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: 2.14). 03/2011; 77(6):525-34. DOI: 10.1111/j.1399-0039.2011.01646.x
Source: PubMed


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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    • "analysis of serum reactivity with Luminex single class II alleles to determine which epitopes, referred to as eplets, were recognized by this patient's antibodies. HLAmatchmaker is a computer algorithm that predicts epitope structure on HLA molecules from stereochemical models of protein antigen-antibody complexes [5]. It is designed to determine HLA compatibility at the epitope level and to analyze serum reactivity for HLA epitope-specific antibodies. "
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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.
    Full-text · Article · Mar 2014 · Transplantation Proceedings
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    • "In case this leaves no eplets to be recognized on a kidney graft, no antibody responses are to be expected [5]. Although HLAMatchmaker predicts which HLA-antigens can potentially induce HLA antibody formation, it does not predict Tcell reactivity towards allogeneic HLA [6]. "
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    ABSTRACT: Background: HLA class-I mismatches selectively induce antibody formation after kidney transplantation. The de novo development of donor-specific IgG HLA class-I antibodies may be dependent on the HLA class-II background of the patient by presenting T-helper epitopes within the recognized HLA class-I antigens. Methods: The correlation between antibody production against mismatched donor human leukocyte antigens (HLA) class I and the number of HLA class II-restricted predicted indirectly recognizable HLA epitopes (PIRCHE-II) in the respective HLA class-I mismatches was investigated. To this end, we analyzed sera taken after nephrectomy from a cohort of 21 non-immunized individuals that received a renal transplant. Results: Fourty-nine HLA class-I mismatches were found which all contained immunogenic eplets according to HLAMatchmaker. Donor specific HLA antibody responses were detected against 38 HLA class-I mismatches after nephrectomy. These mismatches were found to contain a larger number of PIRCHE-II when compared to mismatches which did not induce donor specific HLA antibodies. Most PIRCHE-II (68%) were not part of an eplet as defined by HLAMatchmaker. Conclusions: Our data suggest that presentation of donor-derived HLA class-I peptides by recipient HLA class-II molecules plays a significant role in de novo development of donor-specific IgG HLA antibodies.
    Full-text · Article · Dec 2012 · Human immunology
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    • "Identification of suitable products for alloimmunized patients involves HLA typing of the patient (typically performed with DNA-based techniques), antibody screening for anti- HLA class I and anti-platelet-specific antibodies (solid phase or flow cytometry) as well as platelet crossmatching (solid phase or flow cytometric techniques). Complex computer algorithms for selecting HLA compatible donors based on epitope sharing have been developed to identify compatible products [142] [143]. Thus the ability to generate platelet products ex vivo and platelet products lacking HLA antigens in serum free media would have great clinical value. "
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    ABSTRACT: The primary focus of national blood programs is the provision of a safe and adequate blood supply. This goal is dependent on regular voluntary donations and a regulatory infrastructure that establishes and enforces standards for blood safety. Progress in ex vivo expansion of blood cells from cell sources including peripheral blood, cord blood, induced pluripotent stem cells, and human embryonic stem cell lines will likely make alternative transfusion products available for clinical use in the near future. Initially, alloimmunized patients and individuals with rare blood types are most likely to benefit from alternative products. However, in developed nations voluntary blood donations are projected to be inadequate in the future as blood usage by individuals 60 years and older increases. In developing nations economic and political challenges may impede progress in attaining self-sufficiency. Under these circumstances, ex vivo generated red cells may be needed to supplement the general blood supply.
    Full-text · Article · Apr 2012
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