Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Stem cell transplantation

HLA-DPB1 mismatch induces a graft-versus-leukemia effect without severe acute GVHD after single-unit umbilical cord blood transplantation

Leukemia volume 32, pages 168–175 (2018)Cite this article

Subjects

Abstract

Although it is known that human leukocyte antigen (HLA)-DPB1 disparity has a strong impact on outcomes in unrelated hematopoietic transplantation with induction of acute graft-versus-host disease (GVHD) and a graft-versus-leukemia (GVL) effect, its role in unrelated umbilical cord blood transplantation (UR-CBT) has yet to be fully clarified. Our current study is being conducted to elucidate the impact of HLA-DPB1 mismatch, along with the effect of other HLA loci mismatches at the allele level. HLA six loci alleles were retrospectively typed in 1157 Japanese donors and patients with leukemia or myelodysplastic syndrome who underwent transplantation with a single unit of cord blood. HLA-DPB1 mismatch was associated with a significant reduction in leukemia relapse (hazard ratio 0.61, P<0.001), whereas the other HLA loci allele-level mismatches did not. No significant effect of HLA-DPB1 mismatch was observed in the risk of acute GVHD, engraftment or mortality. This HLA-DPB1 GVL effect without induction of severe acute GVHD or deterioration of survival rate has not been reported in unrelated bone marrow or peripheral blood stem cell transplantations, suggesting apparent advantages of UR-CBT. Accordingly, selection of an HLA-DPB1 mismatch cord blood might be the preferable choice for single-unit UR-CBT.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.

    CAS  Google Scholar 

  2. Gratwohl A, Brand R, Apperley J, Biezen AvA, Bandini G, Devergie A et al. Graft-versus-host disease and outcome in HLA-identical sibling transplantations for chronic myeloid leukemia. Blood 2002; 100: 3877–3886.

    Article  CAS  Google Scholar 

  3. Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol 2005; 23: 1993–2003.

    Article  Google Scholar 

  4. Weisdorf D, Zhang MJ, Arora M, Horowitz MM, Rizzo JD, Eapen M . Graft-versus-host disease induced graft-versus-leukemia effect: greater impact on relapse and disease-free survival after reduced intensity conditioning. Biol Blood Marrow Transplant 2012; 18: 1727–1733.

    Article  Google Scholar 

  5. Li JM, Giver CR, Lu Y, Hossain MS, Akhtari M, Waller EK . Separating graft-versus-leukemia from graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Immunotherapy 2009; 1: 599–621.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Warren EH, Deeg HJ . Dissecting graft-versus-leukemia from graft-versus-host-disease using novel strategies. Tissue Antigens 2013; 81: 183–193.

    Article  CAS  Google Scholar 

  7. Petersdorf EW, Gooley T, Malkki M, Anasetti C, Martin P, Woolfrey A et al. The biological significance of HLA-DP gene variation in haematopoietic cell transplantation. Br J Haematol 2001; 112: 988–994.

    Article  CAS  Google Scholar 

  8. Shaw BE, Potter MN, Mayor NP, Pay AL, Smith C, Goldman JM et al. The degree of matching at HLA-DPB1 predicts for acute graft-versus-host disease and disease relapse following haematopoietic stem cell transplantation. Bone Marrow Transplant 2003; 31: 1001–1008.

    Article  CAS  Google Scholar 

  9. Shaw BE, Mayor NP, Russell NH, Apperley JF, Clark RE, Cornish J et al. Diverging effects of HLA-DPB1 matching status on outcome following unrelated donor transplantation depending on disease stage and the degree of matching for other HLA alleles. Leukemia 2010; 24: 58–65.

    Article  CAS  Google Scholar 

  10. Morishima Y, Yabe T, Matsuo K, Kashiwase K, Inoko H, Saji H et al. Effects of HLA allele and killer immunoglobulin-like receptor ligand matching on clinical outcome in leukemia patients undergoing transplantation with T-cell-replete marrow from an unrelated donor. Biol Blood Marrow Transplant 2007; 13: 315–328.

    Article  CAS  Google Scholar 

  11. Morishima Y, Kashiwase K, Matsuo K, Azuma F, Morishima S, Onizuka M et al. Biological significance of HLA locus matching in unrelated donor bone marrow transplantation. Blood 2015; 125: 1189–1197.

    Article  CAS  Google Scholar 

  12. Bray RA, Hurley CK, Kamani NR, Woolfrey A, Muller C, Spellman S et al. National marrow donor program HLA matching guidelines for unrelated adult donor hematopoietic cell transplants. Biol Blood Marrow Transplant 2008; 14 (9 Suppl): 45–53.

