HLA Mismatches Identified by a Novel Algorithm Predict Risk of Antibody-mediated Rejection From De Novo Donor-specific Antibodies.

Abstract

The development of de novo donor-specific antibodies (dnDSA) and antibody-mediated rejection (AMR) remains a barrier to long-term graft and patient survival. Most dnDSA are directed against mismatched donor HLA-DQ antigens. Here, we describe a novel algorithm, which we have termed categorical amino acid mismatched epitope, to evaluate HLA-DQ mismatches. In this algorithm, amino acid residues of HLA-DQ protein were categorized into 4 groups based on their chemical characteristics. The likelihood of categorically mismatched peptides presented by the recipient's HLA-DRB1 was expressed as a normalized value, %Rank score. Categorical HLA-DQ mismatches were analyzed in 386 heart transplant recipients who were mismatched with their donors at the HLA-DQB1 locus. We found that the presence of DQB1 mismatches with %Rank score ≤1 was associated with the development of dnDSA (P = 0.002). Furthermore, dnDSA increased the risk of AMR only in recipients who had DQ mismatches with %Rank score ≤1 (hazard ratio = 5.8), but the freedom from AMR was comparable between recipients with dnDSA and those without dnDSA if %Rank scores of DQ mismatching were >1. These results suggest that HLA-DQ mismatches evaluated by the categorical amino acid mismatched epitope algorithm can stratify the risk of development of dnDSA and AMR in heart transplant recipients.