‘Chimeric’ Grafts Assembled from Multiple Allodisparate Donors Enjoy Enhanced Transplant Survival

Abstract

Certain components of a graft that provoke alloimmunity may not be vital for graft function or critical as targets of rejection. Corneal transplantation is an example of this since graft epithelium plays a role in allosensitization, while corneal graft endothelium—which shares the same alloantigens—is the critical target in allorejection. In this study, we found that exploiting this biology by replacing donor epithelium of an allograft with an allodisparate 3rd-party epithelium yields a marked enhancement in transplant survival. Such “chimeric” allografts consisted of a C3H/He (H-2k) corneal epithelium over a C57BL/6 (H-2b) epithelial-denuded cornea (or v.v.) and orthotopically placed on BALB/c (H-2d) hosts. Conventional corneal allografts (C3H/He, or C57BL/6) or isografts (BALB/c) were also transplanted on BALB/c hosts. Alloreactive T cell frequencies (CD4+ IFN-gamma+) primed to graft endothelium were strongly diminished in chimeric relative to conventionally allografted hosts. This was corroborated by decreased T cell infiltration (p=0.03) and a marked enhancement of allograft survival (p=0.001). Our results represent the first successful demonstration of chimeric tissue, epithelial-denuded allograft plus 3rd-party allodisparate epithelium, in the promotion of allograft survival. Moreover, chimeric grafting can be readily performed clinically, whereby corneal allograft rejection remains a significant problem particularly in inflamed graft beds.