The Number of Amino Acid Triplet Differences Between Patient and Donor Is Predictive for the Antibody Reactivity Against Mismatched Human Leukocyte Antigens1

Dankers, Marlies K.A.; Witvliet, Marian D.; Roelen, Dave L.; Lange, Peter de; Korfage, Nelleke; Persijn, G. G.; Duquesnoy, René J.; Doxiadis, Ilias; Claas, Frans H.J.

doi:10.1097/01.tp.0000120385.03278.28

Cited by 127 publications

(86 citation statements)

References 12 publications

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“…Although HLA-DQ and -DR may be closely related at an antigen level, it has been shown that small differences in one or more epitopes between donors and recipients at either locus are sufficient to generate a humoral and/or T cell-mediated immune response (18,19). In a nested casecontrol study of a cohort of 52 kidney transplant recipients with established transplant glomerulopathy, an increasing number of HLA-DQ and HLA-DR eplet mismatches was associated with an increased risk of developing transplant glomerulopathy, suggesting that epitope mismatches at either HLA-DQ or HLA-DR locus are equally important in predicting graft outcomes (5).…”

Section: Discussionmentioning

confidence: 99%

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

Lim

Chapman

Coates

et al. 2016

CJASN

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Background and objectives The current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes.Design, setting, participants, & measurements Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models.Results Of the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P,0.01), late rejections (occurring .6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94).Conclusions HLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression. Clinicians should be aware of the potential importance of HLA-DQ matching in the assessment of immunologic risk in kidney transplant recipients.

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Section: Discussionmentioning

confidence: 99%

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

Lim

Chapman

Coates

et al. 2016

CJASN

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“…The humoral alloimmune response to HLA class I mismatches can be successfully predicted by the HLAMatchmaker algorithm (20,21). As HLAMatchmaker takes only Ab-accessible sites of the HLA molecules into consideration, it is not a suitable tool to predict T cell alloreactivity (22).…”

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confidence: 99%

A Proposed Algorithm Predictive for Cytotoxic T Cell Alloreactivity

Jöris

Rood

Roelen

et al. 2012

The Journal of Immunology

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Previously, we showed that with an increasing number of amino acid differences in single HLA class I-mismatched molecules, the probability of T cell alloreactivity decreases. It is unlikely that every amino acid difference will affect T cell alloreactivity in a similar way; we hypothesized that the effect of an amino acid difference may be dependent on its position and/or physicochemical properties. We selected 131 patient/donor pairs with either a single HLA-A or -C mismatch in the graft-versus-host direction and that were compatible for HLA-B, -DRB1, and -DQB1. The alloreactive CTL precursor (CTLp) frequency was determined and associated with the amino acid differences between the single HLA class I mismatches. In the β sheet, only amino acids that are noncompatible in their physicochemical properties affect T cell alloreactivity, whereas in the α helices, both compatible and noncompatible amino acids affect CTLp outcome. Positions 62, 63, 73, 76, 77, 80, 99, 116, 138, 144, 147, and 163 were bivariately associated with CTLp outcome, irrespective of the total number of amino acid differences. In multivariate analysis, positions 62, 63, 73, 80, 116, 138, 144, and 163 were found to be most predictive for negative CTLp outcome. These results formed the basis for a weighted predictive mismatch score; pairs with the highest mismatch scores are estimated to be 13 times more likely to have a negative CTLp. This new algorithm may be a tool in donor selection for hematopoietic stem cell transplantation.

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“…Lobashevsky et al 26 examined sera from highly sensitized renal transplant candidates and found that the number of highly immunogenic triplet mismatches between donor-recipient pairs reliably predicted final crossmatch results. 26 Dankers et al 22 showed a strong correlation between the numbers of triplet mismatches between donors and renal transplant recipients and the development of donor-specific antibodies in these patients, further validating the HLAMatchmaker algorithm. 22 This is the first report of platelet transfusion outcomes when HLA-A and -B locus compatibility between donors and alloimmunized recipients is defined by the HLAMatchmaker program.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that patients' antibody reactivity correlates with the number of mismatched triplets against donor HLA antigens. 22 This example illustrates that some CREG matches are structurally compatible, but others have considerable numbers of mismatched triplets. Conversely, certain antigens that are not considered cross-reacting for this patient's HLA antigens have fewer mismatched triplets.…”

Section: Hlamatchmakermentioning

confidence: 99%

HLAMatchmaker-driven analysis of responses to HLA-typed platelet transfusions in alloimmunized thrombocytopenic patients

Nambiar

Duquesnoy

Adams

et al. 2006

Blood

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This study describes a novel application of HLAMatchmaker to determine platelet compatibility in 16 alloimmunized patients with aplastic anemia refractory to random donor platelet transfusions. HLAMatchmaker is a software algorithm that predicts HLA compatibility by identifying immunogenic epitopes represented by amino acid triplets in antibody-accessible regions of human leukocyte antigen (HLA) molecules and determines the number of triplet mismatches (TMMs) and highly immunogenic triplet mismatches (HIMMs). Corrected count increments (CCIs) and molecular HLA typing were available for 523 transfusions. Conventional compatibility assessment based on cross-reactive group (CREG) determination was not predictive of transfusion outcome. Low HIMMs and TMMs numbers were associated with a higher likelihood of satisfactory (CCIs > 8) compared with unsatisfactory (CCIs < 8) outcomes (median HIMMs ‫؍‬ 4 vs 6, p 2 value < .001; median TMMs ‫؍‬ 11 vs 13, p 2 value < .001). Although receiver operator characteristic curves revealed that HIMMs or TMMs number are not powerful predictors of individual transfusion outcome, a threshold of at least 3 HIMMs or at least 9 TMMs appeared to be associated with successful transfusions. Triplet-matched transfusions were successful, regardless of CREG matching. Our data validate HLAMatchmaker for platelet transfusions and demonstrate its potential to refine and expand donor selection for HLA-alloimmunized patients. (Blood.

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The Number of Amino Acid Triplet Differences Between Patient and Donor Is Predictive for the Antibody Reactivity Against Mismatched Human Leukocyte Antigens1

Abstract: These results indicate that the immunogenicity of the fetus is lower than that of a rejected kidney and that analysis of the number of triplet mismatches can predict the antibody reactivity against the mismatched HLA antigens.

Cited by 127 publications

References 12 publications

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

A Proposed Algorithm Predictive for Cytotoxic T Cell Alloreactivity

HLAMatchmaker-driven analysis of responses to HLA-typed platelet transfusions in alloimmunized thrombocytopenic patients

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