Abstract
Matching strategies based on HLA eplets instead of HLA antigens in solid organ transplantation may not only increase the donor pool for highly sensitized patients, but also decrease the incidence of de novo donor-specific antibody formation. However, since not all eplets are equally capable of inducing an immune response, antibody verification is needed to confirm their ability to be bound by antibodies, such that only clinically relevant eplets are considered. The HLA Epitope Registry has documented all theoretically defined HLA eplets along with their antibody verification status and has been the foundation for many clinical studies investigating eplet mismatch in transplantation. The verification methods for eplets in the Registry range from polyclonal sera from multi- and uni-parous women to murine and human monoclonal antibodies (mAbs), and antibodies purified by adsorption and elution from sera of HLA immunized individuals. The classification of antibody verification based on different methods for validation is problematic, since not all approaches represent the same level of evidence. In this study, we introduce a classification system to evaluate the level of evidence for the antibody-verified status of all eplets in the HLA Epitope Registry. We demonstrate that for a considerable number of eplets, the antibody-verified status is solely based on polyclonal serum reactivity of multiparous women or on reactivity of murine mAbs. Furthermore, we noted that a substantial proportion of patient sera analyses and human mAb data presented in the HLA Epitope Registry Database has never been published in a peer-reviewed journal. Therefore, we tested several unpublished human HLA-specific mAbs by luminex single antigen beads assay to analyze their HLA reactivity for eplet antibody verification. Although the majority of analyzed mAbs indeed verified their assigned eplets, this was not the case for a number of eplets. This comprehensive overview of evidence for antibody verification of eplets in the HLA Epitope Registry is instrumental for future investigations towards eplet immunogenicity and clinical studies considering antibody-verified eplet mismatch in transplantation and warrants further standardization of antibody verification using high quality data.
Highlights
Donor-specific antibodies (DSA) are formed against mismatched polymorphic amino acid residues on donor human leukocyte antigens (HLA) and are a major complication in renal transplantation, leading to chronic rejection and graft loss [1, 2]
We demonstrate that antibody-verified status of 45% of the eplets is based on analysis of polyclonal sera, murine monoclonal antibody (mAb) or experiments with low resolution HLA typed cells and that several human mAbs have been wrongfully attributed to the verification of certain eplets
Human mAb data presented in the database that had not been published in a peer-reviewed journal were considered as not sufficient for antibody verification
Summary
Donor-specific antibodies (DSA) are formed against mismatched polymorphic amino acid residues on donor human leukocyte antigens (HLA) and are a major complication in renal transplantation, leading to chronic rejection and graft loss [1, 2]. Several studies have shown that eplet mismatches are correlated with DSA formation, graft rejection and graft loss [9,10,11,12,13,14]. Antibody-verified eplet mismatches have been demonstrated to correlate with DSA formation and graft survival [13, 14], recent reports indicated that there are still clinically relevant eplets which have not been antibodyverified yet [13, 16]
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