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Prognostic impact of HLA supertype mismatch in single-unit cord blood transplantation

Bone Marrow Transplantation volume 59, pages 466–472 (2024)Cite this article

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Abstract

The “human leukocyte antigen (HLA) supertype” is a functional classification of HLA alleles, which was defined by structural features and peptide specificities, and has been reportedly associated with the clinical outcomes of viral infections and autoimmune diseases. Although the disparity in each HLA locus was reported to have no clinical significance in single-unit cord blood transplantation (sCBT), the clinical significance of the HLA supertype in sCBT remains unknown. Therefore, we retrospectively analyzed clinical data of 1603 patients who received sCBT in eight institutes in Japan between 2000 and 2017. Each HLA allele was categorized into 19 supertypes, and the prognostic effect of disparities was then assessed. An HLA-B supertype mismatch was identified as a poor prognostic factor (PFS: hazard ratio [HR] = 1.23, p = 0.00044) and was associated with a higher cumulative incidence (CI) of relapse (HR = 1.24, p = 0.013). However, an HLA-B supertype mismatch was not associated with the CI of acute and chronic graft-versus-host-disease. The multivariate analysis for relapse and PFS showed the significance of an HLA-B supertype mismatch independent of allelic mismatches, and other previously reported prognostic factors. HLA-B supertype-matched grafts should be selected in sCBT.

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Fig. 1: Relationship between post-transplant outcomes and HLA supertype compatibility.
Fig. 2: Multivariate analysis.
Fig. 3: Subgroup analysis.
Fig. 4: Schema of the effect of supertype matching on the graft-versus-tumor effect.

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References

  1. Eapen M, Rubinstein P, Zhang M-J, Stevens C, Kurtzberg J, Scaradavou A, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. 2007;369:1947–54.

    Article  PubMed  Google Scholar 

  2. Barker JN, Byam C, Scaradavou A. How I treat: the selection and acquisition of unrelated cord blood grafts. Blood. 2011;117:2332–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kawase T, Morishima Y, Matsuo K, Kashiwase K, Inoko H, Saji H, et al. High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism. Blood. 2007;110:2235–41.

    Article  CAS  PubMed  Google Scholar 

  4. Morishima S, Kashiwase K, Matsuo K, Azuma F, Yabe T, Sato-Otsubo A, et al. High-risk HLA alleles for severe acute graft-versus-host disease and mortality in unrelated donor bone marrow transplantation. Haematologica. 2016;101:491–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Koyama M, Hill GR. Alloantigen presentation and graft-versus-host disease: fuel for the fire. Blood. 2016;127:2963–70.

    Article  CAS  PubMed  Google Scholar 

  6. Sidney J, Peters B, Frahm N, Brander C, Sette A. HLA class I supertypes: a revised and updated classification. BMC Immunol. 2008;9:1–15.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lund O, Nielsen M, Kesmir C, Petersen AG, Lundegaard C, Worning P, et al. Definition of supertypes for HLA molecules using clustering of specificity matrices. Immunogenetics. 2004;55:797–810.

    Article  CAS  PubMed  Google Scholar 

  8. Harjanto S, Ng LFP, Tong JC. Clustering HLA class I superfamilies using structural interaction patterns. PLoS One 2014; 9. e86655. https://doi.org/10.1371/journal.pone.0086655.

  9. Sette A, Sidney J. Nine major HLA class I supertypes account for the vast preponderance of HLA-A and -B polymorphism. Immunogenetics. 1999;50:201–12.

    Article  CAS  PubMed  Google Scholar 

  10. Tong JC, Tan TW, Ranganathan S. In silico grouping of peptide/HLA class I complexes using structural interaction characteristics. Bioinformatics. 2007;23:177–83.

    Article  CAS  PubMed  Google Scholar 

  11. Doytchinova IA, Guan P, Flower DR. Identifiying human MHC supertypes using bioinformatic methods. J Immunol. 2004;172:4314–23.

    Article  CAS  PubMed  Google Scholar 

  12. Richardson J, Reyburn HT, Luque I, Valés‐Gómez M, Strominger JL. Definition of polymorphic residues on killer Ig‐like receptor proteins which contribute to the HLA‐C binding site. Eur J Immunol. 2000;30:1480–5.

    Article  CAS  PubMed  Google Scholar 

  13. Doytchinova IA, Flower DR. In silico identification of supertypes for class II MHCs. J Immunol. 2005;174:7085–95.

    Article  CAS  PubMed  Google Scholar 

  14. Trachtenberg E, Korber B, Sollars C, Kepler TB, Hraber PT, Hayes E, et al. Advantage of rare HLA supertype in HIV disease progression. Nat Med. 2003;9:928–35.

    Article  CAS  PubMed  Google Scholar 

  15. Deutekom HWM, van, Hoof I, Bontrop RE, Kesmir C. A comparative analysis of viral peptides presented by contemporary human and chimpanzee MHC class I molecules. J Immunol. 2011;187:5995–6001.

    Article  PubMed  Google Scholar 

  16. Lazaryan A, Song W, Lobashevsky E, Tang J, Shrestha S, Zhang K, et al. Human leukocyte antigen class I supertypes and HIV-1 control in African Americans. J Virol. 2010;84:2610–7.

