Adaptation of HLA testing to characterize the cynomolgus macaque MHC polymorphisms and alloantibody signatures.

Nonhuman primates are the closest animal models to humans with respect to genetics and physiology. Consequently, a critical component of immunogenetics research relies on drawing inferences from the cynomolgus macaque to inform human trials. Despite the conserved organization of the Major Histocompatibility Complex (MHC) between cynomolgus macaques and humans, MHC genotyping of cynomolgus macaques is challenging due to high rates of copy number variants, duplications, and rearrangements, particularly at the MHC class I loci.

Autobiographical perspectives on HLA epitopes: Past, present and future.

This article describes my personal perspectives on HLA epitopes. It is not intended to be a general review of HLA epitopes as several versions have been published before. This article is an autobiographical reflection with three sections.

Immunogenetics of heteroclitic recognition of HLA-DQB1 55R eplet specificity by human alloantibody.

Heteroclitic antibodies bind to a related antigen with higher affinity than to the immunizing antigen to which they were generated. This uncommon phenomenon is not well characterized for antibodies to HLA antigens. Here we analyzed allosera reactivity from two transplant recipients sensitized to mismatched donor alleles DQB1*06:01 and DQB1*06:02 respectively.

High-throughput sequencing defines donor and recipient HLA B-cell epitope frequencies for prospective matching in transplantation.

Compatibility for human leukocyte antigen (HLA) genes between transplant donors and recipients improves graft survival but prospective matching is rarely performed due to the vast heterogeneity of this gene complex. To reduce complexity, we have combined next-generation sequencing and in silico mapping to determine transplant population frequencies and matching probabilities of 150 antibody-binding eplets across all 11 classical HLA genes in 2000 ethnically heterogeneous renal patients and donors. We show that eplets are more common and uniformly distributed between donors and recipients than the respective HLA isoforms.

Second update of the International Registry of HLA Epitopes. I. The HLA-ABC Epitope Database.

The International Registry of HLA Epitopes (http://www.epregistry.com.

Epitope-based human leukocyte antigen matching for transplantation: a personal perspective of its future.

Purpose Of Review: This study reflects my personal experience with the characterization of human leukocyte antigen (HLA) epitopes and their significance in HLA matching for transplantation. It offers a subjective assessment what further studies are needed to have this concept be applied in the clinical setting.

Recent Findings: This study addresses the structural characteristics of antibody-reactive HLA epitopes determined by different methods, eplet-associated antibody analysis and acceptable mismatching for sensitized patients and eplet immunogenicity and determination of mismatch permissibility.

Case report: A transplant candidate with unexpected serum reactivity against the 45KE eplet on HLA-B alleles.

This case report describes the serum antibody specificity against the 45KE eplet which had not been yet shown to be antibody-verified. This antibody was produced by a 41-year-old European male with Berger's disease. His serum had HLA class I antibody reactivity as determined in IgG binding assays with single allele panels (OneLambda, ThermoFisher, Lot 8 and Lot 9).

Usefulness of the ElliPro epitope predictor program in defining the repertoire of HLA-ABC eplets.

HLA matching at the epitope level offers new opportunities to identify suitable donors for transplant patients. The International HLA Epitope Registry (www.Epregistry.

Are We Ready for Epitope-Based HLA Matching in Clinical Organ Transplantation?

This overview describes recent developments demonstrating the significance of epitopes in HLA antibody responses and matching for organ transplantation. HLA epitopes are defined by molecular modeling and amino acid comparisons between HLA alleles and the HLAMatchmaker algorithm considers eplets as essential components. Each allele represents a distinct string of eplets and matching is done by aligning donor and recipient strings.

Reflections on HLA Epitope-Based Matching for Transplantation.

HLA antibodies are primary causes of transplant rejection; they recognize epitopes that can be structurally defined by eplets. There are many reviews about HLA epitope-based matching in transplantation. This article describes some personal reflections about epitopes including a historical perspective of HLA typing at the antigen and allele levels, the repertoires of antibody-verified HLA epitopes, the use of HLAMatchmaker in determining the specificities of antibodies tested in different assays, and, finally, possible strategies to control HLA antibody responses.

Should epitope-based HLA compatibility be used in the kidney allocation system?