    Article  Google Scholar 

  13. Hurley CK, Wagner JE, Setterholm MI, Confer DL . Advances in HLA: practical implications for selecting adult donors and cord blood units. Biol Blood Marrow Transplant 2006; 12 (1 Suppl 1): 28–33.

    Article  Google Scholar 

  14. Kamani N, Spellman S, Hurley CK, Barker JN, Smith FO, Oudshoorn M et al. State of the art review: HLA matching and outcome of unrelated donor umbilical cord blood transplants. Biol Blood Marrow Transplant 2008; 14: 1–6.

    Article  Google Scholar 

  15. Atsuta Y, Kanda J, Takanashi M, Morishima Y, Taniguchi S, Takahashi S et al. Different effects of HLA disparity on transplant outcomes after single-unit cord blood transplantation between pediatric and adult patients with leukemia. Haematologica 2013; 98: 814–822.

    Article  Google Scholar 

  16. Spellman SR, Eapen M, Logan BR, Mueller C, Rubinstein P, Setterholm MI et al. A perspective on the selection of unrelated donors and cord blood units for transplantation. Blood 2012; 120: 259–265.

    Article  CAS  Google Scholar 

  17. Eapen M, Rubinstein P, Zhang MJ, 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: 1947–1954.

    Article  Google Scholar 

  18. Rocha V, Gluckman E . Improving outcomes of cord blood transplantation: HLA matching, cell dose and other graft- and transplantation-related factors. Br J Haematol 2009; 147: 262–274.

    Article  CAS  Google Scholar 

  19. Barker JN, Scaradavou A, Stevens CE . Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies. Blood 2010; 115: 1843–1849.

    Article  CAS  Google Scholar 

  20. Stevens CE, Carrier C, Carpenter C, Sung D, Scaradavou A . HLA mismatch direction in cord blood transplantation: impact on outcome and implications for cord blood unit selection. Blood 2011; 118: 3969–3978.

    Article  CAS  Google Scholar 

  21. Kogler G, Enczmann J, Rocha V, Gluckman E, Wernet P . High-resolution HLA typing by sequencing for HLA-A, -B, -C, -DR, -DQ in 122 unrelated cord blood/patient pair transplants hardly improves long-term clinical outcome. Bone Marrow Transplant 2005; 36: 1033–1041.

    Article  CAS  Google Scholar 

  22. Eapen M, Klein JP, Sanz GF, Spellman S, Ruggeri A, Anasetti C et al. Effect of donor-recipient HLA matching at HLA A, B, C, and DRB1 on outcomes after umbilical-cord blood transplantation for leukaemia and myelodysplastic syndrome: a retrospective analysis. Lancet Oncol 2011; 12: 1214–1221.

    Article  CAS  Google Scholar 

  23. Eapen M, Klein JP, Ruggeri A, Spellman S, Lee SJ, Anasetti C et al. Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood 2014; 123: 133–140.

    Article  CAS  Google Scholar 

  24. Brunstein CG, Petersdorf EW, DeFor TE, Noreen H, Maurer D, MacMillan ML et al. Impact of allele-level HLA mismatch on outcomes in recipients of double umbilical cord blood transplantation. Biol Blood Marrow Transplant 2016; 22: 487–492.

    Article  Google Scholar 

  25. Mugishima H, Takahashi T, Nagamura T, Asano S, Saito H . Umbilical cord blood for unrelated bone marrow replacement; Asia bank and Japan cord blood bank network update. Int J Hematol 2002; 76 (Suppl 2): 284–286.

    Article  Google Scholar 

  26. Isoyama K, Ohnuma K, Kato K, Takahashi TA, Kai S, Kato S et al. Cord blood transplantation from unrelated donors: a preliminary report from the Japanese Cord Blood Bank Network. Leuk Lymphoma 2003; 44: 429–438.

    Article  CAS  Google Scholar 

  27. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  Google Scholar 

  28. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217.

    Article  CAS  Google Scholar 

  29. Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA et al. Nomenclature for factors of the HLA system, 2010. Tissue Antigens 2010; 75: 291–455.

    Article  CAS  Google Scholar 

  30. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  Google Scholar 

  31. Cox D . Regression model and life tables. J R Stat Soc B 1972; 34: 187–200.

    Google Scholar 

  32. Fine JP, Gray R . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.

    Article  Google Scholar 

  33. Kanda Y . Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 2013; 48: 452–458.

    Article  CAS  Google Scholar 

  34. Narimatsu H, Miyakoshi S, Yamaguchi T, Kami M, Matsumura T, Yuji K et al. Chronic graft-versus-host disease following umbilical cord blood transplantation: retrospective survey involving 1072 patients in Japan. Blood 2008; 112: 2579–2582.

