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In solid organ transplantation, formation of de novo donor-specific HLA antibodies is induced by mismatched eplets on donor HLA molecules. While several studies have shown a strong correlation between the number of eplet mismatches and inferior outcomes, not every eplet mismatch is immunogenic. Eplets are theoretically defined entities, necessitating formal proof that they can be recognised and bound by antibodies. This antibody verification is pivotal to ensure that clinically relevant eplets are considered in studies on molecular matching. Recombinant human HLA-specific monoclonal antibodies (mAbs) were generated from HLA-reactive B cell clones isolated from HLA immunised individuals using recombinant HLA molecules. Subsequently, the reactivity patterns of the mAbs obtained from single antigen bead assay were analysed using HLA-EMMA software to identify single or configurations of solvent accessible amino acids uniquely present on the reactive HLA alleles and were mapped to eplets. Two HLA class I and seven HLA class II-specific human mAbs were generated from four individuals. Extensive mAb reactivity analysis, led to antibody verification of three HLA-DR-specific eplets, and conversion of five eplets (one HLA-A, one HLA-B, two HLA-DR, and one HLA-DP), from provisionally verified to truly antibody-verified. Finally, one HLA-DQ-specific eplet was upgraded from level A2 to level A1 verification evidence. The generation of recombinant human HLA-specific mAbs with different specificities contributes significantly to the antibody verification of eplets and therefore is instrumental for implementation of eplet matching in the clinical setting.

Titel:	Antibody verification of HLA class I and class II eplets by human monoclonal HLA antibodies.
Autor/in / Beteiligte Person:	Kramer, CSM ; Bezstarosti, S ; Franke-van Dijk, MEI ; Vergunst, M ; Roelen, DL ; Uyar-Mercankaya, M ; Voogt-Bakker, KH ; Heidt, S
Zeitschrift:	HLA, Jg. 103 (2024), Heft 1, S. e15345
Veröffentlichung:	Oxford : Wiley Blackwell, [2016]-, 2024
Medientyp:	academicJournal
ISSN:	2059-2310 (electronic)
DOI:	10.1111/tan.15345
Schlagwort:	Humans Epitopes Alleles Tissue Donors HLA-B Antigens HLA Antigens Histocompatibility Testing Graft Rejection Antibodies, Monoclonal HLA-DR Antigens
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [HLA] 2024 Jan; Vol. 103 (1), pp. e15345. MeSH Terms: Antibodies, Monoclonal* ; HLA-DR Antigens* ; Humans ; Epitopes ; Alleles ; Tissue Donors ; HLA-B Antigens ; HLA Antigens ; Histocompatibility Testing ; Graft Rejection References: Heidt S, Haasnoot GW, van Rood JJ, Witvliet MD, Claas FHJ. Kidney allocation based on proven acceptable antigens results in superior graft survival in highly sensitized patients. Kidney Int. 2018;93(2):491-500. doi:10.1016/j.kint.2017.07.018. ; Lachmann N, Terasaki PI, Budde K, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87(10):1505-1513. doi:10.1097/TP.0b013e3181a44206. ; Duquesnoy RJ, Askar M. HLAMatchmaker: a molecularly based algorithm for histocompatibility determination. V. 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Int J Immunogenet. 2013;40(1):54-59. doi:10.1111/iji.12017. ; Bezstarosti S, Bakker KH, Kramer CSM, et al. A comprehensive evaluation of the antibody-verified status of eplets listed in the HLA epitope registry. Front Immunol. 2022;12:800946. doi:10.3389/fimmu.2021.800946. ; Kramer CSM, Franke-van Dijk MEI, Bakker KH, et al. Generation and reactivity analysis of human recombinant monoclonal antibodies directed against epitopes on HLA-DR. Am J Transplant. 2020;20(12):3341-3353. doi:10.1111/ajt.15950. ; Kramer CSM, Franke-van Dijk MEI, Priddey AJ, et al. Recombinant human monoclonal HLA antibodies of different IgG subclasses recognising the same epitope: excellent tools to study differential effects of donor-specific antibodies. HLA. 2019;94(5):415-424. doi:10.1111/tan.13664. ; Bezstarosti S, Kramer CSM, Franke-van Dijk MEI, et al. HLA-DQ-specific recombinant human monoclonal antibodies allow for in-depth analysis of HLA-DQ epitopes. 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Impact of donor mismatches at individual HLA-A, -B, -C, -DR, and -DQ loci on the development of HLA-specific antibodies in patients listed for repeat renal transplantation. Kidney Int. 2014;86(5):1039-1048. doi:10.1038/ki.2014.106. ; Ladowski JM, Mullins H, Romine M, et al. Eplet mismatch scores and de novo donor-specific antibody development in simultaneous pancreas-kidney transplantation. Hum Immunol. 2020;82:139-146. doi:10.1016/j.humimm.2020.12.009. ; Senev A, Coemans M, Lerut E, et al. Eplet mismatch load and de novo occurrence of donor-specific anti-HLA antibodies, rejection, and graft failure after kidney transplantation: an observational cohort study. J Am Soc Nephrol. 2020;31:2193-2204. doi:10.1681/asn.2020010019. ; Tafulo S, Malheiro J, Santos S, et al. HLA class II eplet mismatch load improves prediction of dnDSA development after living donor kidney transplantation. Int J Immunogenet. 2020;48:1-7. doi:10.1111/iji.12519. ; Wiebe C, Kosmoliaptsis V, Pochinco D, et al. HLA-DR/DQ molecular mismatch: a prognostic biomarker for primary alloimmunity. Am J Transplant. 2019;19(6):1708-1719. doi:10.1111/ajt.15177. ; Bryan CF, Chadha V, Warady BA. Donor selection in pediatric kidney transplantation using DR and DQ eplet mismatching: a new histocompatibility paradigm. Pediatr Transplant. 2016;20(7):926-930. doi:10.1111/petr.12762. ; Honger G, Niemann M, Schawalder L, et al. Toward defining the immunogenicity of HLA epitopes: impact of HLA class I eplets on antibody formation during pregnancy. HLA. 2020;96(5):589-600. doi:10.1111/tan.14054. ; Schawalder L, Honger G, Kleiser M, et al. Development of an immunogenicity score for HLA-DQ eplets: a conceptual study. HLA. 2021;97(1):30-43. 10.1111/tan.14110. ; Sapir-Pichhadze R, Zhang X, Ferradji A, et al. Epitopes as characterized by antibody-verified eplet mismatches determine risk of kidney transplant loss. Kidney Int. 2020;97(4):778-785. doi:10.1016/j.kint.2019.10.028. ; Meng T, Bezstarosti S, Singh U, et al. Site-directed mutagenesis of HLA molecules reveals the functional epitope of a human HLA-A1/A36-specific monoclonal antibody. HLA. 2023;101(2):138-142. doi:10.1111/tan.14895. Grant Information: National Reference Center for Histocompatibility Research Contributed Indexing: Keywords: HLA; antibody verification; eplet; human monoclonal antibody Substance Nomenclature: 0 (Antibodies, Monoclonal) ; 0 (Epitopes) ; 0 (HLA-DR Antigens) ; 0 (HLA-B Antigens) ; 0 (HLA Antigens) Entry Date(s): Date Created: 20240119 Date Completed: 20240122 Latest Revision: 20240201 Update Code: 20240201

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Antibody verification of HLA class I and class II eplets by human monoclonal HLA antibodies.