The new kidney allocation system (KAS) still applies donor-recipient HLA compatibility mostly at the antigen level and although some four-digit alleles have been included. This system is used to record unacceptable mismatches for sensitized transplant candidates with serum HLA antibodies. Since the reactivities of such antibodies are specifically associated with epitopes rather than HLA antigens, a more scientifically accurate assessment of mismatch acceptability could be based on epitopes.

Epitope analysis of DQ6-reactive antibodies in sera from a DQ6-positive transplant candidate sensitized during pregnancy.

This case report describes DQ6-reactive serum antibody reactivity in a patient who types as DQ6. DNA typing showed DQB1*06:09 on the antibody producer and serum reactivity with DQB1*06:01, *06:02 and *06:03 but not with *06:04 and *06:09. HLAMatchmaker serum analysis showed antibody reactivity with a new antibody-verified 85VA eplet on DQB but additional reactivity with DQB1*02:01 could not be readily interpreted.

Antibody-defined epitopes on HLA-DQ alleles reacting with antibodies induced during pregnancy and the design of a DQ eplet map.

The concept that HLA antibodies recognize epitopes is leading to new approaches of HLA matching at the epitope level. HLA-DQ plays an important role and many studies have identified structurally defined DQ epitopes specifically recognized by antibodies; they have been recorded in the International HLA Epitope Registry http://www.epregistry.

Detection of newly antibody-defined epitopes on HLA class I alleles reacting with antibodies induced during pregnancy.

The determination of HLA mismatch acceptability at the epitope level can be best performed with epitopes that have been verified experimentally with informative antibodies. The website-based International Registry of HLA Epitopes (http://www.epregistry.

Identification of epitopes on HLA-DRB alleles reacting with antibodies in sera from women sensitized during pregnancy.

This report describes a HLAMatchmaker-based antibody analysis of post-pregnancy sera with antibodies against child-specific HLA-DR epitopes. These sera were reactive in IgG-binding assays with single allele bead (SAB) panels on a Luminex platform. The antibody specificity analysis focused on DRB epitopes that have been recorded in the International HLA Epitope Registry (http://www.

Usefulness of the Nonself-Self Algorithm of HLA Epitope Immunogenicity in the Specificity Analysis of Monospecific Antibodies Induced during Pregnancy.

Background: HLAMatchmaker is a program to analyze the epitope specificities of HLA antibodies. It considers each HLA allele as a string of eplets. Intralocus and interlocus comparisons between donor and recipient alleles offer a structural assessment of compatibility and an analysis of allele panel reactivity patterns can generate information about epitope specificities of HLA antibodies.

HLA-A2 reactive antibodies in a patient who types as HLA-A2: The importance of high resolution typing and epitope-based antibody analysis.

This report describes a case of a highly sensitized patient who had serum antibodies reacting with HLA-A2 but whose phenotype included HLA-A2. The determination of HLA mismatch acceptability at the antigen level was problematic, but high-resolution HLA typing information and epitope-based antibody specificity analysis based on the nonself-self paradigm of HLA epitope immunogenicity have provided a solution. This case supports the concept that HLA typing at the allele level offers a better approach to identifying suitable donors for sensitized patients.

Should HLA mismatch acceptability for sensitized transplant candidates be determined at the high-resolution rather than the antigen level?

Defining HLA mismatch acceptability of organ transplant donors for sensitized recipients has traditionally been based on serologically defined HLA antigens. Now, however, it is well accepted that HLA antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoires. Hence, determination of HLA compatibility at the allele level represents a more accurate approach to identify suitable donors for sensitized patients.

Guidance on platelet transfusion for patients with hypoproliferative thrombocytopenia.

Patients with hypoproliferative thrombocytopenia are at an increased risk for hemorrhage and alloimmunization to platelets. Updated guidance for optimizing platelet transfusion therapy is needed as data from recent pivotal trials have the potential to change practice. This guideline, developed by a large international panel using a systematic search strategy and standardized methods to develop recommendations, incorporates recent trials not available when previous guidelines were developed.

First report on the antibody verification of HLA-DR, HLA-DQ and HLA-DP epitopes recorded in the HLA Epitope Registry.

The International Registry of Antibody-Defined HLA Epitopes (http://www.epregistry.com.

First report on the antibody verification of MICA epitopes recorded in the HLA epitope registry.

The International Registry of HLA Epitopes (http://epregistry.com.br) has been recently established as a tool to understand antibody responses to HLA mismatches.