Exploratory Study of Predicted Indirectly ReCognizable HLA Epitopes in Mismatched Hematopoietic Cell Transplantations

Geneugelijk, Kirsten; Thus, Kirsten A.; Deutekom, Hanneke W. M. van; Calis, Jorg J.A.; Borst, Eric; Keşmir, Can; Oudshoorn, Machteld; Meijer, Ellen; Groot, Marco R. de; Borne, Peter A. von dem; Cornelissen, Jan J.; Kuball, Jürgen; Spierings, Eric

doi:10.3389/fimmu.2019.00880

Cited by 24 publications

(13 citation statements)

References 46 publications

(59 reference statements)

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“…Two cardinal groups of epitopes are now recognized, those involved in indirect recognition of the donor HLA antigen array by recipient T cell which are predicted through the PIRCHE algorithm 20 , and those which are antibody-accessible and are involved in the humoral response (defined here as B-cell epitopes), predicted through the HLAMatchmaker algorithm 10 . Studies confirm that the mismatch between donor and recipient for each of these two sets of molecular targets is directly related to the risk of rejection and graft loss 11,12,[21][22][23] . In this study we focus on antibody-accessible eplets, restricting our attention to those for which biological relevance has been verified by the detection of specific antibodies to the target (http://www.epitopes.net/ publications.html).…”

Section: Discussionmentioning

confidence: 92%

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

Tran

Günther²,

Sherwood

et al. 2021

Commun Biol

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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. Simulations of targeted eplet matching shows that a high degree of overall compatibility, and perfect identity at the clinically important HLA class II loci, can be obtained within a patient waiting list of approximately 250 subjects. Internal epitope-based allocation is thus feasible for most major renal transplant programs, while regional or national sharing may be required for other solid organs.

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Section: Discussionmentioning

confidence: 92%

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

Tran

Günther²,

Sherwood

et al. 2021

Commun Biol

View full text Add to dashboard Cite

show abstract

“…Two cardinal groups of epitopes are now recognized, those involved in indirect recognition of the donor HLA antigen array by recipient T cell which are predicted through the PIRCHE algorithm 17 , and those which are antibody-accessible and are involved in the humoral response, predicted through the HLAMatchmaker algorithm 10 . Studies confirm that the mismatch between donor and recipient for each of these two sets of molecular targets is directly related to the risk of rejection and graft loss 11,12,[18][19][20] . In this study we focus on antibody-accessible eplets, restricting our attention to those for which biological relevance has The results reported reinforce the small proportion of documented HLA alleles commonly observed in routine practice 21 .…”

Section: Discussionmentioning

confidence: 92%

Population Frequencies Determined by Next-generation Sequencing Provide Strategies for Prospective HLA Epitope Matching for Transplantation

Tran¹,

Günther²,

Sherwood³

et al. 2020

Preprint

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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 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 more uniformly distributed between donors and recipients than the respective HLA isoforms. Simulation of targeted eplet matching shows that a high degree of overall compatibility, and perfect identity at the clinically important HLA class II loci, can be obtained within a patient waiting list of approximately 250 subjects. Internal epitope-based allocation is thus feasible for most major renal transplant programs, while regional or national sharing may be required for other solid organs.

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“…Both of these measures have been found to be associated with GVHD risk, each contributing in an independent capacity. 10,42,43 Consequently, there is reason to believe that simple amino acid mismatch count may also have implications in HSCT and may correlate with adverse outcomes, as in SOT.…”

Section: Discussionmentioning

confidence: 99%

A Combined HLA Molecular Mismatch and Expression Analysis for Evaluating HLA-DPB1 de novo Donor-Specific Antibody Risk in Pediatric Solid Organ Transplantation: Implications for Solid Organ & Hematopoietic Stem Cell Transplantation

Shieh¹,

Hayeck

Dinh

et al. 2020

Preprint

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Background. HLA molecular mismatch (MM) has been shown to be a risk factor for de novo donor-specific antibody (dnDSA) development in solid organ transplantation (SOT). HLA expression differences have also been associated with adverse outcomes in hematopoietic cell transplantation. We sought to study both MM and expression in assessing dnDSA risk. Methods. One-hundred-and-three HLA-DP-mismatched SOT pairs were retrospectively analysed. MM was computed using amino acids (aa), eplets and, supplementarily, Grantham/Epstein scores. DPB1 alleles were classified as rs9277534-A (low-expression) or -G (high-expression) linked. To determine the associations between risk factors and dnDSA, logistic regression, linkage disequilibrium (LD) and population-based analyses were performed. Results. A high-risk AA:GX (recipient:donor) expression combination (X=A or G) demonstrated strong association with DP-dnDSA (p=0.001). MM was also associated with DP-dnDSA when evaluated by itself (eplet_p=0.007, aa_p=0.003, Grantham_p=0.005, Epstein_p=0.004). When attempting to determine the relative individual effects of the risk factors in multivariable analysis, only AA:GX expression status retained a strong association (RR=18.6, p=0.007 with eplet; RR=15.8, p=0.02 with aa), while MM was no longer significant (eplet_p=0.56, aa_p=0.51). Importantly, these risk factors are correlated, due to LD between the expression-tagging SNP and polymorphisms along HLA-DPB1. Conclusions. The MM and expression risk factors each appear to be strong predictors of DP-dnDSA and to possess clinical utility; however, the two risk factors are closely correlated. These metrics may represent distinct ways of characterizing a common overlapping dnDSA risk profile, but they are not independent. Further, we demonstrate the importance and detailed implications of LD effects in risk assessment of dnDSA and possibly transplantation overall.

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Exploratory Study of Predicted Indirectly ReCognizable HLA Epitopes in Mismatched Hematopoietic Cell Transplantations

Cited by 24 publications

References 46 publications

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

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

Population Frequencies Determined by Next-generation Sequencing Provide Strategies for Prospective HLA Epitope Matching for Transplantation

A Combined HLA Molecular Mismatch and Expression Analysis for Evaluating HLA-DPB1 de novo Donor-Specific Antibody Risk in Pediatric Solid Organ Transplantation: Implications for Solid Organ & Hematopoietic Stem Cell Transplantation

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