Antibody-reactive epitope determination with HLAMatchmaker and its clinical applications.

Division of Transplantation Pathology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Tissue Antigens (Impact Factor: 2.93). 03/2011; 77(6):525-34. DOI: 10.1111/j.1399-0039.2011.01646.x
Source: PubMed

ABSTRACT Antibodies against allogeneic human leukocyte antigen (HLA) molecules are important impediments to the success of different clinical procedures including transplantation and platelet transfusion. In these settings, characterization of the repertoire of immunogenic epitopes is important for permissible mismatch determination and the identification of acceptable mismatches for sensitized patients. HLAMatchmaker is a computer algorithm that considers small configurations of polymorphic residues referred to as eplets as essential components of HLA epitopes. This review critically elaborates the concepts underlying the HLAMatchmaker and describes the usefulness of HLAMatchmaker in the clinical setting. Recent developments have increased our understanding of structural basis of HLA antigenicity (i.e. reactivity with specific antibody) and immunogenicity (i.e. its ability to induce an antibody response).

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    ABSTRACT: HLA antibodies usually recognize epitopes rather than antigens. This case report reveals that acute antibody-mediated rejection (AMR) that occurred in a kidney transplant recipient with low-level donor-specific antibodies (DSAs) could be explained by shared epitope. A 39-year-old woman received a first kidney transplant from a deceased donor (HLA-DRB1*11:06, *12:02, DRB3*02:02, *03:01). She developed acute AMR confirmed by kidney biopsy on day 4 after transplantation. Antibody testing with pretransplant serum showed anti-DR11 DSA below cutoff level (mean fluorescence intensity [MFI], 702; cutoff >1,000). However, high-level DSAs were detected on day 5 after transplantation (anti-DR11 MFI, 8,531; anti-DR12 MFI, 3,146). We hypothesized that the sharp rise in DSA levels was a result of anamnestic response with donor-antigen sensitization that occurred during pregnancy. High-resolution HLA-DR typing of her husband showed HLA-DRB1*03:01, *15:02:01, DRB3*02:02, DRB5*01:02. No sharing between donor HLAs eliciting reactive antibodies and her husband's HLAs was detected. Nevertheless, we speculated that shared epitope, not antigen, was the cause of allosensitization. To identify the shared epitope recognized by patient's antibodies, we used HLAmatchmaker, a computer algorithm that considers small configurations of polymorphic residues referred to as eplets as essential components of HLA epitopes for analysis. The results showed that 149H, which was the eplet shared by HLA-DRB1*03:01 (from her husband) and DRB1*11:06, DRB1*12:02, DRB3*03:01 (from donor), was the most prevalent eplet on DRB1 reactive alleles in Luminex assay. In conclusion, pretransplant low-level DSAs can induce AMR early after transplantation as a result of shared epitopes with a previous immunizer.
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    ABSTRACT: As important risk factors for transplant rejection and failure, HLA antibodies are now recognized as being specific for epitopes which can be defined structurally with amino acid differences between HLA alleles. Donor-recipient compatibility should therefore be assessed at the epitope rather than the antigen level. HLAMatchmaker is a computer algorithm that considers each HLA antigen as a series of small configurations of polymorphic residues referred to as eplets as essential components of HLA epitopes. It includes epitopes on antigens encoded by all HLA-A, B, C, DR, DQ and DP loci as well as MICA. HLA epitopes have two characteristics namely antigenicity, i.e. the reactivity with antibody and immunogenicity, i.e. the ability of eliciting an antibody response. This article addresses the relevance of determining epitope-specificities of HLA antibodies, the effect of epitope structure on technique-dependent antibody reactivity and the identification of acceptable mismatches for sensitized patients considered for transplantation. Permissible mismatching for non-sensitized patients aimed to prevent or reduce HLA antibody responses could consider epitope loads of mismatched antigens and the recently developed nonself-self paradigm of epitope immunogenicity.
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