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.

Effects of HLA mismatch on cytomegalovirus reactivation in cord blood transplantation

Abstract

Although human leukocyte antigen (HLA) mismatch is often thought to be associated with a high incidence of cytomegalovirus (CMV) reactivation, it is not clear whether this process is mediated by HLA mismatch or other factors, such as acute graft-versus-host disease (aGVHD). Here we focused on cord blood transplantation (CBT) and examined the effects of HLA mismatch on the incidence of CMV reactivation while minimizing the effects of aGVHD. In a multivariate analysis considering aGVHD as a time-dependent covariate, a significant effect on the incidence of CMV reactivation was noted for HLA disparity (hazard ratio [HR]: 0.54 for 8/8 match compared with 3-allele mismatch) and development of aGVHD (HR: 1.26). Next, in an analysis excluding cases that developed aGVHD, the incidences of CMV reactivation for 8/8 match and 1-allele mismatch were low compared with those for other mismatches. These findings were supported by the multivariate analysis (HR: 0.49 for 8/8 match and 0.64 for 1-allele mismatch compared with 3-allele mismatch). Together, these results suggested that HLA mismatch was involved in CMV reactivation and was associated with high morbidity of opportunistic infection after CBT.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1
Fig. 2
Fig. 3

References

  1. Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang M-J, Champlin RE, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med. 2004;351:2265–75.

    Article  CAS  Google Scholar 

  2. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004;351:2276–85.

    Article  CAS  Google Scholar 

  3. Parody R, Martino R, Rovira M, Vazquez L, Vázquez MJ, de la Cámara R, et al. Severe infections after unrelated donor allogeneic hematopoietic stem cell transplantation in adults: comparison of cord blood transplantation with peripheral blood and bone marrow transplantation. Biol Blood Marrow Transplant. 2006;12:734–48.

    Article  Google Scholar 

  4. Rénard C, Barlogis V, Mialou V, Galambrun C, Bernoux D, Goutagny MP, et al. Lymphocyte subset reconstitution after unrelated cord blood or bone marrow transplantation in children. Br J Haematol. 2011;152:322–30.

    Article  Google Scholar 

  5. Beaudette-Zlatanova BC, Le PT, Knight KL, Zhang S, Zakrzewski S, Parthasarathy M, et al. A potential role for B cells in suppressed immune responses in cord blood transplant recipients. Bone Marrow Transplant. 2013;48:85–93.

    Article  CAS  Google Scholar 

  6. Jacobson CA, Turki AT, McDonough SM, Stevenson KE, Kim HT, Kao G, et al. Immune reconstitution after double umbilical cord blood stem cell transplantation: comparison with unrelated peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2012;18:565–74.

    Article  CAS  Google Scholar 

  7. Kanda J, Chiou L-W, Szabolcs P, Sempowski GD, Rizzieri DA, Long GD, et al. Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18:1664–76.e1.

    Article  CAS  Google Scholar 

  8. Servais S, Lengline E, Porcher R, Carmagnat M, Peffault de Latour R, Robin M, et al. Long-term immune reconstitution and infection burden after mismatched hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20:507–17.

    Article  Google Scholar 

  9. Ruggeri A, Peffault de Latour R, Carmagnat M, Clave E, Douay C, Larghero J, et al. Outcomes, infections, and immune reconstitution after double cord blood transplantation in patients with high-risk hematological diseases. Transpl Infect Dis. 2011;13:456–65.

    Article  CAS  Google Scholar 

  10. Komanduri KV, St John LS, de Lima M, McMannis J, Rosinski S, et al. Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing. Blood. 2007;110:4543–51.

    Article  CAS  Google Scholar 

  11. Politikos I, Boussiotis VA. The role of the thymus in T-cell immune reconstitution after umbilical cord blood transplantation. Blood. 2014;124:3201–11.

    Article  CAS  Google Scholar 

  12. Servais S, Hannon M, Peffault de Latour R, Socie G, Beguin Y. Reconstitution of adaptive immunity after umbilical cord blood transplantation: impact on infectious complications. Stem Cell Investig. 2017;4:40.

    Article  Google Scholar 

  13. Jameson SC. Maintaining the norm: T-cell homeostasis. Nat Rev Immunol. 2002;2:547–56.

    Article  CAS  Google Scholar 

  14. 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  Google Scholar 

  15. Saliba RM, Rezvani K, Leen A, Jorgensen J, Shah N, Hosing C, et al. General and virus-specific immune cell reconstitution after double cord blood transplantation. Biol Blood Marrow Transplant. 2015;21:1284–90.

