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:

Pediatric Transplants

Early evaluation of immune reconstitution following allogeneic CD3/CD19-depleted grafts from alternative donors in childhood acute leukemia

Bone Marrow Transplantation volume 47, pages 1419–1427 (2012)Cite this article

Subjects

Abstract

Graft engineering procedures for hematopoietic SCT (HSCT) may improve the chance of success in matched unrelated donor (MUD) and haploidentical donor transplantations. Successful donor immune reconstitution is important to mediate GVL effects in reduced-intensity conditioning (RIC) HSCT. We prospectively investigated early immune reconstitution and clinical outcome in 30 CD3/CD19-depleted MUD (n=15) or HP (n=15) HSCTs for high-risk childhood leukemia using a fludarabine-based RIC without serotherapy. The graft consisted of a mean of 10.5 × 106/kg CD34+, 77 × 103/kg CD3+ and 39 × 106/kg CD56+ cells. After transplantation, 86% of the patients engrafted. In all, 13% of patients had >grade 3 acute GVHD. Natural killer (NK) cell, DC and T-cell recovery achieved normal values within the first 60 days after transplantation. DC recovery was dominated by the DC2− subset. NK-cell phenotype was altered and cytotoxicity was lower compared with their donors. EFS was 50±9% (73±11% for those in CR1 and 26±11% for those with advanced disease). Faster DC2− recovery was associated with better outcome, especially in the MUD setting. In summary, CD3/CD19-depleted HSCT with fludarabine-based RIC without serotherapy resulted in favorable patient survival, and rapid NK, DC and T-cell recovery.

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
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Aversa F, Reisner Y, Martelli MF . Hematopoietic stem cell transplantation from alternative sources in adults with high-risk acute leukemia. Blood Cells Mol Dis 2004; 33: 294–302.

    Article  Google Scholar 

  2. Cairo MS, Rocha V, Gluckman E, Hale G, Wagner J . Alternative allogeneic donor sources for transplantation for childhood diseases: unrelated cord blood and haploidentical family donors. Biol Blood Marrow Transplant 2008; 14: 44–53.

    Article  Google Scholar 

  3. Pérez A, González-Vicent M, Ramírez M, Sevilla J, Madero L, Díaz MA . Intentional induction of mixed hematopoietic chimerism as platform for cellular therapy after HLA-matched allogeneic stem cell transplantation in childhood leukemia patients. Br J Haematol 2008; 140: 340–343.

    Article  Google Scholar 

  4. González-Vicent M, Pérez A, Abad L, Sevilla J, Ramirez M, Diaz MA . Graft manipulation and reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation from mismatched unrelated and mismatched/haploidentical related donors in pediatric leukemia patients. J Pediatr Hematol Oncol 2010; 32: e85–e90.

    Article  Google Scholar 

  5. Weimer R, Staak A, Süsal C, Streller S, Yildiz S, Pelzl S et al. ATG induction therapy: long-term effects on Th1 but not on Th2 responses. Transpl Int 2005; 18: 226–236.

    Article  CAS  Google Scholar 

  6. Locatelli F, Pende D, Maccario R, Mingari MC, Moretta A, Moretta L . Haploidentical hemopoietic stem cell transplantation for the treatment of high-risk leukemias: how NK cells make the difference. Clin Immunol 2009; 133: 171–178.

    Article  CAS  Google Scholar 

  7. Gassas A, Sung L, Saunders EF, Doyle J . Graft-versus-leukemia effect in hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia: significantly lower relapse rate in unrelated transplantations. Bone Marrow Transplant 2007; 40: 951–955.

    Article  CAS  Google Scholar 

  8. Pfeiffer MM, Feuchtinger T, Teltschik HM, Schumm M, Müller I, Handgretinger R et al. Reconstitution of NK cell receptors influences NK activity and relapse rate after haploidentical transplantation of T and B cell depleted grafts in children. Haematologica 2010; 95: 1381–1388.

    Article  CAS  Google Scholar 

  9. Dulphy N, Haas P, Busson M, Belhadj S, Peffault de Latour R, Robin M et al. An unusual CD56(bright) CD16(low) NK cell subset dominates the early post transplant period following HLA-matched hematopoietic stem cell transplantation. J Immunol 2008; 181: 2227–2237.

    Article  CAS  Google Scholar 

  10. Vakkila J, Thomson AW, Hovi L, Vettenranta K, Saarinen-Pihkala UM . Circulating dendritic cell subset levels after allogeneic stem cell transplantation in children correlate with time post transplant and severity of acute graft-versus-host disease. Bone Marrow Transplant 2005; 35: 501–507.

