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Histocompatibility and Donor Selection Issues

Risk associations between HLA-DPB1 T-cell epitope matching and outcome of unrelated hematopoietic cell transplantation are independent of HLA-DPA1

Bone Marrow Transplantation volume 49, pages 1176–1183 (2014)Cite this article

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Abstract

HLA-DP antigens are beta-alpha heterodimers encoded by polymorphic HLA-DPB1 and -DPA1 alleles, respectively, in strong linkage disequilibrium (LD) with each other. Non-permissive unrelated donor (UD)-recipient HLA-DPB1 mismatches across three different T-cell epitope (TCE) groups are associated with increased mortality after hematopoietic SCT (HCT), but the role of HLA-DPA1 is unclear. We studied 1281 onco-hematologic patients after 10/10 HLA-matched UD-HCT facilitated by the National Marrow Donor Program. Non-permissive mismatches defined solely by HLA-DPB1 TCE groups were associated with significantly higher risks of TRM compared to permissive mismatches (hazard ratio (HR) 1.30, confidence interval (CI) 1.06–1.53; P=0.009) or allele matches. Moreover, non-permissive HLA-DPB1 TCE group mismatches in the graft versus host (GvH) direction significantly decreased the risk of relapse compared to permissive mismatches (HR 0.55, CI 0.37–0.80; P=0.002) or allele matches. Splitting each group into HLA-DPA1*02:01 positive or negative, in frequent LD with HLA-DPB1 alleles from two of the three TCE groups, or into HLA-DPA1 matched or mismatched, did not significantly alter the observed risk associations. Our findings suggest that the effects of clinically non-permissive HLA-DPB1 TCE group mismatches are independent of HLA-DPA1, and that selection of donors with non-permissive DPB1 TCE mismatches in GvH direction might provide some protection from disease recurrence.

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Acknowledgements

This work was supported by a grant (no. IG12042) from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to KF. The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two grants, N00014-12-1-0142 and N00014-13-1-0039, from the Office of Naval Research; grants from Allos, Inc., Amgen, Inc., Angioblast; anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children’s Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; RemedyMD; Sanofi; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience, Inc.; THERAKOS, Inc.; and Wellpoint, Inc.

Author information

Authors and Affiliations

  1. Institute of Experimental Cellular Therapy, Essen University Hospital, Essen, Germany

    K Fleischhauer

  2. Unit of Molecular and Functional Immunogenetics, San Raffaele Scientific Institute, Milan, Italy

    K Fleischhauer

  3. Histocompatibility, Immunogenetics, and Disease Profiling Laboratory, Stanford University Medical School, Stanford, CA, USA

    M A Fernandez-Viña

  4. Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA

    T Wang

  5. Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA,

    M Haagenson & S R Spellman

  6. National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    M Battiwalla

  7. Immunogentics and Transplantation Lab, University of California San Francisco Medical Center, San Francisco, CA, USA

    L A Baxter-Lowe

  8. Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy

    F Ciceri

  9. National Marrow Donor Program, Minneapolis, MN, USA

    J Dehn

  10. Oregon Health and Science University, Portland, OR, USA

    J Gajewski

  11. Pediatric Hematology/Oncology/BMT, All Children’s Hospital, St Petersburg, FL, USA,

    G A Hale

  12. Dutch Transplant Foundation, Leiden, The Netherlands

    M B A Heemskerk

  13. Department of Pathology, University of Chicago Hospitals, Chicago, IL, USA

    S R Marino

  14. Blood and Marrow Transplant, Roswell Park Cancer Institute, Buffalo, NY, USA

    P L McCarthy

  15. Department of Medicine/Bone Marrow Transplant, Stanford Hospitals and Clinics, Stanford, CA, USA

    D Miklos

  16. Europdonor Foundation, Leiden University Medical Center, Leiden, Netherlands

    M Oudshoorn

  17. Department of Pathology, University of Texas Health Care System, San Antonio, TX, USA

    M S Pollack

  18. Department of Hemaotology/Oncology, University of Florida, Gainesville, FL, USA

    V Reddy

  19. Hematology/Hematopoietic Cell Transplant, City of Hope National Medical Center, Duarte, CA, USA

    D Senitzer

  20. Anthony Nolan Research Institute, London, UK

    B E Shaw

  21. Bone Marrow and Stem Cell Transplant Center, Emory University Hospital, Atlanta, GA, USA

    E K Waller

  22. Clinical Transplant Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S J Lee

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  1. K Fleischhauer
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  2. M A Fernandez-Viña
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  3. T Wang
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  10. G A Hale
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  18. D Senitzer
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  19. B E Shaw
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  21. S J Lee
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  22. S R Spellman
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Correspondence to K Fleischhauer.

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Fleischhauer, K., Fernandez-Viña, M., Wang, T. et al. Risk associations between HLA-DPB1 T-cell epitope matching and outcome of unrelated hematopoietic cell transplantation are independent of HLA-DPA1. Bone Marrow Transplant 49, 1176–1183 (2014). https://doi.org/10.1038/bmt.2014.122

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