Matchmaker, matchmaker make me a match: Opportunities and challenges in optimizing compatibility of HLA eplets in transplantation

Abstract

The development of donor‐specific antibodies (DSAs) is a major complication in transplantation, which is associated with inferior graft survival, impaired quality of life, and increased healthcare costs. DSA develop upon recognition of nonself HLA by the recipient's immune system. HLA molecules contain epitopes, which are the surface regions of HLA molecules recognized by antibodies. HLAMatchmaker is an algorithm for assessing donor:recipient HLA compatibility at the level of structurally defined HLA targets called eplets. The consideration of eplets, rather than the whole HLA molecule, could offer some advantages when classifying the immune risk associated with particular donor:recipient pairs. Assessing compatibility at the level of HLA eplets could decrease misclassification of post‐transplant immune risk by improving specificity, when antibodies are confirmed to be directed against donor eplets missing from the recipient's repertoire of eplets. Consideration of eplets may also increase the sensitivity of immune risk assessment, when identifying mismatched eplets that could give rise to new, not previously detected, donor‐specific antibodies post‐transplant. Eplet matching can serve as a rational strategy for immune risk mitigation. Herein, we review the evolution of HLA (in) compatibility assessment for organ allocation. We outline challenges in the implementation of eplet‐based donor:recipient matching, including unavailability of allele‐level donor genotypes for 11 HLA loci at the time of organ allocation and difficulty in assessing the hierarchy of immune risk associated with particular HLA eplet mismatches. Opportunities to address some of the current shortcomings of donor genotyping and HLAMatchmaker are also discussed. While there is a demonstrated benefit in the application of HLAMatchmaker for donor: recipient HLA (in)compatibility assessment, evolving long‐read genotyping methods, compilation of large data sets with allele‐level genotypes, and standardization of methods to verify eplets as determinants of immune‐mediated injuries are required before HLA eplet matching is implemented in organ allocation to improve upon transplant outcomes.

Advances in allergen‐specific immune cell measurements for improved detection of allergic sensitization and immunotherapy responses

“…14 Human leukocyte antigens (HLA) corresponding to MHC class II are HLA‐DP, HLA‐DM, HLA‐DOA, HLA‐DOB, HLA‐DQ, and HLA‐DR. While for MHC class I, there is a dominant allele in the population worldwide (HLA‐A*02; 29–46%), this is not the case for any MHC class II encoding genes 15 . As a result, there is a large inter‐individual variation in HLA and the peptides that are presented.…”

“…While for MHC class I, there is a dominant allele in the population worldwide (HLA-A*02; 29-46%), this is not the case for any MHC class II encoding genes. 15 As a result, there is a large inter-individual variation in HLA and the peptides that are presented. Each T cell expresses a TCR with distinct specificity, which results from genomic rearrangement of V, D, and J genes in their TCR loci to create a unique first exon that encodes the variable domain.…”

A Comprehensive Evaluation of the Antibody-Verified Status of Eplets Listed in the HLA Epitope Registry

“…HLA eplets are small configurations of surface-exposed amino acids within a 3-3.5 Ångstrom (Å) radius (3,4) and resemble the functional epitope, which generally determines the specificity of the antibody through interaction with the complementaritydetermining region 3 (CDR3) of the heavy chain of the antibody (5)(6)(7). Consideration of HLA eplets instead of HLA antigens may not only refine HLA matching strategies, resulting in decreased DSA formation, but also expand the donor pool for highly sensitized patients and facilitate personalized immunosuppressive treatment based on immunological risk evaluation (8). Indeed, several studies have shown that eplet mismatches are correlated with DSA formation, graft rejection and graft loss (9)(10)(11)(12)(13)(14).…”

“…Indeed, several studies have shown that eplet mismatches are correlated with DSA formation, graft rejection and graft loss (9)(10)(11)(12)(13)(14). However, as eplets have been theoretically defined, their clinical relevance needs to be validated by antibody verification (8,15). Although antibody-verified eplet mismatches have been demonstrated to correlate with DSA formation and graft survival (13,14), recent reports also indicated that there are still clinically relevant eplets which have not been antibodyverified yet (13,16).…”

HLA-DQ-Specific Recombinant Human Monoclonal Antibodies Allow for In-Depth Analysis of HLA-DQ Epitopes

“…Multiple studies have demonstrated an association between eplet mismatches and formation of dnDSA (12)(13)(14)(15)(16)(17). However, not all theoretically defined eplets are immunogenic and thus verification of actual interactions with antibodies is needed to determine the clinically relevant eplets (18)(19)(20). For HLA class I, a large number of eplets has been verified by several different methods (21)(22)(23)(24)(25)(26)(27).…”