    Article  CAS  Google Scholar 

  11. Fagnoni FF, Oliviero B, Giorgiani G, De Stefano P, Dehò A, Zibera C et al. Reconstitution dynamics of plasmacytoid and myeloid dendritic cell precursors after allogeneic myeloablative hematopoietic stem cell transplantation. Blood 2004; 104: 281–289.

    Article  CAS  Google Scholar 

  12. Talarn C, Urbano-Ispizua A, Martino R, Pérez-Simón JA, Batlle M, Herrera C et al. Kinetics of recovery of dendritic cell subsets after reduced-intensity conditioning allogeneic stem cell transplantation and clinical outcome. Haematologica 2007; 92: 1655–1663.

    Article  Google Scholar 

  13. Sevilla J, González-Vicent M, Lassaletta A, Ramírez M, Pérez-Martínez A, Madero L et al. Peripheral blood progenitor cell collection adverse events for childhood allogeneic donors: variables related to the collection and safety profile. Br J Haematol 2009; 144: 909–916.

    Article  Google Scholar 

  14. Blomberg K, Hautala R, Lovgren J, Mukkala VM, Lindqvist C, Akerman K . Time-resolved fluorometric assay for natural killer activity using target cells labeled with a fluorescence enhancing ligand. J Immunol Methods 1995; 193: 199–206.

    Article  Google Scholar 

  15. Park SH, Choi SM, Lee DG, Choi JH, Yoo JH, Kim SH et al. Infectious complications associated with alemtuzumab use for allogeneic hematopoietic stem cell transplantation: comparison with anti-thymocyte globulin. Transpl Infect Dis 2009; 11: 413–423.

    Article  CAS  Google Scholar 

  16. Ciurea SO, Saliba R, Rondon G, Pesoa S, Cano P, Fernandez-Vina M et al. Reduced-intensity conditioning using fludarabine, melphalan and thiotepa for adult patients undergoing haploidentical SCT. Bone Marrow Transplant 2010; 45: 429–436.

    Article  CAS  Google Scholar 

  17. Westerhuis G, Maas WG, Toes RE, Fibbe WE . Persisting NK cell alloreactivity in the presence of long-term stable hematopoietic chimerism. Exp Hematol 2009; 37: 739–743.

    Article  CAS  Google Scholar 

  18. Westerhuis G, Maas WG, Willemze R, Toes RE, Fibbe WE . Long-term mixed chimerism after immunologic conditioning and MHC-mismatched stem-cell transplantation is dependent on NK-cell tolerance. Blood 2005; 106: 2215–2220.

    Article  CAS  Google Scholar 

  19. Larsen CP, Page A, Linzie KH, Russell M, Deane T, Stempora L et al. An MHC-defined primate model reveals significant rejection of bone marrow after mixed chimerism induction despite full MHC matching. Am J Transplant 2010; 10: 2396–2409.

    Article  CAS  Google Scholar 

  20. Kean LS, Hamby K, Koehn B, Lee E, Coley S, Stempora L et al. NK cells mediate costimulation blockade-resistant rejection of allogeneic stem cells during nonmyeloablative transplantation. Am J Transplant 2006; 6: 292–304.

    Article  CAS  Google Scholar 

  21. Brunstein CG, Hirsch BA, Miller JS, McGlennen RC, Verfaillie CM, McGlave PB et al. Non-leukemic autologous reconstitution after allogeneic bone marrow transplantation for Ph-positive chronic myelogenous leukemia: extended remission preceding eventual relapse. Bone Marrow Transplant 2000; 26: 1173–1177.

    Article  CAS  Google Scholar 

  22. De Somer L, Sprangers B, Fevery S, Rutgeerts O, Lenaerts C, Boon L et al. Recipient lymphocyte infusion in MHC-matched bone marrow chimeras induces a limited lymphohematopoietic host-versus-graft reactivity but a significant antileukemic effect mediated by CD8+ T cells and natural killer cells. Haematologica 2011; 96: 424–431.

    Article  CAS  Google Scholar 

  23. Ball LM, Bernardo ME, Roelofs H, Lankester A, Cometa A, Egeler RM et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood 2007; 110: 2764–2767.

    Article  CAS  Google Scholar 

  24. Lang P, Mueller I, Greil J, Bader P, Schumm M, Pfeiffer M et al. Retransplantation with stem cells from mismatched related donors after graft rejection in pediatric patients. Blood Cells Mol Dis 2008; 40: 33–39.

    Article  Google Scholar 

  25. Chakraverty R, Sykes M . The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia. Blood 2007; 110: 9–17.

    Article  CAS  Google Scholar 

  26. Reddy P, Maeda Y, Liu C, Krijanovski OI, Korngold R, Ferrara J . A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses. Nat Med 2005; 11: 1244–1249.

