The Role of Eplet Matching in Solid Organ Transplantation

Viola A Stögner^1,2*Dean M Pucciarelli³Lauren Harkins⁴Adam Littleton⁵Richard Formica⁶Bohdan Pomahac¹Siba Haykal¹

• ¹Division of Plastic and Reconstructive Surgery, Yale School of Medicine Department of Surgery, New Haven, United States
• ²Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Burn Center, Medizinische Hochschule Hannover, Hanover, Germany
• ³Rutgers Robert Wood Johnson Medical School, New Brunswick, United States
• ⁴Department of Biomedical Engineering, Yale University, New Haven, CT, USA, Yale University, New Haven, United States
• ⁵Yale School of Medicine, New Haven, United States
• ⁶Section of Nephrology, Yale School of Medicine Department of Internal Medicine, New Haven, United States

Introduction: Donor–recipient compatibility remains a central determinant of transplant success, yet conventional antigen-level human leukocyte antigen (HLA) matching provides limited resolution for predicting alloimmune risk. Molecular matching at the eplet level, which quantifies structural motifs on HLA molecules recognized by Band T-cells, has emerged as a promising strategy to refine immunologic risk assessment. Methods: We conducted a scoping review of 98 studies encompassing 286,101 solid organ transplant (SOT) recipients across kidney, heart, lung, liver, pancreas, and combined grafts. Data on HLA typing approaches, eplet mismatch (epMM) algorithms, thresholds, and associations with clinical outcomes were systematically extracted and synthesized. Results: The majority of studies were retrospective kidney transplant cohorts, though evidence from heart, lung, and liver transplantation is expanding. Across organs, higher class II epMM burden— particularly at HLA-DQ and HLA-DR—was consistently associated with de novo donor-specific antibodies, antibody mediated rejection, and graft dysfunction. Reported thresholds varied but were most robust for class II loci, while findings for class I loci were less consistent. Observed differences in thresholds and effect sizes reflected both organ-specific immunobiology and methodological heterogeneity, including variation in typing resolution, mismatch algorithms, immunosuppression exposure, and study design. Conclusion: Eplet matching demonstrates significant potential to improve risk stratification and long-term graft outcomes across SOT. However, clinical translation is limited by inconsistent methods, equity concerns, and the absence of standardized thresholds. Prospective studies, harmonized molecular typing, and integration with allocation frameworks are needed to establish the clinical utility and policy implications of molecular-level HLA matching.