    Article  CAS  Google Scholar 

  16. Vandenbosch K, Ovetchkine P, Champagne MA, Haddad E, Alexandrov L, Duval M. Varicella-zoster virus disease is more frequent after cord blood than after bone marrow transplantation. Biol Blood Marrow Transplant. 2008;14:867–71.

    Article  Google Scholar 

  17. de Pagter PJA, Schuurman R, Visscher H, de Vos M, Bierings M, van Loon AM, et al. Human herpes virus 6 plasma DNA positivity after hematopoietic stem cell transplantation in children: an important risk factor for clinical outcome. Biol Blood Marrow Transplant. 2008;14:831–9.

    Article  Google Scholar 

  18. Dumas PY, Ruggeri A, Robin M, Crotta A, Abraham J, Forcade E, et al. Incidence and risk factors of EBV reactivation after unrelated cord blood transplantation: a Eurocord and Société Française de Greffe de Moelle-Therapie Cellulaire collaborative study. Bone Marrow Transplant. 2013;48:253–6.

    Article  CAS  Google Scholar 

  19. Sashihara J, Tanaka-Taya K, Tanaka S, Amo K, Miyagawa H, Hosoi G, et al. High incidence of human herpesvirus 6 infection with a high viral load in cord blood stem cell transplant recipients. Blood. 2002;100:2005–11.

    CAS  PubMed  Google Scholar 

  20. Chan ST, Logan AC. The clinical impact of cytomegalovirus infection following allogeneic hematopoietic cell transplantation: why the quest for meaningful prophylaxis still matters. Blood Rev. 2017;31:173–83.

    Article  Google Scholar 

  21. Fox JM, Letellier E, Oliphant CJ, Signoret N. TLR2-dependent pathway of heterologous down-modulation for the CC chemokine receptors 1, 2, and 5 in human blood monocytes. Blood. 2011;117:1851–60.

    Article  CAS  Google Scholar 

  22. Boeckh M, Nichols WG, Papanicolaou G, Rubin R, Wingard JR, Zaia J. Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies. Biol Blood Marrow Transplant. 2003;9:543–58.

    Article  Google Scholar 

  23. Boeckh M, Nichols WG. The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood. 2004;103:2003–8.

    Article  CAS  Google Scholar 

  24. George B, Pati N, Gilroy N, Ratnamohan M, Huang G, Kerridge I, et al. Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy. Transpl Infect Dis. 2010;12:322–9.

    Article  CAS  Google Scholar 

  25. George B, Kerridge IHH, Gilroy N, Huang G, Hertzberg MSS, Bradstock KFF, et al. A risk score for early cytomegalovirus reactivation after allogeneic stem cell transplantation identifies low-, intermediate-, and high-risk groups: reactivation risk is increased by graft-versus-host disease only in the intermediate-risk group. Transpl Infect Dis. 2012;14:141–8.

    Article  CAS  Google Scholar 

  26. Ozdemir E, Saliba RM, Champlin RE, Couriel DR, Giralt SA, de Lima M, et al. Risk factors associated with late cytomegalovirus reactivation after allogeneic stem cell transplantation for hematological malignancies. Bone Marrow Transplant. 2007;40:125–36.

    Article  CAS  Google Scholar 

  27. Camargo JF, Komanduri KV. Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther. 2017;10:233–8.

    Article  CAS  Google Scholar 

  28. Walker CM, van Burik J-AH, De For TE, Weisdorf DJ. Cytomegalovirus infection after allogeneic transplantation: comparison of cord blood with peripheral blood and marrow graft sources. Biol Blood Marrow Transplant. 2007;13:1106–15.

    Article  Google Scholar 

  29. Al-Hajjar S, Al Seraihi A, Al Muhsen S, Ayas M, Al Jumaah S, Al Jefri A, et al. Cytomegalovirus infections in unrelated cord blood transplantation in pediatric patients: incidence, risk factors, and outcomes. Hematol Oncol Stem Cell Ther. 2011;4:67–72.

    Article  Google Scholar 

  30. Cook M, Briggs D, Craddock C, Mahendra P, Milligan D, Fegan C, et al. Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation. Blood. 2006;107:1230–2.

