Immune privilege of corneal allografts

Abstract

Corneal transplantation has been performed successfully for over 100 years. Normally, HLA typing and systemic immunosuppressive drugs are not utilized, yet 90% of corneal allografts survive. In rodents, corneal allografts representing maximal histoincompatibility enjoy >50% survival even without immunosuppressive drugs. By contrast, other categories of transplants are invariably rejected in such donor/host combinations. The acceptance of corneal allografts compared to other categories of allografts is called immune privilege. The cornea expresses factors that contribute to immune privilege by preventing the induction and expression of immune responses to histocompatibility antigens on the corneal allograft. Among these are soluble and cell membrane molecules that block immune effector elements and also apoptosis of T lymphocytes. However, some conditions rob the corneal allograft of its immune privilege and promote rejection, which remains the leading cause of corneal allograft failure. Recent studies have examined new strategies for restoring immune privilege to such high-risk hosts.

FIGURE 1

Cell membrane-bound molecules expressed on the corneal endothelium block the expression of effector T cells and complement activation. Complement regulatory proteins (CRPs) are expressed on the cell membranes of corneal endothelial cells and are also present in soluble forms in the aqueous humor. CRPs disable the complement cascade and protect the corneal allograft from complement-mediated cytolysis. Fas ligand (FasL) is expressed on the corneal endothelium and in soluble forms in the aqueous humor and induces apoptosis of activated T cells and neutrophils. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expressed on the corneal endothelium and induces apoptosis of activated T cells expressing its receptor (TRAIL-R2). The role of TRAIL in the immune privilege of corneal allografts is unknown at the present time. Programmed death ligand-1 (PD-L1) is expressed on the corneal endothelium, inhibits T-cell proliferation, and, in some circumstances, induces apoptosis of T cells expressing its receptor, PD-1.

FIGURE 2

Stratification of actuarial corneal transplant survival according to the number of quadrants of recipient cornea vascularized at the time of transplantation. (Adapted with permission from Coster DJ, Williams KA. The impact of corneal allograft rejection on long-term outcome of corneal transplantation. Am J Ophthalmol. 2005;140:1112–1122.)

FIGURE 3

Stratification of actuarial corneal transplant survival according to the number of rejected previous ipsilateral transplants. (Adapted with permission from Coster DJ, Williams KA. The impact of corneal allograft rejection on long-term outcome of corneal transplantation. Am J Ophthalmol. 2005;140:1112–1122.)

FIGURE 4

Neovascularization in corneal allograft rejection. Corneal neovascularization dramatically increases the risk of immune rejection. Deep stromal vessels are easily seen in many rejected corneal allografts (A), yet some corneal allografts undergo rejection without evidence of macroscopically detectable vessels (B).