HLAMatchmaker: a molecularly based algorithm for histocompatibility determination. II. Verification of the algorithm and determination of the relative immunogenicity of amino acid triplet-defined epitopes

Duquesnoy, René J.; Marrari, Marilyn

doi:10.1016/s0198-8859(02)00381-6

Cited by 108 publications

(95 citation statements)

References 13 publications

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“…Exposure to mismatched X will not lead to PQR-specific antibodies in recipients who type for Y or Z. This concept has been verified by observations that highly sensitized patients do not have antibodies against intralocus and interlocus triplet matches [7,10,11,15]. On the other hand, PQR can be immunogenic for a recipient who does not type for X, Y or Z. Anti-PQR antibodies will react with the immunizing X and also with Y and Z but there might be exceptions for two reasons.…”

Section: Discussionmentioning

confidence: 80%

“…Several reports have described a conformational effect of hidden residues on HLA epitope reactivity with antibody [78,83,84,85,86]. This scenario would only apply to epitope antigenicity but not immunogenicity because highly sensitized patients do not produce antibodies to self-epitopes expressed on mismatched HLA antigens [7,10,11,15].…”

Section: Discussionmentioning

confidence: 99%

“…The patient's HLA phenotype represents the repertoire of self-triplets and HLAMatchmaker determines for each mismatched HLA antigen, which triplets in corresponding sequence positions are different. HLAMatchmaker-based matching improves transplant outcome [2][3][4][5][6], and is useful in serum analysis and the identification of acceptable mismatches for alloimmunized kidney transplant candidates [7][8][9][10][11][12][13][14][15][16] and refractory thrombocytopenic patients requiring matched platelet transfusions [17,18] The original version of HLAMatchmaker considers triplets, i.e. linear sequences of three residues at least one of which would be polymorphic [1].…”

Section: Introductionmentioning

confidence: 99%

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A Structurally Based Approach to Determine HLA Compatibility at the Humoral Immune Level

2006

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HLAMatchmaker is a structurally based matching program. Each HLA antigen is viewed as a string of epitopes represented by short sequences (triplets) involving polymorphic amino acid residues in antibody-accessible positions. HLAMatchmaker determines which triplets are different between donor and recipient and this algorithm is clinically useful in determining HLA mismatch acceptability. Triplets provide however an incomplete description of the HLA epitope repertoire and expanded criteria must be used including longer sequences and polymorphic residues in discontinuous positions. Such criteria should consider the structural basis of antibody-antigen interactions including contact areas and binding energy, the essence of antigenicity.This report describes the development of a structurally defined HLA epitope repertoire based on stereochemical modeling of crystallized complexes of antibodies and different protein antigens. This analysis considered also data in the literature about contributions of amino acid residues to antigenantibody binding energy. The results have led to the concept that HLA antigens like other antigenic proteins have structural epitopes consisting of 15-22 residues that constitute the binding face with alloantibody. Each structural epitope has a functional epitope of about 2-5 residues that dominate the strength and specificity of binding with antibody. The remaining residues of a structural epitope provide supplementary interactions that increase the stability of the antigen-antibody complex. Each functional epitope has one or more non-self residues and the term "eplet" is used to describe polymorphic HLA residues within 3.0-3.5 Ångstroms of a given sequence position on the molecular surface. Many eplets represent short linear sequences identical to those referred to as triplets but others have residues in discontinuous sequence positions that cluster together on the molecular surface. Serologically defined HLA determinants correspond well to eplets. The eplet version of HLAMatchmaker represents therefore a more complete repertoire of structurally defined HLA epitopes and provides a more detailed assessment of HLA compatibility.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Structurally Based Approach to Determine HLA Compatibility at the Humoral Immune Level

2006

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“…Many triplets are marked with one or two residues because their neighboring residues are the same on all HLA-A,B,C chains and they are therefore not shown. As an example, 12aM represents an alanine residue in position 11 and a methionine residue in position 12. The triplet 9s has a serine in position 9, and the two neighboring monomorphic residues are not shown.…”