    Article  CAS  Google Scholar 

  31. Acar K, Akı SZ, Ozkurt ZN, Bozdayı G, Rota S, Türköz Sucak G. Factors associated with cytomegalovirus reactivation following allogeneic hematopoietic stem cell transplantation: human leukocyte antigens might be among the risk factors. Turk J Haematol. 2014;31:276–85.

    Article  Google Scholar 

  32. Tong J, Sun Z, Liu H, Geng L, Zheng C, Tang B, et al. Risk factors of CMV infection in patients after umbilical cord blood transplantation: a multicenter study in China. Chin J Cancer Res. 2013;25:695–703.

    PubMed  PubMed Central  Google Scholar 

  33. Matsumura T, Narimatsu H, Kami M, Yuji K, Kusumi E, Hori A, et al. Cytomegalovirus infections following umbilical cord blood transplantation using reduced intensity conditioning regimens for adult patients. Biol Blood Marrow Transplant. 2007;13:577–83.

    Article  Google Scholar 

  34. Takami A, Mochizuki K, Asakura H, Yamazaki H, Okumura H, Nakao S. High incidence of cytomegalovirus reactivation in adult recipients of an unrelated cord blood transplant. Haematologica. 2005;90:1290–2.

    PubMed  Google Scholar 

  35. Mikulska M, Raiola AM, Bruzzi P, Varaldo R, Annunziata S, Lamparelli T, et al. CMV infection after transplant from cord blood compared to other alternative donors: the importance of donor-negative CMV serostatus. Biol Blood Marrow Transplant. 2012;18:92–99.

    Article  Google Scholar 

  36. Castillo N, García-Cadenas I, Barba P, Canals C, Díaz-Heredia C, Martino R, et al. Early and long-term impaired T lymphocyte immune reconstitution after cord blood transplantation with antithymocyte globulin. Biol Blood Marrow Transplant. 2017;23:491–7.

    Article  CAS  Google Scholar 

  37. Harris DT, Schumacher MJ, Locascio J, Besencon FJ, Olson GB, DeLuca D, et al. Phenotypic and functional immaturity of human umbilical cord blood T lymphocytes. Proc Natl Acad Sci USA. 1992;89:10006–10.

    Article  CAS  Google Scholar 

  38. Szabolcs P, Niedzwiecki D. Immune reconstitution after unrelated cord blood transplantation. Cytotherapy. 2007;9:111–22.

    Article  CAS  Google Scholar 

  39. Lucchini G, Perales M-A, Veys P. Immune reconstitution after cord blood transplantation: peculiarities, clinical implications and management strategies. Cytotherapy. 2015;17:711–22.

    Article  CAS  Google Scholar 

  40. Szabolcs P. T-lymphocyte recovery and function after cord blood transplantation. Immunol Res. 2011;49:56–69.

    Article  CAS  Google Scholar 

  41. Albano MS, Taylor P, Pass RF, Scaradavou A, Ciubotariu R, Carrier C, et al. Umbilical cord blood transplantation and cytomegalovirus: posttransplantation infection and donor screening. Blood. 2006;108:4275–82.

    Article  CAS  Google Scholar 

  42. Tomonari A, Iseki T, Ooi J, Takahashi S, Shindo M, Ishii K, et al. Cytomegalovirus infection following unrelated cord blood transplantation for adult patients: a single institute experience in Japan. Br J Haematol. 2003;121:304–11.

    Article  Google Scholar 

  43. Barker JN, Hough RE, van Burik J-AH, DeFor TE, MacMillan ML, O’Brien MR, et al. Serious infections after unrelated donor transplantation in 136 children: impact of stem cell source. Biol Blood Marrow Transplant. 2005;11:362–70.

    Article  Google Scholar 

  44. Sedky M, Mekki Y, Mialou V, Bleyzac N, Girard S, Salama E, et al. Cytomegalovirus infection in pediatric allogenic hematopoietic stem cell transplantation. A single center experience. Pediatr Hematol Oncol. 2014;31:743–53.

    Article  CAS  Google Scholar 

  45. Beck JC, Wagner JE, DeFor TE, Brunstein CG, Schleiss MR, Young J, et al. Impact of cytomegalovirus (CMV) reactivation after umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2010;16:215–22.

