Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Pediatric Nephrology
Published in: Pediatric Nephrology 10/2017

01-10-2017 | Educational Review

HLA epitope matching in pediatric renal transplantation

Authors: Matthew P. Sypek, Peter Hughes, Joshua Y. Kausman

Published in: Pediatric Nephrology | Issue 10/2017

Login to get access

Abstract

Chronic graft loss due to antibody-mediated rejection (AMR) and the difficulty of re-transplanting highly sensitized patients are two of the major long-term challenges in pediatric renal transplantation. Treatments for AMR are often ineffective and desensitization protocols can be a high risk, making prevention a highly appealing strategy. Insights into the structural determinants of humoral alloantigenicity present an exciting opportunity to reassess our current paradigm of tissue matching and potentially preventing these complications. We review the theory behind human leukocyte antigen (HLA) B cell epitopes and the various systems that have been proposed to define them, including eplets. There is a growing body of clinical evidence suggesting that epitope-based tissue matching may be superior to traditional HLA antigen matching at predicting a range of clinical outcomes. However, additional studies are required to better understand the biological relevance of these systems of defining epitopes and their role in pediatric transplantation.
Appendix
Available only for authorised users
Literature
1.
2.
Arias M, Rush DN, Wiebe C, Gibson IW, Blydt-Hansen TD, Nickerson PW, Sellarés J, López-Hoyos M, San Segundo D, Crespo-Leiro M, Marzoa-Rivas R, Barge-Caballero E, Paniagua-Martín M, Román A, Serón D, Böhmig G, Schwaiger E (2014) Antibody-mediated rejection: analyzing the risk, proposing solutions. Transplantation 98:S3–S21CrossRefPubMed
3.
Everly MJ, Rebellato LM, Haisch CE, Ozawa M, Parker K, Briley KP, Catrou P, Bolin P, Kendrick W, Kendrick S, Harland R, Terasaki P (2013) Incidence and impact of de novo donor-specific alloantibody in primary renal allografts. Transplantation 95:410–417CrossRefPubMed
4.
Kim JJ, Balasubramanian R, Michaelides G, Wittenhagen P, Sebire NJ, Mamode N, Shaw O, Vaughan R, Marks S (2014) The clinical spectrum of de novo donor-specific antibodies in pediatric renal transplant recipients. Am J Transplant 14:2350–2358CrossRefPubMed
5.
Cai J, Terasaki PI (2008) Post-transplantation antibody monitoring and HLA antibody epitope identification. Curr Opin Immunol 20:602–606CrossRefPubMed
6.
Fichtner A, Süsal C, Höcker B, Rieger S, Waldherr R, Westhoff JH, Sander A, Opelz G, Tonshoff B (2016) Association of C1q-fixing DSA with late graft failure in pediatric renal transplant recipients. Pediatr Nephrol 31:1157–1166CrossRefPubMed
7.
Foster BJ, Dahhou M, Zhang X, Platt RW, Smith JM, Hanley JA (2014) Impact of HLA mismatch at first kidney transplant on lifetime with graft function in young recipients. Am J Transplant 14:876–885CrossRefPubMed
8.
Gralla J, Tong S, Wiseman AC (2013) The impact of human leukocyte antigen mismatching on sensitization rates and subsequent retransplantation after first graft failure in pediatric renal transplant recipients. Transplantation 95:1218–1224CrossRefPubMed
9.
10.
Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M (2014) Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant 14:255–271CrossRefPubMedPubMedCentral
11.
Roberts DM, Jiang SH, Chadban SJ (2012) The treatment of acute antibody-mediated rejection in kidney transplant recipients—a systematic review. Transplantation 94:775–783CrossRefPubMed
12.
