods: A hydrogel with 48/80 (a snake venom-like compound) or blank hydrogel was injected subconjunctivally in Sprague-Dawley rats. MCs were stained with nonspecific esterase (NSE), retinal pigment epithelial cells (RPE) labeled with RPE65 in whole mount choroids, and retinal and choroidal area were determined in cryosections stained with picrosirius red. The generic FDA approved MC stabilizer, ketotifen fumarate (KTF), was evaluated in the model.

Results: Choroidal MC degranulation was significant at one week post implantation of 48/80. By 4-6 weeks, there was significant loss of RPE in eyes with 48/80 compared to blank hydrogel (p<0.005). The areas of retina and choroid were reduced at 8-10 weeks post implantation in 48/80 eyes compared to blank hydrogel (p<0.05). RPE loss and retinal and choroidal thinning did not occur in rats without MCs (cKit-/-). Daily KTF (10 mg/kg) orally inhibited RPE loss at 6 wks and thinning of retina and choroid at 8-10 weeks.

Conclusion: Inducing MC degranulation in rat choroid resulted in loss of RPE at 6 weeks post implantation and reduced retinal and choroidal areas by 10 weeks. Inhibiting MC degranulation with KTF prevented three phenotypic characteristics of GA: RPE loss and retinal and choroidal thinning.