Epitopes as characterized by antibody-verified eplet mismatches determine risk of kidney transplant loss

Sapir‐Pichhadze, Ruth; Zhang, Xun; Ferradji, Abdelhakim; Madbouly, Abeer; Tinckam, Kathryn; Gebel, Howard M.; Blum, Daniel; Marrari, Marilyn; Kim, S. Joseph; Fingerson, Stephanie; Bashyal, Pradeep; Cardinal, Héloïse; Foster, Bethany J.

doi:10.1016/j.kint.2019.10.028

Cited by 56 publications

(54 citation statements)

References 33 publications

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“…There was substantial heterogeneity with respect to the immunosuppressive protocols used; this was to some extent related to the multi-center nature of this study. Our eplet mismatch data (primarily associated with HLA-DRB1,3,4,5, and DQB1) were comparable to findings from previous reports (12,16,17,19,25,26,34), although class I DSAs were not considered in this analysis. We calculated PIRCHE score based on typing information of recipient HLA-DRB1,3,4,5, DQA1, and DQB1 as the presenting HLA class II molecules; the addition of DRB3,4,5, and DQA1/DQB1 explains why our PIRCHE scores were higher in range than those included in previous reports that were based on DRB1 alone (21,34,35), even though we did not consider HLA-C among the donorderived peptides.…”

Section: Discussionsupporting

confidence: 89%

“…We found that analyses of both B cell and T cell epitopes (i.e., eplet mismatches and PIRCHE scores, respectively), had positive predictive capabilities with respect to de novo DSA production. Recent studies reported strong associations of eplet mismatch and/or PIRCHE-II scores with de novo DSA production or graft outcomes (25,26,34,35), whereas it was also reported that allelic and epitope mismatch analysis presented no additional value with respect to risk management (36). Differences in immunogenicity might be dependent on the nature of the eplet and the precise mismatch position (37,38).…”

Section: Discussionmentioning

confidence: 99%

“…MFI levels of class I DSA and class II DSA were 2,481 +/-2,073, and 11,404 +/-8,389, respectively. Chronic ABMR was reported to be mainly associated with HLA class II DSA (5,6,11,12,19,25,26). For these reasons, only class II (DR and/or DQ) DSAs were considered in the risk assessment.…”

Section: De Novo Dsa Productionmentioning

confidence: 99%

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Analysis of T and B Cell Epitopes to Predict the Risk of de novo Donor-Specific Antibody (DSA) Production After Kidney Transplantation: A Two-Center Retrospective Cohort Study

et al. 2020

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Risk prediction of de novo donor specific antibody (DSA) would be very important for long term graft outcome after organ transplantation. The purpose of this study was to elucidate the association of eplet mismatches and predicted indirectly recognizable HLA epitopes (PIRCHE) scores with de novo DSA production. Our retrospective cohort study enrolled 691 living donor kidney transplantations. HLA-A, B, DRB and DQB eplet mismatches and PIRCHE scores (4 digit of HLA-A, B, DR, and DQ) were determined by HLA matchmaker (ver 2.1) and PIRCHE-II Matching Service, respectively. Weak correlation between eplet mismatches and PIRCHE scores was identified, although both measurements were associated with classical HLA mismatches. Class II (DRB+DQB) eplet mismatches were significantly correlated with the incidence of de novo class II (DR/DQ) DSA production [8/235 (3.4%) in eplet mismatch ≤ 13 vs. 92/456 (20.2%) in eplet mismatch ≥ 14, p < 0.001]. PIRCHE scores were also significantly correlated with de novo class II DSA production [26/318 (8.2%) in PIRCHE ≤ 175 vs. 74/373 (19.8%) in PIRCHE ≥ 176, p < 0.001]. Patients with low levels of both class II eplet mismatches and PIRCHE scores developed de novo class II DSA only in 4/179 (2.2%). Analysis of T cell and B cell epitopes can provide a beneficial information on the design of individualized immunosuppression regimens for prevention of de novo DSA production after kidney transplantation.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Analysis of T and B Cell Epitopes to Predict the Risk of de novo Donor-Specific Antibody (DSA) Production After Kidney Transplantation: A Two-Center Retrospective Cohort Study

