Abstract
Purpose :
Approximately 90% of first time corneal transplants survive without histocompatibility matching. Despite the success rate, second corneal transplants often experience a three-fold increase in rejection . Using a mouse model of keratoplasty, we found that severing corneal nerves during the initial surgery, induces a neuropeptide substance P (SP) in both eyes. SP acts on CD11c+ dendritic cells at the graft/host interface and converts them to contrasuppressor (CS) cells. The CS cells disable the T regulatory (Treg) cells needed for graft survival, thus leading to increased rejection of subsequent transplants. We tested the hypothesis that depletion of CD11c+ cells at the ocular surface or topical corticosteroids would prevent the generation of CS cells and restore T reg function.
Methods :
Naïve BALB/c CD11c+ /CD11c-cells were exposed to SP invitro and adoptively transferred to mice at days 7, 21 and 35 post-transplantation. In other experiments, ocular surface CD11c+ cells were depleted by sub-conjunctival injection of clodronate liposomes prior to corneal transplantation. BALB/c mice received BALB/c syngrafts OS at day 0 and a C57BL/6 allografts OD 21 days later. Mice were treated topically with 0.1% dexamethasone (3 drops/day) to test If the generation of CS cells could be blocked.
Results :
Adoptive transfer of SP treated CD11c+ cells abolished the immune privilege of first time corneal grafts and led to 81% rejection (9/11 mice) compared to 9% rejection(1/11) in recipients of SP treated CD11c- cells. Depletion of CD11c+ cells by clodronate liposomes prevented the generation of CS cells and restored T reg function, resulting in enhanced graft survival. Topical steroids also prevented the generation of CS cells and restored graft survival (15/19 mice experienced graft survival).
Conclusions :
The transient release of SP during transplantation induces the generation of CD11c+ CS cells that disable T regs. The generation of CS cells can be prevented by either subconjunctival injection of clodronate liposomes or by topical application of corticosteroids. Depletion of CD11c+ cells using clodronate liposomes has less deleterious effects than corticosteroids and is an effective method to prevent CS cells that are induced by initial transplant and to restore T reg function to ensure the survival of subsequent transplants.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.