Mamode N, Marks SD (2016) Desensitization protocols for prospective pediatric renal transplant recipients. Pediatr Nephrol 31:1549–1551CrossRefPubMed
13.
Terasaki PI, Vredevoe DL, Porter KA, Mickey MR, Marchioro TL, Faris TD, Herrmann J, Starzl T (1966) Serotyping for homotransplantation. V. Evaluation of a matching scheme. Transplantation 4:688–699CrossRefPubMedPubMedCentral
14.
Williams RC, Opelz G, Mcgarvey CJ, Weil EJ, Chakkera HA (2016) The risk of transplant failure with HLA mismatch in first adult kidney allografts from deceased donors. Transplantation 100:1094–1102CrossRefPubMed
15.
16.
Duquesnoy RJ, Awadalla Y, Lomago J, Jelinek L, Howe J, Zern D, Hunter B, Martell J, Girnita A, Zeevi A (2008) Retransplant candidates have donor-specific antibodies that react with structurally defined HLA-DR, DQ, DP epitopes. Transpl Immunol 18:352–360CrossRefPubMed
17.
Duquesnoy RJ (2002) HLAMatchmaker: a molecularly based algorithm for histocompatibility determination. I. Description of the algorithm. Hum Immunol 63:339–352CrossRefPubMed
18.
Wiebe C, Nickerson P (2014) Acceptable mismatching at the class II epitope level: the Canadian experience. Curr Opin Organ Transplant 19:442–446CrossRefPubMed
19.
Tambur AR, Claas FHJ (2013) Toward HLA epitope matching in clinical transplantation. Am J Transplant 13:3059–3060CrossRefPubMed
20.
Filippone EJ, Farber JL (2015) Humoral immunity in renal transplantation: epitopes, Cw and DP, and complement-activating capability—an update. Clin Transplant 29:279–287CrossRefPubMed
21.
22.
MacCallum RM, Martin AC, Thornton JM (1996) Antibody–antigen interactions: contact analysis and binding site topography. J Mol Biol 262:732–745CrossRefPubMed
23.
Cunningham BC, Wells J (1993) Comparison of a structural and a functional epitope. J Mol Biol 234:554–563CrossRefPubMed
24.
Mylvaganam SE, Paterson Y, Getzoff ED (1998) Structural basis for the binding of an anti-cytochrome c antibody to its antigen: crystal structures of FabE8-cytochrome c complex to 1.8 A resolution and FabE8 to 2.26 A resolution. J Mol Biol 281:301–322CrossRefPubMed
25.
Hülsmeyer M, Chames P, Hillig RC, Stanfield RL, Held G, Coulie PG, Alings C, Wille G, Saenger W, Uchanska-Ziegler B, Hoogenboom H, Ziegler A (2005) A major histocompatibility complex-peptide-restricted antibody and T cell receptor molecules recognize their target by distinct binding modes: crystal structure of human leukocyte antigen (HLA)-A1-MAGE-A1 in complex with Fab-Hyb3. J Biol Chem 280:2972–2980CrossRefPubMed
26.
27.
28.
Stave JW, Lindpaintner K (2013) Antibody and antigen contact residues define epitope and paratope size and structure. J Immunol 191:1428–1435CrossRefPubMed
29.
Mallon DH, Bradley JA, Taylor CJ, Kosmoliaptsis V (2014) Structural and electrostatic analysis of HLA B-cell epitopes: inference on immunogenicity and prediction of humoral alloresponses. Curr Opin Organ Transplant 19:420–427CrossRefPubMed
30.
El-Awar N, Lee JH, Tarsitani C, Terasaki PI (2007) HLA class I epitopes: recognition of binding sites by mAbs or eluted alloantibody confirmed with single recombinant antigens. Hum Immunol 68:170–180CrossRefPubMed
31.
El-Awar NR, Akaza T, Terasaki PI, Nguyen A (2007) Human leukocyte antigen class I epitopes: update to 103 total epitopes, including the C locus. Transplantation 84:532–540CrossRefPubMed
32.
El-Awar N, Terasaki PI, Cai J, Deng CT, Ozawa M, Nguyen A, Lias M CN (2009) Chapter 24: Epitopes of HLA-A, B, C, DR, DQ, DP and MICA antigens. Clin Transpl 2009:295–321. Published by Terasaki Research Institute.
33.
34.
Duquesnoy RJ, Marrari M, Sousa L, Barroso J, Aita K, da Silva AS, do Monte SJ (2013) 16th IHIW: a website for the antibody-defined HLA epitope registry. Int J Immunogenet 40:54–59PubMed