    Article  CAS  PubMed  Google Scholar 

  17. Matsueda S, Takedatsu H, Sasada T, Azuma K, Ishihara Y, Komohara Y, et al. New peptide vaccine candidates for epithelial cancer patients With HLA-A3 supertype alleles. J Immunother. 2007;30:274–81.

    Article  CAS  PubMed  Google Scholar 

  18. Matsueda S, Takedatsu H, Yao A, Tanaka M, Noguchi M, Itoh K, et al. Identification of peptide vaccine candidates for prostate cancer patients with HLA-A3 supertype alleles. Clin Cancer Res. 2005;11:6933–43.

    Article  CAS  PubMed  Google Scholar 

  19. Chowell D, Morris LGT, Grigg CM, Weber JK, Samstein RM, Makarov V, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2018;359:582–7.

    Article  CAS  PubMed  Google Scholar 

  20. Karosiene E, Lundegaard C, Lund O, Nielsen M. NetMHCcons: a consensus method for the major histocompatibility complex class I predictions. Immunogenetics. 2012;64:177–86.

    Article  CAS  PubMed  Google Scholar 

  21. Thomsen M, Lundegaard C, Buus S, Lund O, Nielsen M. MHCcluster, a method for functional clustering of MHC molecules. Immunogenetics. 2013;65:655–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kalita P, Padhi AK, Zhang KYJ, Tripathi T. Design of a peptide-based subunit vaccine against novel coronavirus SARS-CoV-2. Micro Pathog. 2020;145:104236.

    Article  CAS  Google Scholar 

  23. Lazaryan A, Wang T, Spellman SR, Wang H-L, Pidala J, Nishihori T, et al. Human leukocyte antigen supertype matching after myeloablative hematopoietic cell transplantation with 7/8 matched unrelated donor allografts: a report from the Center for International Blood and Marrow Transplant Research. Haematologica. 2016;101:1267–74.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014;123:3664–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. report of a workshop convened by the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Traspl. 2009;15:367–9.

    Article  Google Scholar 

  27. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transpl. 2009;15:1628–33.

    Article  Google Scholar 

  28. Gaballa A, Clave E, Uhlin M, Toubert A, Arruda LCM. Evaluating thymic function after human hematopoietic stem cell transplantation in the personalized medicine era. Front Immunol. 2020;11:1341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Clave E, Lisini D, Douay C, Giorgiani G, Busson M, Zecca M, et al. Thymic function recovery after unrelated donor cord blood or T-cell depleted HLA-haploidentical stem cell transplantation correlates with leukemia relapse. Front Immunol. 2013;4:54.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Song ES, Linsk R, Olson CA, McMillan M, Goodenow RS. Allospecific cytotoxic T lymphocytes recognize an H-2 peptide in the context of a murine major histocompatibility complex class I molecule. Proc Natl Acad Sci. 1988;85:1927–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kievits F, Ivanyi P. A subpopulation of mouse cytotoxic T lymphocytes recognizes allogeneic H-2 class I antigens in the context of other H-2 class I molecules. J Exp Med. 1991;174:15–19.

    Article  CAS  PubMed  Google Scholar 

  32. Krenger W, Holländer GA. The immunopathology of thymic GVHD. Semin Immunopathol. 2008;30:439.

    Article  PubMed  Google Scholar 

  33. Godthelp BC, van Tol MJ, Vossen JM, van Den Elsen PJ. T-cell immune reconstitution in pediatric leukemia patients after allogeneic bone marrow transplantation with T-cell–depleted or unmanipulated grafts: evaluation of overall and antigen-specific T-cell repertoires. Blood. 1999;94:4358–69.

    Article  CAS  PubMed  Google Scholar 

  34. Eyrich M, Croner T, Leiler C, Lang P, Bader P, Klingebiel T, et al. Distinct contributions of CD4+ and CD8+naive and memory T-cell subsets to overall T-cell–receptor repertoire complexity following transplantation of T-cell–depleted CD34-selected hematopoietic progenitor cells from unrelated donors. Blood. 2002;100:1915–8.

    Article  CAS  PubMed  Google Scholar 

  35. Roux E, Dumont-Girard F, Starobinski M, Siegrist CA, Helg C, Chapuis B, et al. Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood. 2000;96:2299–303.

    Article  CAS  PubMed  Google Scholar 

  36. Touma W, Brunstein CG, Cao Q, Miller JS, Curtsinger J, Verneris MR, et al. Dendritic cell recovery impacts outcomes after umbilical cord blood and sibling donor transplantation for hematologic malignancies. Biol Blood Marrow Transpl. 2017;23:1925–31.

    Article  Google Scholar 

  37. Reddy P, Maeda Y, Liu C, Krijanovski OI, Korngold R, Ferrara JLM. A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses. Nat Med. 2005;11:1244–9.

    Article  CAS  PubMed  Google Scholar 

  38. Prugnolle F, Manica A, Charpentier M, Guégan JF, Guernier V, Balloux F. Pathogen-driven selection and worldwide HLA class I diversity. Curr Biol. 2005;15:1022–7.