et al. 2020

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“…However, increasing data suggests that eplet compatibility at certain class II gene loci, particularly HLA-DRB1/3/4/5 and DQB1 is of primary importance in minimizing graft injury 11,12,20 , reflecting the frequent occurrence of antibodies to these gene products in AMR [27][28][29] . Our studies (R.S-P) utilizing the US Scientific Registry of Transplant Recipients (SRTR) confirm this understanding, documenting an increased risk of transplant glomerulopathy and death-censored graft failure in donor/recipient pairs mismatched at these loci 30 . The data reported here demonstrate that the probability of identity at these class II loci is substantially higher than for the full epitype, ranging from 30% at HLA-DRB1/3/4/5 + DQB1 to 79% at DQB1 alone, so providing a logistical basis for deliberate matching at these loci.…”

Section: Discussionsupporting

confidence: 62%

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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“…For HLA class I, the results clearly showed that Abverified eplet mismatches predicted transplant glomerulopathy and graft failure. 7 On a population level, the eplet load (ie, sum of mismatched eplets in donor-recipient constellations) is associated with the degree of DSA formation. 8,9 However, the clinical utility of immunological risk assessment based on eplet load for an individual patient is restricted, since not all eplets are generating a similar immune response.…”

Section: Introductionmentioning

confidence: 99%

Toward defining the immunogenicity of HLA epitopes: Impact of HLA class I eplets on antibody formation during pregnancy

Hönger

Niemann²,

Schawalder

et al. 2020

HLA

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Eplets are functional units of structural epitopes on donor HLA, potentially recognized by complementarity‐determining regions of the paratope of the recipients' B‐cell receptors or antibodies (Ab). Their individual immunogenicity is poorly described, yet this feature would be of clinical importance for pretransplant risk assessment. The aim of this study was to determine the relative immunogenicity of HLA class I eplets in the pregnancy setting, where mismatched eplets are present on paternal HLA antigens of the unborn child. One hundred fifty‐nine predominantly Caucasian mothers giving birth at the University Hospital Basel and their first newborns were HLA‐typed at high‐resolution by next‐generation sequencing (NGS) (NGSgo Workflow and NGSengine from GenDx; sequencing with a Miseq from Illumina) and eplets were determined using HLAMatchmaker. HLA class I specific IgG Ab was assessed in maternal sera drawn immediately after full‐term delivery, by OneLambda LABScreen single antigen ibeads. The Ab profile was subsequently evaluated for eplet‐associated patterns. All 72 currently Ab‐verified HLA class I eplets were examined for their immunogenicity according to the frequency of child‐specific HLA Ab (CSA) directed against their structures. Four hundred twelve of 477 (86.4%) paternal HLA‐A, ‐B or ‐C alleles were mismatched. CSA were present in 46 mothers (28.9%), directed against 80 (19.4%) of these mismatches. The 10 most immunogenic eplets were 62GK, 145KHA, 144TKH, 62GE, 107W, 80I, 82LR, 41T, 127K, 45KE with immunogenicity rates between 45.8% and 27.3%. This pregnancy study also identified five non‐reactive eplets: 62RR, 76ESN, 80TLR, 156DA, 163RW. Based on our results, immunogenic hot and cold spots on the surface of HLA class I molecules were localized and visualized on 3D models. This study strengthens the presumption that different eplets represent different immunogenic potentials. Validation of these results in the clinical transplant setting is an essential next step in identifying those eplets representing a particularly high‐risk potential.

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Epitopes as characterized by antibody-verified eplet mismatches determine risk of kidney transplant loss

Cited by 56 publications

References 33 publications

Analysis of T and B Cell Epitopes to Predict the Risk of de novo Donor-Specific Antibody (DSA) Production After Kidney Transplantation: A Two-Center Retrospective Cohort Study

Analysis of T and B Cell Epitopes to Predict the Risk of de novo Donor-Specific Antibody (DSA) Production After Kidney Transplantation: A Two-Center Retrospective Cohort Study

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

Toward defining the immunogenicity of HLA epitopes: Impact of HLA class I eplets on antibody formation during pregnancy

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