    Article  CAS  Google Scholar 

  27. Miller JS, Warren EH, van den Brink MR, Ritz J, Shlomchik WD, Murphy WJ et al. NCI First International Workshop on The Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on the Biology Underlying Recurrence of Malignant Disease following Allogeneic HSCT: Graft-versus-Tumor/Leukemia Reaction. Biol Blood Marrow Transplant 2010; 16: 565–586.

    Article  Google Scholar 

  28. Perez-Martinez A, Iyengar R, Gan K, Chotsampancharoen T, Rooney B, Holladay M et al. Blood dendritic cells suppress NK cell function and increase the risk of leukemia relapse after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2011; 17: 598–607.

    Article  CAS  Google Scholar 

  29. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.

    Article  CAS  Google Scholar 

  30. Triplett BM, Horwitz EM, Iyengar R, Turner V, Holladay MS, Gan K et al. Effects of activating NK cell receptor expression and NK cell reconstitution on the outcomes of unrelated donor hematopoietic cell transplantation for hematologic malignancies. Leukemia 2009; 23: 1278–1287.

    Article  CAS  Google Scholar 

  31. Federmann B, Hägele M, Pfeiffer M, Wirths S, Schumm M, Faul C et al. Immune reconstitution after haploidentical hematopoietic cell transplantation: impact of reduced intensity conditioning and CD3/CD19 depleted grafts. Leukemia 2011; 25: 121–129.

    Article  CAS  Google Scholar 

  32. Nguyen S, Dhedin N, Vernant JP, Kuentz M, Al Jijakli A, Rouas-Freiss N et al. NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. Blood 2005; 105: 4135–4142.

    Article  CAS  Google Scholar 

  33. Spaner DE, Masellis A . Toll-like receptor agonists in the treatment of chronic lymphocytic leukemia. Leukemia 2007; 21: 53–60.

    Article  CAS  Google Scholar 

  34. Link BK, Ballas ZK, Weisdorf D, Wooldridge JE, Bossler AD, Shannon M et al. Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma. J Immunother 2006; 29: 558–568.

    Article  CAS  Google Scholar 

  35. Zhang X, Munegowda MA, Yuan J, Wei Y, Xiang J . Optimal TLR9 signal converts tolerogenic CD4-8- DCs into immunogenic ones capable of stimulating antitumor immunity via activating CD4+ Th1/Th17 and NK cell responses. J Leukoc Biol 2010; 88: 393–403.

    Article  CAS  Google Scholar 

  36. Leung W, Iyengar R, Turner V, Lang P, Bader P, Conn P et al. Determinants of anti leukemia effects of allogeneic NK cells. J Immunol 2004; 172: 644–650.

    Article  CAS  Google Scholar 

  37. Stern M, Ruggeri L, Mancusi A, Bernardo ME, de Angelis C, Bucher C et al. Survival after T cell-depleted haploidentical stem cell transplantation is improved using the mother as donor. Blood 2008; 112: 2990–2995.

    Article  CAS  Google Scholar 

  38. Leung W, Campana D, Yang J, Pei D, Coustan-Smith E, Gan K et al. High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood 2011; 118: 223–230.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge Dr W Leung from St Jude Children's Research Hospital for the critical review of the manuscript. We would also like to thank Hannah Maxwell from Cardiff University for the English edition of the manuscript. This work was supported in part by National Health Service of Spain grant FIS PS09/02393, Fundación Mutua Madrileña and ‘La hucha de Tomás’ project (http://www.lahuchadetomas.com/).

Author information

Authors and Affiliations

  1. Department of Hemato-Oncology and Stem Cell Transplantation, Servicio de Hemato-Oncología y Trasplante Hematopoyético, Hospital Infantil Universitario Niño Jesús, Madrid, Spain

    A Pérez-Martínez, M González-Vicent, J Valentín, E Aleo, A Lassaletta, J Sevilla, M Ramírez & M A Díaz

  2. Centro de Transfusiones de la Comunidad de Madrid, Madrid, Spain

    J L Vicario

Authors
  1. A Pérez-Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M González-Vicent
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Valentín
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Aleo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Lassaletta
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Sevilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J L Vicario
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Ramírez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M A Díaz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Pérez-Martínez.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Bone Marrow Transplantation website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pérez-Martínez, A., González-Vicent, M., Valentín, J. et al. Early evaluation of immune reconstitution following allogeneic CD3/CD19-depleted grafts from alternative donors in childhood acute leukemia. Bone Marrow Transplant 47, 1419–1427 (2012). https://doi.org/10.1038/bmt.2012.43

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2012.43

Keywords

This article is cited by

Search

Advanced search

Quick links