    Article  CAS  Google Scholar 

  35. Kanda J, Morishima Y, Terakura S, Wake A, Uchida N, Takahashi S et al. Impact of graft-versus-host disease on outcomes after unrelated cord blood transplantation. Leukemia 2017; 31: 663.

    Article  CAS  Google Scholar 

  36. Brown JA, Boussiotis VA . Umbilical cord blood transplantation: basic biology and clinical challenges to immune reconstitution. Clin Immunol 2008; 127: 286–297.

    Article  CAS  Google Scholar 

  37. Atsuta Y, Suzuki R, Nagamura-Inoue T, Taniguchi S, Takahashi S, Kai S et al. Disease-specific analyses of unrelated cord blood transplantation compared with unrelated bone marrow transplantation in adult patients with acute leukemia. Blood 2009; 113: 1631–1638.

    Article  Google Scholar 

  38. Atsuta Y, Morishima Y, Suzuki R, Nagamura-Inoue T, Taniguchi S, Takahashi S et al. Comparison of unrelated cord blood transplantation and HLA-mismatched unrelated bone marrow transplantation for adults with leukemia. Biol Blood Marrow Transplant 2012; 18: 780–787.

    Article  Google Scholar 

  39. Kuwatsuka Y, Atsuta Y, Horowitz MM, Inagaki J, Kanda J, Kato K et al. Graft-versus-host disease and survival after cord blood transplantation for acute leukemia: a comparison of Japanese versus White populations. Biol Blood Marrow Transplant 2014; 20: 662–667.

    Article  Google Scholar 

  40. Terakura S, Atsuta Y, Tsukada N, Kobayashi T, Tanaka M, Kanda J et al. Comparison of outcomes of 8/8 and 7/8 allele-matched unrelated bone marrow transplantation and single-unit cord blood transplantation in adults with acute leukemia. Biol Blood Marrow Transplant 2016; 22: 330–338.

    Article  Google Scholar 

  41. Konuma T, Kato S, Ishii H, Takeda R, Oiwa-Monna M, Tojo A et al. HLA-DRB1 mismatch is associated with a decreased relapse in adult acute myeloid leukemia after single-unit myeloablative cord blood transplantation. Ann Hematol 2015; 94: 1233–1235.

    Article  Google Scholar 

  42. Tanaka J, Morishima Y, Takahashi Y, Yabe T, Oba K, Takahashi S et al. Effects of KIR ligand incompatibility on clinical outcomes of umbilical cord blood transplantation without ATG for acute leukemia in complete remission. Blood Cancer J 2013; 3: e164.

    Article  CAS  Google Scholar 

  43. Kawase T, Matsuo K, Kashiwase K, Inoko H, Saji H, Ogawa S et al. HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanism. Blood 2009; 113: 2851–2858.

    Article  CAS  Google Scholar 

  44. Pidala J, Lee SJ, Ahn KW, Spellman S, Wang HL, Aljurf M et al. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood 2014; 124: 2596–2606.

    Article  CAS  Google Scholar 

  45. Wagner JE, Rosenthal J, Sweetman R, Shu XO, Davies SM, Ramsay NK et al. Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. Blood 1996; 88: 795–802.

    CAS  PubMed  Google Scholar 

  46. Takanashi M, Atsuta Y, Fujiwara K, Kodo H, Kai S, Sato H et al. The impact of anti-HLA antibodies on unrelated cord blood transplantations. Blood 2010; 116: 2839–2846.

    Article  CAS  Google Scholar 

  47. Yamamoto H, Uchida N, Matsuno N, Ota H, Kageyama K, Wada S et al. Anti-HLA antibodies other than against HLA-A, -B, -DRB1 adversely affect engraftment and nonrelapse mortality in HLA-mismatched single cord blood transplantation: possible implications of unrecognized donor-specific antibodies. Biol Blood Marrow Transplant 2014; 20: 1634–1640.

    Article  CAS  Google Scholar 

  48. Shaw BE, Robinson J, Fleischhauer K, Madrigal JA, Marsh SG . Translating the HLA-DPB1 T-cell epitope-matching algorithm into clinical practice. Bone Marrow Transplant 2013; 48: 1510–1512.

    Article  CAS  Google Scholar 

  49. Petersdorf EW, Malkki M, O'HUigin C, Carrington M, Gooley T, Haagenson MD et al. High HLA-DP expression and graft-versus-host disease. N Engl J Med 2015; 373: 599–609.

