High-resolution, three-dimensional modeling of human leukocyte antigen class I structure and surface electrostatic potential reveals the molecular basis for alloantibody binding epitopes

Kosmoliaptsis, Vasilis; Dafforn, Timothy R.; Chaudhry, Afzal; Halsall, David; Bradley, J. Andrew; Taylor, Craig

doi:10.1016/j.humimm.2011.07.303

Cited by 51 publications

(37 citation statements)

References 47 publications

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“…In addition to the number of eplets as determined by HLAMatchmaker, additional determinants can be used to define allogeneic HLA acceptability, for instance, physiochemical properties of polymorphic amino acids [68]. Differences in physiochemical properties between mismatches, including electrostatic potential and hydrophobicity, are useful to predict HLA class-I- and class-II-specific alloantibody responses prior to solid-organ transplantation [68–70].…”

Section: Prediction Of Direct Hla Recognition By Antibodiesmentioning

confidence: 99%

“…Differences in physiochemical properties between mismatches, including electrostatic potential and hydrophobicity, are useful to predict HLA class-I- and class-II-specific alloantibody responses prior to solid-organ transplantation [68–70]. With higher physiochemical disparity between HLA mismatches, the risk of antibody development increases after kidney transplantation [68–70]. These observations suggest that differences in physiochemical properties between polymorphic amino acids may be relevant in defining acceptable HLA mismatches.…”

Section: Prediction Of Direct Hla Recognition By Antibodiesmentioning

confidence: 99%

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Predicting Alloreactivity in Transplantation

Geneugelijk

Thus

Spierings

2014

Journal of Immunology Research

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Human leukocyte Antigen (HLA) mismatching leads to severe complications after solid-organ transplantation and hematopoietic stem-cell transplantation. The alloreactive responses underlying the posttransplantation complications include both direct recognition of allogeneic HLA by HLA-specific alloantibodies and T cells and indirect T-cell recognition. However, the immunogenicity of HLA mismatches is highly variable; some HLA mismatches lead to severe clinical B-cell- and T-cell-mediated alloreactivity, whereas others are well tolerated. Definition of the permissibility of HLA mismatches prior to transplantation allows selection of donor-recipient combinations that will have a reduced chance to develop deleterious host-versus-graft responses after solid-organ transplantation and graft-versus-host responses after hematopoietic stem-cell transplantation. Therefore, several methods have been developed to predict permissible HLA-mismatch combinations. In this review we aim to give a comprehensive overview about the current knowledge regarding HLA-directed alloreactivity and several developed in vitro and in silico tools that aim to predict direct and indirect alloreactivity.

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Section: Prediction Of Direct Hla Recognition By Antibodiesmentioning

confidence: 99%

Section: Prediction Of Direct Hla Recognition By Antibodiesmentioning

confidence: 99%

Predicting Alloreactivity in Transplantation

Geneugelijk

Thus

Spierings

2014

Journal of Immunology Research

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“…This was demonstrated clearly in exon shuffling experiments (75–77). The properties, such as electrostatic potential and hydrophobicity, of the amino acids that comprise an epitope affect the identity and immunogenicity of the epitope and must also be taken into consideration (78, 79). Improvements in HLA antibody identification have permitted serologic confirmation of several proposed epitopes.…”

Section: Hla Mismatches and Sensitizationmentioning

confidence: 99%

HLA Mismatching Strategies for Solid Organ Transplantation – A Balancing Act

Zachary

Leffell

2016

Front. Immunol.

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HLA matching provides numerous benefits in organ transplantation including better graft function, fewer rejection episodes, longer graft survival, and the possibility of reduced immunosuppression. Mismatches are attended by more frequent rejection episodes that require increased immunosuppression that, in turn, can increase the risk of infection and malignancy. HLA mismatches also incur the risk of sensitization, which can reduce the opportunity and increase waiting time for a subsequent transplant. However, other factors such as donor age, donor type, and immunosuppression protocol, can affect the benefit derived from matching. Furthermore, finding a well-matched donor may not be possible for all patients and usually prolongs waiting time. Strategies to optimize transplantation for patients without a well-matched donor should take into account the immunologic barrier represented by different mismatches: what are the least immunogenic mismatches considering the patient’s HLA phenotype; should repeated mismatches be avoided; is the patient sensitized to HLA and, if so, what are the strengths of the patient’s antibodies? This information can then be used to define the HLA type of an immunologically optimal donor and the probability of such a donor occurring. A probability that is considered to be too low may require expanding the donor population through paired donation or modifying what is acceptable, which may require employing treatment to overcome immunologic barriers such as increased immunosuppression or desensitization. Thus, transplantation must strike a balance between the risk associated with waiting for the optimal donor and the risk associated with a less than optimal donor.

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“…Modeling provided strong rationale for the experimental findings. HLA amino acids R79 and R82 are oriented outward with the potential to form highly energetic bonds with complementary antibody amino acids [4]. Even though antibody-antigen contact sites are large, a few amino acid side chains often provide most of the binding energy [5].…”

Section: Introductionmentioning

confidence: 99%

“…Even though antibody-antigen contact sites are large, a few amino acid side chains often provide most of the binding energy [5]. Substitution of residue 83 (G83R) abrogated binding by the BB7.6 anti-Bw6 mAb [3], probably by steric hindrance [4]. The HLA-B*07:02 R82L and G83R single amino acid substitutions each severely reduced binding by human anti-Bw6 alloantisera.…”

Section: Introductionmentioning

confidence: 99%

Human leukocyte antigen Bw4 and Bw6 epitopes recognized by antibodies and natural killer cells

Lutz

2014

Current Opinion in Organ Transplantation

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Purpose of review To describe the structural basis of HLA Bw4 and Bw6 epitopes that are recognized by antibodies and the KIR3DL1 NK cell receptor. Recent finding Molecular modeling and x-ray crystallography have refined our understanding of Bw4 and Bw6. These epitopes had been defined by comparison of HLA allele sequences and by site-directed mutagenesis. Anti-Bw4 and anti-Bw6 antibodies and KIR3DL1 receptors recognize HLA α-1 α-helix residues 77–83 in combination with other HLA regions. The variability of HLA sequences within the 77–83 region and at other sites indicates that the Bw4 epitope is complex. Adding complexity, HLA-bound peptides influence Bw4 and Bw6 epitopes. These structures are recognized by diverse antibodies and KIR3DL1 allotypes. This diversity allowed a Bw4+ patient to produce anti-Bw4 antibody without breaking self-tolerance. Summary Bw4 and Bw6 epitopes are best regarded as families of related structures that are recognized by a diverse array of antibodies and KIR3DL1 allotypes.

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High-resolution, three-dimensional modeling of human leukocyte antigen class I structure and surface electrostatic potential reveals the molecular basis for alloantibody binding epitopes

Cited by 51 publications

References 47 publications

Predicting Alloreactivity in Transplantation

Predicting Alloreactivity in Transplantation

HLA Mismatching Strategies for Solid Organ Transplantation – A Balancing Act

Human leukocyte antigen Bw4 and Bw6 epitopes recognized by antibodies and natural killer cells

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