35.
Duquesnoy RJ, Marrari M (2009) Correlations between Terasaki’s HLA class i epitopes and HLAMatchmaker-defined eplets on HLA-A, -B and -C antigens. Tissue Antigens 74:117–133CrossRefPubMed
36.
37.
Duquesnoy RJ, Marrari M, Mulder A, da Mata Sousa LCD, da Silva AS, do Monte SJH (2014) First report on the antibody verification of HLA-ABC epitopes recorded in the website-based HLA Epitope Registry. Tissue Antigens 83:391–400CrossRefPubMed
38.
Duquesnoy RJ, Marrari M, Tambur AR, Mulder A, da Mata Sousa LCD, da Silva AS, do Monte SJ (2014) First report on the antibody verification of HLA-DR, HLA-DQ and HLA-DP epitopes recorded in the HLA Epitope Registry. Hum Immunol 75:1097–1103CrossRefPubMed
39.
Duquesnoy RJ (2014) Human leukocyte antigen epitope antigenicity and immunogenicity. Curr Opin Organ Transplant 19:428–435CrossRefPubMed
40.
Kosmoliaptsis V, Chaudhry AN, Sharples LD, Halsall DJ, Dafforn TR, Bradley JA, Taylor C (2009) Predicting HLA class I alloantigen immunogenicity from the number and physiochemical properties of amino acid polymorphisms. Transplantation 88:791–798CrossRefPubMed
41.
Mallon DH, Bradley JA, Winn PJ, Taylor CJ, Kosmoliaptsis V (2015) Three-dimensional structural modelling and calculation of electrostatic potentials of HLA Bw4 and Bw6 epitopes to explain the molecular basis for alloantibody binding: toward predicting HLA antigenicity and immunogenicity. Transplantation 99:4–9CrossRef
42.
Duquesnoy RJ (2012) The antibody response to an HLA mismatch: a model for nonself-self discrimination in relation to HLA epitope immunogenicity. Int J Immunogenet 39:1–9CrossRefPubMed
43.
Duquesnoy RJ (2011) Humoral alloimmunity in transplantation: relevance of HLA epitope antigenicity and immunogenicity. Front Immunol 2:8–13CrossRef
44.
Lobashevsky AL, Senkbeil RW, Shoaf JL, Stephenson AK, Skelton SB, Burke RM, Deierhoi M, Thomas JM (2002) The number of amino acid residues mismatches correlates with flow cytometry crossmatching results in high PRA renal patients. Hum Immunol 63:364–374CrossRefPubMed
45.
Duquesnoy RJ, Takemoto S, de Lange P, Doxiadis IIN, Schreuder GMT, Persijn GG, Claas FHJ (2003) HLAmatchmaker: a molecularly based algorithm for histocompatibility determination. III. Effect of matching at the HLA-A, B amino acid triplet level on kidney transplant survival. Transplantation 75:884–889CrossRefPubMed
46.
Heidt S, Witvliet MD, Haasnoot GW, Claas FHJ (2015) The 25th anniversary of the Eurotransplant Acceptable Mismatch program for highly sensitized patients. Transpl Immunol 33:51–57CrossRefPubMed
47.
Dankers MKA, Witvliet MD, Roelen DL, De Lange P, Korfage N, Persijn GG, Duquesnoy R, Doxiadis I, Claas FHJ (2004) The number of amino acid triplet differences between patient and donor is predictive for the antibody reactivity against mismatched human leukocyte antigens1. Transplantation 77:1236–1239CrossRefPubMed
48.
Wiebe C, Pochinco D, Blydt-Hansen TD, Ho J, Birk PE, Karpinski M, Goldberg A, Storsley L, Gibson I, Rush D, Nickerson P (2013) Class II HLA epitope matching—a strategy to minimize de novo donor-specific antibody development and improve outcomes. Am J Transplant 13:3114–3122CrossRefPubMed
49.
Wiebe C, Nevins TE, Robiner WN, Thomas W, Matas AJ, Nickerson PW (2015) The synergistic effect of class II HLA epitope-mismatch and nonadherence on acute rejection and graft survival. Am J Transplant 15:2197–2202CrossRefPubMed
50.
Sapir-Pichhadze R, Tinckam K, Quach K, Logan AG, Laupacis A, John R, Beyene J, Kim SJ (2015) HLA-DR and -DQ eplet mismatches and transplant glomerulopathy: a nested case-control study. Am J Transplant 15:137–148CrossRefPubMed
