Failed allogeneic corneal lenticules show fibrosis and identity loss without dominant T cell rejection

Abstract

Failed allogeneic corneal stromal lenticules develop progressive opacity, but the state of the implanted tissue is unknown. Here we show that six explants from three patients occupy a fibrotic integration-failure state with scar-matrix production and loss of corneal identity without a dominant T cell rejection program. Scar-matrix, transparency and corneal-identity programs separated every patient from eight unimplanted donor controls, the last defined by independent human single-cell references. Calibrated immune programs and repertoire reconstruction distinguished the explants from canonical adaptive rejection. Exchange reduced interface reflectivity initially, followed by recurrent opacity in two patients and corneal steepening with declining uncorrected acuity in the third. In non-scarring rabbit repair, identity moved toward the uninjured state as backscatter returned toward normal despite increasing similarity to the explant-derived expression signature. Within one culture experiment, marked scar suppression accompanied opposite identity responses. Tacrolimus and rapamycin likewise suppressed canonical rejection while moving identity in opposite directions. Resveratrol combined reduced scar-associated programs and increased identity with improved graft appearance in the source study. These findings establish classic-rejection activity and tissue integration as separable axes and direct treatment of failed lenticules from escalating immunosuppression toward control of stromal remodeling and preservation of corneal identity.