Cyclosporine Immunomodulation Retards Regeneration of Surgically Transected Corneal Nerves

PURPOSE. To determine whether immunomodulation with cyclosporine (CsA) affects reinnervation after surgical transection of stromal nerves. METHODS. Thy1-YFP+ neurofluorescent mice underwent lamellar corneal surgery and 3 days later, received artificial tears or CsA eye drops for 6 weeks. Serial in vivo wide-field stereofluorescent microscopy was performed to determine changes in nerve fiber density (NFD). Real-time quantitative PCR was performed to determine the expression of neurotrophins and cytokines (IL6 and TNF-alpha). Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether CsA directly affects neurite outgrowth. RESULTS. Yellow fluorescent protein (YFP)-positive cells significantly increased at 3 and 7 days after surgery. The number of YFP-positive cells in the cornea was significantly lower in the CsA group than that in the control group. The percentage increase in NFD between 2 to 6 weeks was greater in the control group (80% +/- 10%, P = 0.05) than that in the CsA group (39% +/- 21%). The CsA group also exhibited lower expression of IL6 and TNF-alpha (P = 0.01). In compartmental culture experiments, neurite outgrowth toward side compartments containing CsA was significantly less (2.29 +/- 0.4 mm, P = 0.01) than that toward side compartments containing vehicle (3.97 +/- 0.71 mm). CONCLUSIONS. Immunomodulation with CsA reduces the expression of cytokines (IL6) in the cornea and retards regenerative sprouting from transected corneal stromal nerve trunks. In addition, CsA has a direct growth inhibitory action on neurites as well. (Invest Ophthalmol Vis Sci. 2012;53:732-740) DOI: 10.1167/iovs.11-8445