Destruction of Corneal Nerves Promotes Corneal Allograft Rejection

The human corneal endothelium has very little regenerative capacities and cannot fully heal in response to infection or trauma. Evolutionarily, the eye developed a mechanism to retain visual acuity by protecting the eye from inflammatory damage, referred to as immune privilege. The mechanisms that protect the eye from inflammation-induced injury are 1.) the presence of immunosuppressive molecules within the aqueous humor; 2.) the expression of pro-apoptotic factors on corneal cells ; and 3.) the induction of a form of immune tolerance called anterior chamber-associated immune deviation (ACAID). Immune privilege contributes to the 90% success rate of corneal allografts without the need for histocompatibility matching and use of systemic immunosuppressive therapy.
However, when one or more parameters that contribute to immune privilege are broken, the cornel allograft becomes vulnerable to the immune system, resulting in corneal allograft failure. Patients that elect to have a corneal allograft replaced are the population at the highest risk of immune rejection and have only a 70% success rate with the second corneal allograft, and the rate of rejection continues to increase with each successive graft. Why subsequent corneal allografts have an increased incidence of rejection is unknown. Due to the high success rate of corneal allografts, the donor tissues are not tissue matched to the recipients. With the limited documentation on the histocompatibility gene loci expressed by the corneal tissue donors, it is unknown if the rejection of the initial corneal allograft sensitizes the corneal allograft recipient. This study provides evidence that the sensitization of the corneal transplant recipient towards alloantigens also expressed on the subsequent corneal allografts is not a requisite for the high incidence of graft rejection. Furthermore, the enhanced incidence of graft rejection is an immune response directed towards alloantigens expressed on the subsequent corneal transplant.
The aim of this study is to determine why the corneal transplantation procedure enhances the rejection of subsequent corneal allografts in both eyes. Experimental evidence demonstrates that the destruction of the corneal nerves in one eye fundamentally alters the expression of the immunoregulatory neuropeptides in the contralateral eye. The altered expression of these neuropeptides inhibits both the induction and maintenance of immune privilege. The alteration in the microenvironment mediated a quick and prolonged loss of immune privilege, which could be reversed by blocking the activity of the pro-inflammatory neuropeptide substance P (SP).
The survival of the corneal allograft requires the participation of antigen-specific T regulatory cells. Neuropeptides within the ocular environment are important for immune privilege through the induction of tolerance. Our results demonstrate the destruction of the corneal nerves and the release of the pro-inflammatory neuropeptide SP inhibits both the generation and function of T regulatory cells, which ultimately leads to corneal allograft rejection.