51.
Kosmoliaptsis V, Mallon DH, Chen Y, Bolton EM, Bradley AJ, Taylor CJ (2016) Alloantibody responses after renal transplant failure can be better predicted by donor–recipient HLA amino acid sequence and physicochemical disparities than conventional HLA matching. Am J Transplant 16:2139–2147CrossRefPubMedPubMedCentral
52.
Singh P, Filippone EJ, Colombe BW, Shah AP, Zhan T, Harach M, Gorn C, Frank AM (2016) Sensitization trends after renal allograft failure: the role of DQ eplet mismatches in becoming highly sensitized. Clin Transplant 30:71–80CrossRefPubMed
53.
Walton DC, Hiho SJ, Cantwell LS, Diviney MB, Wright ST, Snell GI, Paraskeva M, Westall G (2016) HLA matching at the eplet level protects against chronic lung allograft dysfunction. Am J Transplant 16:2695–2703CrossRefPubMed
54.
Sullivan PM, Warner P, Kemna MS, Albers EL, Law SP, Weiss NS, Law YM (2015) HLA molecular epitope mismatching and long-term graft loss in pediatric heart transplant recipients. J Hear Lung Transplant 34:950–957CrossRef
55.
Sapir-Pichhadze R, Tinckam KJ, Laupacis A, Logan AG, Beyene J, Kim SJ (2016) Immune sensitization and mortality in wait-listed kidney transplant candidates. J Am Soc Nephrol 27:570–578CrossRefPubMed
56.
Redfield RR, Scalea JR, Zens TJ, Mandelbrot DA, Leverson G, Kaufman DB, Djamali A (2016) The mode of sensitization and its influence on allograft outcomes in highly sensitized kidney transplant recipients. Nephrol Dial Transplant 10:1746–1753CrossRef
57.
Marfo K, Lu A, Ling M, Akalin E (2011) Desensitization protocols and their outcome. Clin J Am Soc Nephrol 6:922–936CrossRefPubMed
58.
Sypek M, Alexander S, Cantwell L, Ierino F, Ferrari P, Walker A, Kausman JY (2016) Optimizing outcomes in pediatric renal transplantation through the Australian Paired Kidney Exchange Program. Am J Transplant. doi:10.​1111/​ajt.​14041 PubMed
59.
60.
Agarwal S, Oak N, Siddique J, Harland RC, Abbo ED (2009) Changes in pediatric renal transplantation after implementation of the revised deceased donor kidney allocation policy. Am J Transplant 9:1237–1242CrossRefPubMed
61.
Bryan CF, Chadha V, Warady BA (2016) Donor selection in pediatric kidney transplantation using DR and DQ eplet mismatching: a new histocompatibility paradigm. Pediatr Transplant 20:926–930CrossRefPubMed
62.
Kausman JY, Walker AM, Cantwell LS, Quinlan C, Sypek MP, Ierino FL (2016) Application of an epitope based allocation system in pediatric kidney transplantation. Pediatr Transplant 20:931–938CrossRefPubMed
Metadata
Title
HLA epitope matching in pediatric renal transplantation
Authors
Matthew P. Sypek
Peter Hughes
Joshua Y. Kausman
Publication date
01-10-2017
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Nephrology / Issue 10/2017
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-016-3557-4

Other articles of this Issue 10/2017

Pediatric Nephrology 10/2017 Go to the issue

Review

Is there such a thing as biocompatible peritoneal dialysis fluid?

Erratum

Erratum to: Viral load of EBV DNAemia is a predictor of EBV-related post-transplant lymphoproliferative disorders in pediatric renal transplant recipients

Review

Spectrum of LMX1B mutations: from nail–patella syndrome to isolated nephropathy

Review

Proteinuria in Dent disease: a review of the literature

Original Article

Measuring hemoglobin prior to early discharge without routine surveillance ultrasound after percutaneous native renal biopsy in children

Original Article

Urinary tract infection in small children: the evolution of renal damage over time