Severing corneal nerves induces the release of substance P which converts ocular surface CD11c+ cells to contrasuppressor cells that abolish ocular immune privilege.

Abstract

Purpose : Corneal allograft survival requires T regulatory cells (Tregs) that block immune rejection. Alloantigens entering the anterior chamber (AC) either during penetrating keratoplasty or by direct injection induce a down-regulation of systemic immune response called anterior chamber-associated immune deviation (ACAID), which promotes corneal graft survival. Penetrating keratoplasty severs corneal nerves and releases substance P (SP), which disables Tregs induced by subsequent corneal allografts. We tested the hypothesis that severing corneal nerves stimulates SP release, which converts ocular surface CD11c+ cells to contrasuppressor (CS) cells that disable the Tregs induced by ACAID or corneal allografts.

Methods : ACAID was induced by AC injection of OVA into BALB/c mice. Treg and CS cell activity was determined by local adoptive transfer (LAT) assays for delayed-type hypersensitivity. Ocular surface CD11c+ cells were depleted by subconjunctival injection of clodronate-containing liposomes prior to severing corneal nerves with a 2.0 mm trephine. In other experiments naïve CD11c+ cells were exposed to SP in vitro and injected into naïve mice that were subsequently tested for CS cell activity in ACAID LAT assays. We also determined the minimal number of CS cells that could disable ACAID T regs and the longevity of CS cells.

Results : Depletion of ocular CD11c+ cells prevented induction of CS cells and restored ACAID in mice subjected to nerve ablation. CD11c+ cells exposed to SP in vitro and transferred to naïve recipients prevented the induction of ACAID and confirmed the role of SP and CD11c+ cells in the termination of immune privilege. As few as 1x10³ CD11c+ CS cells disabled T regs. Moreover, CS cell activity persisted for 60 days.

Conclusions : SP released during corneal transplantation converts CD11c+ cells at the graft/host interface to CS cells that abrogate T reg induction by subsequent corneal transplants. This may account for the heightened risk for rejection in hosts receiving second corneal transplants. Severing corneal nerves also prevents the generation of T regs within the AC. Depleting ocular surface CD11c+ cells at the time of keratoplasty may significantly reduce the risk of graft rejection in patients having a second corneal transplant.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.