Section: Hlamatchmaker-based Strategy Of Identifying Acceptable Mismamentioning

confidence: 99%

“…Patients are sorted from the lowest to the highest PFD values (on a log10 scale) of finding a donor with a zero-antigen mismatch expressed as percentages. The black bars represent PFD values for the zero-HLA-A,B-antigen mismatches; for patients [1][2][3][4][5][6][7][8][9][10][11] these PFD values were <0.01% or less than 1 in 10,000 donors. The stacked bars represent the cumulative effects of matching at the various triplet levels, namely from 0, to 0-1, and to 0-2 triplets.…”

Section: Hlamatchmaker-based Strategy Of Identifying Acceptable Mismamentioning

confidence: 99%

HLAMatchmaker-based strategy to identify acceptable HLA class I mismatches for highly sensitized kidney transplant candidates

et al. 2004

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HLAMatchmaker determines HLA compatibility at the level of polymorphic amino acid triplets in antibody-accessible sequence positions. Recent studies have shown that among HLA-DR-matched kidney transplants, the HLA-A,B antigen mismatches which are compatible at the triplet level have almost identical graft survival rates as the zero-HLA-A,B antigen mismatches. This finding provides the basis of a new strategy to identify HLA-mismatched organs that have similar success rates as the zero-HLA-antigen mismatches. This report describes how in conjunction with the Acceptable Mismatch program in Eurotransplant, HLAMatchmaker can expand the pool of potential donors for highly sensitized patients, for whom it is very difficult to find a compatible transplant. Sera from 35 highly sensitized kidney transplant candidates with an average PRA of 96% were screened by lymphocytotoxicity with HLAtyped panels that included cells that were selectively mismatched for one or two HLA antigens for each patient. Acceptable and unacceptable HLA-A,B antigen mismatches were determined from the serum reactivity with the cell panel. HLAMatchmaker analysis was applied to identify additional HLA class I antigens that were matched at the triplet level. For each patient, we calculated the probability of finding a donor (PFD) in the different match categories from HLA gene frequencies in the kidney donor population. The median PFD for a zero-antigen mismatch was 0.025%. Matching at the triplet level increased the median PFD to 0.037% (P = 0.008). The median PFD was 0.058% for a 0-1-triplet mismatch and 0.226% for a 0-2-triplet mismatch. Serum screening identified acceptable antigen mismatches for 28 of 35 highly sensitized patients, and the median PFD increased to 0.307% for a zero/ acceptable antigen mismatch. The application of HLAMatchmaker permitted for 33 patients (or 92%) the identification of additional antigens that were acceptable at the triplet level, and the median PFD for a zero/acceptable triplet mismatch went up to 0.425%. Inclusion of one-triplet mismatches increased the median PFD to 1.112%. Validation studies have shown that patient sera reacted with none of the zero-tripletmismatched antigens, 8-13% of the one-triplet mismatches, and 12-19% of the two-triplet mismatches. Although most antigens with one or two mismatched triplets appear acceptable to highly sensitized patients, a serum analysis must ascertain that the patient's antibodies do not recognize such mismatched triplets. HLAMatchmaker offers a useful strategy of identifying more 23 donors with acceptable HLA mismatches and could alleviate the problem of accumulation of highly sensitized patients on the transplant waiting list.

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Histocompatibility Matching in Penetrating Keratoplasty

Böhringer

Sundmacher

Reinhard

2006

Essentials in Ophthalmology

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HLAMatchmaker: a molecularly based algorithm for histocompatibility determination. II. Verification of the algorithm and determination of the relative immunogenicity of amino acid triplet-defined epitopes

Cited by 108 publications

References 13 publications

A Structurally Based Approach to Determine HLA Compatibility at the Humoral Immune Level

A Structurally Based Approach to Determine HLA Compatibility at the Humoral Immune Level

HLAMatchmaker-based strategy to identify acceptable HLA class I mismatches for highly sensitized kidney transplant candidates

Histocompatibility Matching in Penetrating Keratoplasty

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