    Article  CAS  Google Scholar 

  50. Crivello P, Heinold A, Rebmann V, Ottinger HD, Horn PA, Beelen DW et al. Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT. Blood 2016; 128: 120–129.

    Article  CAS  Google Scholar 

  51. Crocchiolo R, Zino E, Vago L, Oneto R, Bruno B, Pollichieni S et al. Nonpermissive HLA-DPB1 disparity is a significant independent risk factor for mortality after unrelated hematopoietic stem cell transplantation. Blood 2009; 114: 1437–1444.

    Article  CAS  Google Scholar 

  52. Fleischhauer K, Shaw BE, Gooley T, Malkki M, Bardy P, Bignon JD et al. Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. Lancet Oncol 2012; 13: 366–374.

    Article  CAS  Google Scholar 

  53. Fleischhauer K, Fernandez-Vina MA, Wang T, Haagenson M, Battiwalla M, Baxter-Lowe LA 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 2014; 49: 1176–1183.

    Article  CAS  Google Scholar 

  54. Shiina T, Suzuki S, Ozaki Y, Taira H, Kikkawa E, Shigenari A et al. Super high resolution for single molecule-sequence-based typing of classical HLA loci at the 8-digit level using next generation sequencers. Tissue Antigens 2012; 80: 305–316.

    Article  CAS  Google Scholar 

  55. Hosomichi K, Shiina T, Tajima A, Inoue I . The impact of next-generation sequencing technologies on HLA research. J Hum Genet 2015; 60: 665–673.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the patients and donors taking part in the umbilical cord blood transplantation, and the staff members of the cord blood collection facilities, transplantation centers, cord blood banks and the Japanese Cord Blood Bank Network for their generous cooperation. We also thank Naoya Takeda for proofreading the manuscript; Aiko Ono, Yuko Yamagiwa and Naoya Takeda for the HLA typing; Manabu Kondo for advice on the statistical analysis; and Kazuyo Ohmura, Miyuki Itoh, Mutsuko Minemoto, Atsuko Ogawa, the late Yoshiharu Suzuki, Tadashi Nagai and Mutsuhiko Minami for their encouragement and support for the research. This work was supported in part by grants from the Japanese Ministry of Health, Labor and Welfare (H23-Immunology-010 and H26-Immunology-106) and by the Practical Research Project for Allergic Diseases and Immunology (Research on Technology of Medical Transplantation) from the Japan Agency for Medical Research and Development (15ek0510002h0302 and 16ek0510002h0003).

Author information

Author notes

  1. K Matsumoto

    Present address: 12Current address: Central Japan Cord Blood Bank, Seto, Japan.,

Authors and Affiliations

  1. Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan

    T Yabe, F Azuma, K Kashiwase & K Nakajima

  2. Japanese Red Cross Kinki Cord Blood Bank, Osaka, Japan

    K Matsumoto

  3. Japanese Red Cross Hokkaido Cord Blood Bank, Sapporo, Japan

    T Orihara

  4. Tokai University Cord Blood Bank, Isehara, Japan

    H Yabe & S Kato

  5. Central Japan Cord Blood Bank, Seto, Japan

    K Kato & Y Morishima

  6. Hyogo Cord Blood Bank Nishinomiya, Japan

    S Kai

  7. Japanese Red Cross Kyushu Cord Blood Bank, Chikushino, Japan

    T Mori

  8. Division of Endocrinology, Rheumatology (Second Department of Internal Medicine), Diabetes and Metabolism, Hematology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan

    S Morishima

  9. Japanese Red Cross Blood Service Headquarters, Tokyo, Japan

    M Satake & M Takanashi

  10. Japanese Red Cross Kanto-Koshinetsu Cord Blood Bank, Tokyo, Japan

    K Nakajima

  11. Aichi Cancer Center Research Institute, Nagoya, Japan

    Y Morishima

Authors
  1. T Yabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Azuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Kashiwase
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Orihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Yabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Kai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S Morishima
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M Satake
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M Takanashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. K Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Y Morishima
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of Japanese Cord Blood Transplantation Histocompatibility Research Group

Corresponding author

Correspondence to T Yabe.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yabe, T., Azuma, F., Kashiwase, K. et al. HLA-DPB1 mismatch induces a graft-versus-leukemia effect without severe acute GVHD after single-unit umbilical cord blood transplantation. Leukemia 32, 168–175 (2018). https://doi.org/10.1038/leu.2017.202

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2017.202

This article is cited by

Search

Advanced search

Quick links