    Article  Google Scholar 

  46. Mori T, Okamoto S, Watanabe R, Yajima T, Iwao Y, Yamazaki R, et al. Dose-adjusted preemptive therapy for cytomegalovirus disease based on real-time polymerase chain reaction after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;29:777–82.

    Article  CAS  Google Scholar 

  47. Kanda Y, Mineishi S, Saito T, Seo S, Saito A, Suenaga K, et al. Pre-emptive therapy against cytomegalovirus (CMV) disease guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan. Bone Marrow Transplant. 2001;27:437–44.

    Article  CAS  Google Scholar 

  48. 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 Transplant. 2009;15:1628–33.

    Article  Google Scholar 

  49. Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A, et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol. 2007;86:269–74.

    Article  Google Scholar 

  50. Atsuta Y. Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). Int J Hematol. 2016;103:3–10.

    Article  Google Scholar 

  51. Kanda J. Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation. Int J Hematol. 2016;103:11–19.

    Article  CAS  Google Scholar 

  52. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  Google Scholar 

  53. 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;98:814–22.

    Article  Google Scholar 

  54. Rocha V, Cornish J, Sievers EL, Filipovich A, Locatelli F, Peters C, et al. Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood. 2001;97:2962–71.

    Article  CAS  Google Scholar 

  55. Ramanathan M, Teira P, Battiwalla M, Barrett J, Ahn KW, Chen M, et al. Impact of early CMV reactivation in cord blood stem cell recipients in the current era. Bone Marrow Transplant. 2016;51:1113–20.

    Article  CAS  Google Scholar 

  56. Takenaka K, Nishida T, Asano-Mori Y, Oshima K, Ohashi K, Mori T, et al. Cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation is associated with a reduced risk of relapse in patients with acute myeloid leukemia who survived to day 100 after transplantation: the Japan Society for Hematopoietic Cell Transplantation Transplantation-related Complication Working Group. Biol Blood Marrow Transplant. 2015;21:2008–16.

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all the physicians and data managers who contributed valuable data to the Japan Society for Hematopoietic Cell Transplantation (JSHCT). The authors also would like to thank the staff members of the Data Center of JSHCT for their contributions.

HLA Working Group of the Japan Society for Hematopoietic Cell Transplantation:

Junya Kanda, Yoshiko Atsuta, Kazuhiro Ikegame, Tatsuo Ichinohe, Atae Utsunomiya, Makoto Onizuka, Shunichi Kato, Takakazu Kawase, Yoshinobu Kanda, Sung-Won Kim, Yachiyo Kuwatsuka, Takeshi Kobayashi, Yoshifusa Takatsuka, Yoshiyuki Takahashi, Junji Tanaka, Hiroya Tamaki, Masanori Tsuji, Tetsuya Nishida, Yoshinobu Maeda, Masayoshi Masuko, Ryosuke Matsuno, Makoto Murata, Satoko Morishima, Yasuo Morishima, Hisayuki Yokoyama, Atsushi Wake, Nobuhiro Watanabe, T Ashida, Minoko Takanashi, Takumi Hoshino, Toshio Yabe, Kana Sakamoto, Shigeo Fuji, Koichi Miyamura, Nobuyoshi Arima, Eisei Kondo, Makoto Yoshimitsu, Koji Kawamura, Takahito Kawata, Kenji Kishimoto, Raine Tatara, Takeshi Hagino, Shin-Ichiro Fujiwara, Yoshimitsu Shimomura, Hirotoshi Sakaguchi, Shigeki Hirabayashi, Hiroto Ishii, Yoshiyuki Onda, Itaru Kato, Akihisa Kawajiri, Takero Shindo, Masahito Tokunaga, Atsushi Nonami, Hiroyuki Muranushi, Noriyoshi Yoshinaga, Naomi Kawashima, Souichi Shiratori, Yuma Tada, Susumu Tanoue, Masahiro Hirayama, Keiko Fukunaga, Marie Ohbiki.

Author information

Authors and Affiliations

Authors

Consortia

Corresponding author

Correspondence to Hisayuki Yokoyama.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yokoyama, H., Kanda, J., Kato, S. et al. Effects of HLA mismatch on cytomegalovirus reactivation in cord blood transplantation. Bone Marrow Transplant 54, 1004–1012 (2019). https://doi.org/10.1038/s41409-018-0369-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-018-0369-0

This article is cited by

Search

Quick links