Blockade of CD40–CD154 Costimulatory Pathway Promotes Long‐Term Survival of Full‐Thickness Porcine Corneal Grafts in Nonhuman Primates: Clinically Applicable Xenocorneal Transplantation

The porcine cornea may be a good solution for the shortage of human donor corneas because its size and refractive properties are comparable to those of the human cornea. However, antigenic differences need to be overcome to apply xenocorneal transplantation in actual clinical practice. We aimed to investigate the feasibility of full‐thickness porcine corneas as human corneal substitutes using a CD40–CD154 costimulatory pathway blocking strategy in a clinically applicable pig‐to‐nonhuman primate corneal transplantation model. As a result, the mean survival time of the xenocorneal grafts in recipients who received anti‐CD154 antibody‐based immunosuppressants (POD318 (n = 4); >933, >243, 318 and >192) was significantly longer than that in controls (POD28 (n = 3); 21, 28 and 29; p = 0.010, log‐rank test). Administration of anti‐CD154 antibodies markedly reduced inflammatory cellular infiltrations (predominantly CD8 T cells and macrophages) into the xenocorneal grafts and almost completely blocked xenoantigen‐triggered increases in Th1‐associated cytokines, chemokines and C3a in the aqueous humor. Moreover, systemic expansion of memory T cells was effectively controlled and responses of anti‐Gal/donor pig‐specific antibodies were considerably diminished by programmed injection of anti‐CD154 antibodies. Consequently, porcine corneas might be promising human corneal substitutes when the transplantation is accompanied by potent immunosuppression such as a CD40–CD154 costimulatory pathway blockade. Using a pig‐to‐nonhuman primate full‐thickness corneal transplant model, the authors show that programmed administration of antibodies to CD154 (CD40 ligand) significantly prolongs corneal xenograft survival; markedly reduces inflammatory cellular infiltrations into the graft; almost completely blocks xenoantigen‐triggered increases in Th1‐associated cytokines, chemokines, and C3a in the aqueous humor; and effectively controls systemic expansion of memory T cells and anti‐Gal/donor pig‐specific antibodies.