Not all eplet mismatches are created equal – A cohort study illustrating implications to long-term graft outcomes

Zahran, Somaya; Bourdiec, Amélie; Zhang, Xun; Sapir‐Pichhadze, Ruth

doi:10.1016/j.humimm.2021.11.007

Cited by 7 publications

(6 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The applied epitope matching approaches - including Snowflake - do not weigh individual immunogenicity patterns. Similar to antigen mismatches varying in their immunogenicity, also epitope mismatches’ immunogenicity varies ( 11 , 12 , 19 , 32 ). Although the current epitope matching strategies add prognostic value to classic antigen matching as implemented by many allocation organizations, further refinements of these approaches may specifically integrate epitope immunogenicity, antigenicity and hierarchy ( 44 – 46 ).…”

Section: Discussionmentioning

confidence: 99%

“…The approach of counting the number of mismatched eplets (i.e. eplet/epitope load) introduces the assumption of equi-immunogenic eplets, which has been disproven ( 11 , 12 ). The varying physicochemical properties of mismatched amino acids may be an explanation and matching amino acids based on their electrostatic potentials was shown to be advantageous over the unweighted eplet load ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Snowflake epitope matching correlates with child-specific antibodies during pregnancy and donor-specific antibodies after kidney transplantation

Niemann¹,

Strehler²,

Lachmann³

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

Development of donor-specific human leukocyte antigen (HLA) antibodies (DSA) remains a major risk factor for graft loss following organ transplantation, where DSA are directed towards patches on the three-dimensional structure of the respective organ donor’s HLA proteins. Matching donors and recipients based on HLA epitopes appears beneficial for the avoidance of DSA. Defining surface epitopes however remains challenging and the concepts underlying their characterization are not fully understood. Based on our recently implemented computational deep learning pipeline to define HLA Class I protein-specific surface residues, we hypothesized a correlation between the number of HLA protein-specific solvent-accessible interlocus amino acid mismatches (arbitrarily called Snowflake) and the incidence of DSA. To validate our hypothesis, we considered two cohorts simultaneously. The kidney transplant cohort (KTC) considers 305 kidney-transplanted patients without DSA prior to transplantation. During the follow-up, HLA antibody screening was performed regularly to identify DSA. The pregnancy cohort (PC) considers 231 women without major sensitization events prior to pregnancy who gave live birth. Post-delivery serum was screened for HLA antibodies directed against the child’s inherited paternal haplotype (CSA). Based on the involved individuals’ HLA typings, the numbers of interlocus-mismatched antibody-verified eplets (AbvEPS), the T cell epitope PIRCHE-II model and Snowflake were calculated locus-specific (HLA-A, -B and -C), normalized and pooled. In both cohorts, Snowflake numbers were significantly elevated in recipients/mothers that developed DSA/CSA. Univariable regression revealed significant positive correlation between DSA/CSA and AbvEPS, PIRCHE-II and Snowflake. Snowflake numbers showed stronger correlation with numbers of AbvEPS compared to Snowflake numbers with PIRCHE-II. Our data shows correlation between Snowflake scores and the incidence of DSA after allo-immunization. Given both AbvEPS and Snowflake are B cell epitope models, their stronger correlation compared to PIRCHE-II and Snowflake appears plausible. Our data confirms that exploring solvent accessibility is a valuable approach for refining B cell epitope definitions.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Snowflake epitope matching correlates with child-specific antibodies during pregnancy and donor-specific antibodies after kidney transplantation

Niemann¹,

Strehler²,

Lachmann³

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…The concept that some eplets are more immunogenic than others was explored in a retrospective study in heart and lung transplant recipients; specific eplet mismatches were found to be disproportionally associated with dnDSA formation and modeling avoidance of these high-risk eplets predicted a significant reduction in dnDSA formation (43). Using imputation to determine HR-2F HLA type in the Scientific Registry of Transplant Recipients (SRTR), a subset of 15 eplet mismatches was linked to a higher hazard of death-censored graft failure among KT recipients, even after accounting for other known risk factors (61,62). Additionally, a small subset of Ab-verified eplets have been linked to transplant glomerulopathy in an independent Canadian KT cohort (50).…”

Section: Load Vs Immunogenicitymentioning

confidence: 99%

Pediatric Kidney Transplantation—Can We Do Better? The Promise and Limitations of Epitope/Eplet Matching

Charnaya

Erez²,

Amaral³

et al. 2022

Front. Pediatr.

