Implementation of molecular matching in transplantation requires further characterization of both immunogenicity and antigenicity of individual HLA epitopes

Bezstarosti, Suzanne; Claas, Frans H.J.; Fijter, Johan W. de; Reinders, Marlies E.J.; Heidt, Sebastiaan

doi:10.1016/j.humimm.2021.12.002

Cited by 28 publications

(26 citation statements)

References 70 publications

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“…Defining the immunogenicity of eplets is an area that needs to be further evaluated in solid organ transplantation. As not all molecular mismatches lead to antibody formation, knowledge of the immunogenicity of individual HLA eplets is required before eplet matching is implemented in clinical transplantation [33]. Antibody verification is the most basic method for assessing the clinical relevance of an individual eplets by experimenting that the eplet can bind to alloantibodies.…”

Section: Discussionmentioning

confidence: 99%

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Combined Analysis of HLA Class II Eplet Mismatch and Tacrolimus Levels for the Prediction of De Novo Donor Specific Antibody Development in Kidney Transplant Recipients

Lee

Min

Kang

et al. 2022

IJMS

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We investigated whether HLA class II eplet mismatch was related to dnDSA development and analyzed its combined impact with tacrolimus levels for kidney transplantation outcomes. A total of 347 kidney transplants were included. HLA Matchmaker was used for the single molecular eplet, total eplet, antibody (Ab)-verified eplet mismatch analyses, and Ab-verified single molecular analysis to identify HLA-DR/DQ molecular thresholds for the risk of dnDSA development. A time-weighted tacrolimus trough level (TAC-C0) of 5 ng/mL and a TAC-C0 time-weighted coefficient variability (TWCV) of 20% were applied to find the combined effects on dnDSA development. A high level of mismatch for single molecular eplet (DQ ≥ 10), total eplet (DQ ≥ 12), Ab-verified eplet (DQ ≥ 4), and Ab-verified single molecular eplet (DQ ≥ 4) significantly correlated with HLA class II dnDSA development. Class II dnDSA developed mostly in patients with low TAC-C0 and high eplet mismatch. In the multivariable analyses, low TAC-C0 and high eplet mismatch showed the highest hazard ratio for the development of dnDSA. No significant combined effect was observed in dnDSA development according to TWCV. In conclusion, the determination of HLA class II eplet mismatch may improve the risk stratification for dnDSA development, especially in conjunction with tacrolimus trough levels.

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Section: Discussionmentioning

confidence: 99%

“…These different approaches are complementary. Th evaluation of multiple, large patient cohorts would be necessary, and building a large reference dataset of transplant recipients can contribute to the investigation of the predictive values of each eplet type and mismatch score [33].…”

Section: Discussionmentioning

confidence: 99%

Combined Analysis of HLA Class II Eplet Mismatch and Tacrolimus Levels for the Prediction of De Novo Donor Specific Antibody Development in Kidney Transplant Recipients

Lee

Min

Kang

et al. 2022

IJMS

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“…As can be seen in cumulative percentages, 12 HLA antigen mismatches at the split level make up at least 90% of mismatches at this locus, indicating that when looking at HLA-A in isolation, around 12 CAR Treg specificities would be required to serve 90% of the Eurotransplant population. As CAR Tregs in the setting of transplantation use HLA-specific antibodies as antigen receptor, not HLA antigens, but HLA epitopes are targeted (106). Since epitopes are shared between different HLA antigens, this will reduce the number of required CAR-specificities, as they can cover multiple mismatched HLA molecules.…”

Section: Future Perspectivesmentioning

confidence: 99%

Chimeric Antigen Receptor (CAR) Regulatory T-Cells in Solid Organ Transplantation

et al. 2022

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Solid organ transplantation is the treatment of choice for various end-stage diseases, but requires the continuous need for immunosuppression to prevent allograft rejection. This comes with serious side effects including increased infection rates and development of malignancies. Thus, there is a clinical need to promote transplantation tolerance to prevent organ rejection with minimal or no immunosuppressive treatment. Polyclonal regulatory T-cells (Tregs) are a potential tool to induce transplantation tolerance, but lack specificity and therefore require administration of high doses. Redirecting Tregs towards mismatched donor HLA molecules by modifying these cells with chimeric antigen receptors (CAR) would render Tregs far more effective at preventing allograft rejection. Several studies on HLA-A2 specific CAR Tregs have demonstrated that these cells are highly antigen-specific and show a superior homing capacity to HLA-A2+ allografts compared to polyclonal Tregs. HLA-A2 CAR Tregs have been shown to prolong survival of HLA-A2+ allografts in several pre-clinical humanized mouse models. Although promising, concerns about safety and stability need to be addressed. In this review the current research, obstacles of CAR Treg therapy, and its potential future in solid organ transplantation will be discussed.

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“…Antibody‐mediated rejection is one of the major causes of graft failure in kidney transplantation and is caused by pre‐existing or de novo donor‐specific antibodies (dnDSA) mainly directed against a mismatched HLA molecule 1,2 . Increasing evidence indicates that HLA mismatch analysis on the amino acid or eplet level is superior in predicting dnDSA development compared to the HLA antigen level 3 . HLA eplets are configurations of polymorphic amino acids within a 3.5 Å radius and resemble the functional epitope that interacts with the complementarity‐determining region 3 on the heavy chain of the B cell receptor 4 .…”

Section: Introductionmentioning

confidence: 99%

Site‐directed mutagenesis of HLA molecules reveals the functional epitope of a human HLA‐A1/A36‐specific monoclonal antibody

Meng

Bezstarosti

Singh

et al. 2022

HLA

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Eplet 44KM is currently listed in the HLA Epitope Registry but does not adhere to the eplet definition of an amino acid configuration within a 3.5 Å radius. Eplet 44KM has been previously redefined to the antibody‐verified reactivity pattern 44K/150V/158V, based on reactivity analysis of monoclonal antibody VDK1D12. Since the three residues are always simultaneously present on common HLA alleles, methods to define which residue is crucial for antibody‐induction and binding are limited. In this proof‐of‐concept study, we performed site‐directed mutagenesis to narrow down the antibody‐verified reactivity pattern 44K/150V/158V to a single amino acid and defined 44K as the eplet or functional epitope of mAb VDK1D12.

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Implementation of molecular matching in transplantation requires further characterization of both immunogenicity and antigenicity of individual HLA epitopes

Cited by 28 publications

References 70 publications

Combined Analysis of HLA Class II Eplet Mismatch and Tacrolimus Levels for the Prediction of De Novo Donor Specific Antibody Development in Kidney Transplant Recipients

Combined Analysis of HLA Class II Eplet Mismatch and Tacrolimus Levels for the Prediction of De Novo Donor Specific Antibody Development in Kidney Transplant Recipients

Chimeric Antigen Receptor (CAR) Regulatory T-Cells in Solid Organ Transplantation

Site‐directed mutagenesis of HLA molecules reveals the functional epitope of a human HLA‐A1/A36‐specific monoclonal antibody

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