    Article  CAS  PubMed  Google Scholar 

  39. Francisco R, dos S, Buhler S, Nunes JM, Bitarello BD, França GS, et al. HLA supertype variation across populations: new insights into the role of natural selection in the evolution of HLA-A and HLA-B polymorphisms. Immunogenetics. 2015;67:651–63.

    Article  Google Scholar 

  40. Lu Z, Chen H, Jiao X, Wang Y, Wu L, Sun H, et al. Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer. Genome Med. 2021;13:175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kiepiela P, Leslie AJ, Honeyborne I, Ramduth D, Thobakgale C, Chetty S, et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature. 2004;432:769–75.

    Article  CAS  PubMed  Google Scholar 

  42. Proietto, Dommelen AI, van S, Zhou P, Rizzitelli A, D’Amico A, et al. Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc Natl Acad Sci. 2008;105:19869–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Teshima T, Reddy P, Liu C, Williams D, Cooke KR, Ferrara JLM. Impaired thymic negative selection causes autoimmune graft-versus-host disease. Blood. 2003;102:429–35.

    Article  CAS  PubMed  Google Scholar 

  44. Wu T, Young JS, Johnston H, Ni X, Deng R, Racine J, et al. Thymic damage, impaired negative selection, and development of chronic graft-versus-host disease caused by donor CD4+ and CD8+ T cells. J Immunol. 2013;191:488–99.

    Article  CAS  PubMed  Google Scholar 

  45. Hogquist KA, Baldwin TA, Jameson SC. Central tolerance: learning self-control in the thymus. Nat Rev Immunol. 2005;5:772–82.

    Article  CAS  PubMed  Google Scholar 

  46. Jiménez M, Martínez C, Ercilla G, Carreras E, Urbano-Ispízua Á, Aymerich M, et al. Reduced-intensity conditioning regimen preserves thymic function in the early period after hematopoietic stem cell transplantation. Exp Hematol. 2005;33:1240–8.

    Article  PubMed  Google Scholar 

  47. Chen X, Hale GA, Barfield R, Benaim E, Leung WH, Knowles J, et al. Rapid immune reconstitution after a reduced‐intensity conditioning regimen and a CD3‐depleted haploidentical stem cell graft for paediatric refractory haematological malignancies. Br J Haematol. 2006;135:524–32.

    Article  PubMed  Google Scholar 

  48. Castermans E, Hannon M, Dutrieux J, Humblet-Baron S, Seidel L, Cheynier R, et al. Thymic recovery after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning is limited to patients younger than 60 years of age. Haematologica. 2011;96:298–306.

    Article  CAS  PubMed  Google Scholar 

  49. Palmer DB. The effect of age on thymic function. Front Immunol. 2013;4:316.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Terakura S, Wake A, Inamoto Y, Murata M, Sakai R, Yamaguchi T, et al. Exploratory research for optimal GvHD prophylaxis after single unit CBT in adults: short-term methotrexate reduced the incidence of severe GvHD more than mycophenolate mofetil. Bone Marrow Transpl. 2017;52:423–30.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the patients who participated in this study and the medical and nursing staff for providing patient care. We also thank Eriko Makizumi Kabayama and Miyuki Yoshikawa for their assistance with the data collection.

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Authors and Affiliations

  1. Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan

    Takeshi Sugio, Kohta Miyawaki, Yasuo Mori, Goichi Yoshimoto, Yoshikane Kikushige, Yuya Kunisaki, Koichi Akashi & Koji Kato

  2. Divisions of Oncology and Hematology, Department of Medicine, Stanford University, Stanford, CA, USA

    Takeshi Sugio

  3. Department of Hematology, Toranomon Hospital, Tokyo, Japan

    Naoyuki Uchida & Shuichi Taniguchi

  4. Department of Hematology, Kitakyushu Municipal Medical Center, Fukuoka, Japan

    Yuju Ohno

  5. Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan

    Tetsuya Eto & Shuichi Taniguchi

  6. Department of Health Sciences, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

    Shinichi Mizuno

  7. Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan

    Koji Nagafuji

  8. Department of Hematology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan

    Hiromi Iwasaki

  9. Department of Hematology, Harasanshin Hospital, Fukuoka, Japan

    Tomohiko Kamimura

  10. Department of Hematology, JCHO Kyushu Hospital, Fukuoka, Japan

    Ryosuke Ogawa

  11. Department of Hematology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan

    Toshihiro Miyamoto

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  1. Takeshi Sugio
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Contributions

TS, NU, KM, SM, and KK designed experiments and wrote the manuscript. TS and NU collected the clinical data. TS, NU, KM, and KK analyzed the data. YO, TE, YM, GY, KY, YK, KN, HI, TK, RO, TM, ST, and KA reviewed the data.

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Correspondence to Koji Kato.

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Sugio, T., Uchida, N., Miyawaki, K. et al. Prognostic impact of HLA supertype mismatch in single-unit cord blood transplantation. Bone Marrow Transplant 59, 466–472 (2024). https://doi.org/10.1038/s41409-023-02183-1

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