View full text Add to dashboard Cite

Kidney transplant is the optimal treatment for end-stage kidney disease as it offers significant survival and quality of life advantages over dialysis. While recent advances have significantly improved early graft outcomes, long-term overall graft survival has remained largely unchanged for the last 20 years. Due to the young age at which children receive their first transplant, most children will require multiple transplants during their lifetime. Each subsequent transplant becomes more difficult because of the development of de novo donor specific HLA antibodies (dnDSA), thereby limiting the donor pool and increasing mortality and morbidity due to longer time on dialysis awaiting re-transplantation. Secondary prevention of dnDSA through increased post-transplant immunosuppression in children is constrained by a significant risk for viral and oncologic complications. There are currently no FDA-approved therapies that can meaningfully reduce dnDSA burden or improve long-term allograft outcomes. Therefore, primary prevention strategies aimed at reducing the risk of dnDSA formation would allow for the best possible long-term allograft outcomes without the adverse complications associated with over-immunosuppression. Epitope matching, which provides a more nuanced assessment of immunological compatibility between donor and recipient, offers the potential for improved donor selection. Although epitope matching is promising, it has not yet been readily applied in the clinical setting. Our review will describe current strengths and limitations of epitope matching software, the evidence for and against improved outcomes with epitope matching, discussion of eplet load vs. variable immunogenicity, and conclude with a discussion of the delicate balance of improving matching without disadvantaging certain populations.

show abstract

“…Nevertheless, the determination of compatibility between a recipient and a donor still relies on the antigen level in organ allocation programs worldwide. The deleterious clinical implication of eplet mismatching has been clearly demonstrated over the last years, at least for some eplets, in patients involved in organ transplantation programs 2,4–7 …”

Section: Introductionmentioning

confidence: 99%

Assessing the allogenic realness of the Cw1/12/15 pattern occurring in the LABScreen single antigen assay

Devriese

Usureau

Lion

et al. 2023

HLA

View full text Add to dashboard Cite

Several technical limitations of Luminex single antigen (LSA) assays have been described so far. This study focused on a reactivity pattern observed in many sera that cannot be explained by eplets described in the Epitope Registry database and sometimes appearing against a self‐HLA allele or antigen. In most cases, this pattern is revealed by a discrepant result when compared with other assays (Luminex PRA, cell‐binding assays such as flow cytometry cross match, LSA from another manufacturer…). We focus here on the Cw1/12/15 pattern appearing on the LABScreen class I LSA provided by One Lambda. We documented its behavior using this LSA after acid denaturation of the beads, using Lifecodes LSA from Immucor, and adsorption of sera either on spleen mononuclear cells from deceased donors or on single HLA transfected cell clones. We studied 33 sera from different patients positive for the three Cw beads, selected from our routine patients' LSA database. Nine patients had transplants from a Cw12 or Cw15 donor without any pejorative evolution of the graft, nor post‐transplant MFI (mean fluorescence intensity) increase of the Cw1/12/15 beads. A significant increase of MFI was observed after acid denaturation of the LABScreen beads. All sera tested by Lifecodes LSA were negative for these Cw beads. Finally, we found no significant difference of MFI after adsorption on cells from either origin. Therefore, the Cw1/12/15 pattern appears to be a false positive reactivity of the LABScreen single antigen assay.

show abstract

Not all eplet mismatches are created equal – A cohort study illustrating implications to long-term graft outcomes

Cited by 7 publications

References 42 publications

Snowflake epitope matching correlates with child-specific antibodies during pregnancy and donor-specific antibodies after kidney transplantation

Snowflake epitope matching correlates with child-specific antibodies during pregnancy and donor-specific antibodies after kidney transplantation

Pediatric Kidney Transplantation—Can We Do Better? The Promise and Limitations of Epitope/Eplet Matching

Assessing the allogenic realness of the Cw1/12/15 pattern occurring in the LABScreen single antigen assay

Contact Info

Product

Resources

About