Epitope-Based HLA Matching in Allogeneic Transplantation: A Literature Review on Computational Methods to Reduce Antibody-Mediated Rejection

Abstract

Long-term success in allogeneic transplantation currently relies on the precise matching of donor and recipient HLA alleles to minimise immune-mediated complications. These complications can occur when either B- or T-cell receptors recognize subtle mismatches on the HLA molecule or when T-cells respond to donor peptides presented by the recipient’s HLA molecules, both of which can lead to the formation of de novo DSA causing AMR. Shifting to HLA epitope-based matching can potentially reduce de novo DSA formation and increase the number of suitable donors for highly sensitised patients. Epitope-based computational tools such as HLAMatchmaker, HLA-EMMA, Snowflake, and PIRCHE-II offer innovative approaches to identifying immunologically relevant epitopes and assessing immune compatibility. HLAMatchmaker identifies mismatched eplets, however, it assumes that inter- and intra-locus eplets have equal immunogenicity, even though certain eplets may provoke a stronger immune response than others. HLA-EMMA addresses this limitation by focusing primarily on intralocus solvent-accessible polymorphic amino acids, which are more likely to be recognised by B-cell receptors, thereby improving the consistency of mismatch analysis. The Snowflake method further refines B-cell epitope predictions by emphasising allele-specific accessibility. On the other hand, PIRCHE-II uniquely assesses T-cell reactivity by modelling the donor peptide presentation on recipient HLA class II molecules, thereby estimating potential alloreactivity. These tools have been correlated with reduced de novo DSA formation, highlighting the potential of epitope-based matching to improve donor selection and expand transplant options for sensitised patients. However, integrating these tools into clinical practice requires further validation and refinement, promising a future of more precise and durable allogeneic transplants.