Operational post-keratopasty graft tolerance due to differential HLAMatchmaker matching

摘要

Purpose: Penetrating keratoplasty canrestore vision in corneal blindness. However, immunologic rejectionthreatens graft survival. Matching donors at swine leukocyte antigen(SLA)-class II convey allo-specific tolerance in a large animalkidney-transplantation model despite mismatches at SLA-class I. Thesame matching pattern seems to account for the blood transfusion effectin kidney transplantation. Relying on the molecular basis ofHLAMatchmaker eplets, we assessed whether this finding would also applyto keratoplasty, and if it would enhance the benefit from matchinghuman leukocyte antigen (HLA)-class I alone. Methods: We retrospectively selected twoindependent cohorts comprising 586 and 975 penetrating keratoplasties.Our computations revealed a quantitative tolerogenicity factoranalogous to the animal model. The number of mismatched HLA-class Ieplets functioned as a factor for conventional histocompatibility. Inthe first cohort, we empirically determined the thresholds with thehighest predictive power on graft rejection for both factors, andconfirmed those thresholds in the second cohort. We applied Coxproportional hazards regression for these analyses. Results: The thresholds with highestpredictive power revealed 220 eplets2 for the tolerancefactor and 10 eplets for HLA-class I histocompatibility. The respectivehazards ratios were 2.22 (p=0.04) versus 3.63 (p0.01) in the firstcohort and 2.09 (p0.01) versus 1.51 (p=0.02) in the second,confirmatory cohort. The threshold factors proved to be additive inpredicting immune reactions in both cohorts, (hazard ratios 2.66 incohort 1 versus 1.70; p0.01 in cohort 2). Conclusions: Operational tolerance maybe inducible by balanced matching of HLA-class I and II HLAMatchmakereplets. Furthermore, such tolerance is additive to histocompatibliityat HLA-class I.