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:

Immunology

Fully functional NK cells after unrelated cord blood transplantation

Leukemia volume 23, pages 721–728 (2009)Cite this article

Abstract

Promising results of umbilical cord blood transplantation (UCBT) from unrelated donors have been reported in patients with hematologic disorders. These transplants, having potential to trigger beneficial donor-versus-recipient natural killer (NK) cell-mediated alloreaction, we have conducted the first extensive analysis of the phenotypic and functional properties of NK cells after UCBT. NK cells from 25 patients with high-risk hematologic malignancies were compared with cells derived from both healthy adult and CB cells. We found that following UCBT, NK cells display not only some phenotypic features associated with maturity but also unique characteristics that make them fully functional against leukemic blasts. We propose that this full functionality of alloreactive donor-derived NK may drive graft-versus-leukemia reactions after UCBT.

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

Similar content being viewed by others

References

  1. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S . Functions of natural killer cells. Nat Immunol 2008; 9: 503–510.

    Article  CAS  PubMed  Google Scholar 

  2. Di Santo JP . Natural killer cell developmental pathways: a question of balance. Annu Rev Immunol 2006; 24: 257–286.

    Article  CAS  PubMed  Google Scholar 

  3. Anasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger W, Buckner CD et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Engl J Med 1989; 320: 197–204.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang Y, Wallace DL, de Lara CM, Ghattas H, Asquith B, Worth A et al. In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology 2007; 121: 258–265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Ruggeri L, Aversa F, Martelli MF, Velardi A . Allogeneic hematopoietic transplantation and natural killer cell recognition of missing self. Immunol Rev 2006; 214: 202–218.

    Article  CAS  PubMed  Google Scholar 

  7. Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005; 23: 3447–3454.

    Article  PubMed  Google Scholar 

  8. Schaffer M, Malmberg KJ, Ringdén O, Ljunggren HG, Remberger M . Increased infection-related mortality in KIR-ligand-mismatched unrelated allogeneic hematopoietic stem-cell transplantation. Transplantation 2004; 78: 1081–1085.

    Article  PubMed  Google Scholar 

  9. 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  PubMed  Google Scholar 

  10. Nguyen S, Kuentz M, Vernant JP, Dhedin N, Bories D, Debré P et al. Involvement of mature donor T cells in the NK cell reconstitution after haploidentical hematopoietic stem-cell transplantation. Leukemia 2008; 22: 344–352.

    Article  CAS  PubMed  Google Scholar 

  11. Tse W, Bunting KD, Laughlin MJ . New insights into cord blood stem cell transplantation. Curr Opin Hematol 2008; 15: 279–284.

    Article  PubMed  Google Scholar 

  12. Wall DA, Chan KW . Selection of cord blood unit(s) for transplantation. Bone Marrow Transplant 2008; 42: 1–7.

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. Gluckman E, Broxmeyer HA, Auerbach AD, Friedman HS, Douglas GW, Devergie A et al. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 1989; 321: 1174–1178.

    Article  CAS  PubMed  Google Scholar 

  15. Barker JN, Wagner JE . Umbilical cord blood transplantation: current state of the art. Curr Opin Oncol 2002; 14: 160–164.

    Article  PubMed  Google Scholar 

  16. Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, 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: 2265–2275.

    Article  CAS  PubMed  Google Scholar 

  17. 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: 2276–2285.

    Article  CAS  PubMed  Google Scholar 

  18. Symons HJ, Fuchs EJ . Hematopoietic SCT from partially HLA-mismatched (HLA-haploidentical) related donors. Bone Marrow Transplant 2008; 42: 365–377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cooper MA, Fehniger TA, Caligiuri MA . The biology of human natural killer-cell subsets. Trends Immunol 2001; 22: 633–640.

    Article  CAS  PubMed  Google Scholar 

  20. Dalle JH, Menezes J, Wagner E, Blagdon M, Champagne J, Champagne MA et al. Characterization of cord blood natural killer cells: implications for transplantation and neonatal infections. Pediatr Res 2005; 5: 649–655.

    Article  Google Scholar 

  21. André P, Spertini O, Guia S, Rihet P, Dignat-George F, Brailly H et al. Modification of P-selectin glycoprotein ligand-1 with a natural killer cell-restricted sulfated lactosamine creates an alternate ligand for L-selectin. Proc Natl Acad Sci USA 2000; 97: 3400–3405.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Vivier E, Sorrell JM, Ackerly M, Robertson MJ, Rasmussen RA, Levine H et al. Developmental regulation of a mucinlike glycoprotein selectively expressed on natural killer cells. J Exp Med 1993; 178: 2023–2033.

    Article  CAS  PubMed  Google Scholar 

  23. Addison EG, North J, Bakhsh I, Marden C, Haq S, Al-Sarraj S et al. Ligation of CD8alpha on human natural killer cells prevents activation-induced apoptosis and enhances cytolytic activity. Immunology 2005; 116: 354–361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Parham P . MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol 2005; 5: 201–214.

    Article  CAS  PubMed  Google Scholar 

  25. Jacobs R, Stoll M, Stratmann G, Leo R, Link H, Schmidt RE . CD16-CD56+ natural killer cells after bone marrow transplantation. Blood 1992; 79: 3239–3244.

    CAS  PubMed  Google Scholar 

  26. Davies SM, Ruggieri L, DeFor T, Wagner JE, Weisdorf DJ, Miller JS et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor. Blood 2002; 100: 3825–3827.

    Article  CAS  PubMed  Google Scholar 

  27. Cooley S, McCullar V, Wangen R, Bergemann TL, Spellman S, Weisdorf DJ et al. KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation. Blood 2005; 106: 4370–4376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yu J, Heller G, Chewning J, Kim S, Yokoyama WM, Hsu KC . Hierarchy of the human natural killer cell response is determined by class and quantity of inhibitory receptors for self-HLA-B and HLA-C ligands. J Immunol 2007; 179: 5977–5989.

    Article  CAS  PubMed  Google Scholar 

  29. Freud AG, Caligiuri MA . Human natural killer cell development. Immunol Rev 2006; 214: 56–72.

    Article  CAS  PubMed  Google Scholar 

  30. Yawata M, Yawata N, Draghi M, Partheniou F, Little AM, Parham P . MHC class I-specific inhibitory receptors and their ligands structure diverse human NK cell repertoires towards a balance of missing-self response. Blood 2008; 112: 2369–2380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Grzywack B, Katara N, Skora M, Ostendorp RA, Dzierzak EA, Blazar BR et al. Coordinated acquisition of inhibitory and activating receptors and functional properties by developing human natural killer cells. Blood 2006; 108: 3824–3833.

    Article  Google Scholar 

  32. Mingari MC, Vitale C, Cantoni C, Bellomo R, Ponte M, Schiavetti F et al. Interleukin-15-induced maturation of human natural killer cells from early thymic precursors: selective expression of CD94/NKG2-A as the only HLA class I-specific inhibitory receptor. Eur J Immunol 1997; 27: 1374–1380.

    Article  CAS  PubMed  Google Scholar 

  33. Vitale C, Chiossone L, Morreale G, Lanino E, Cottalasso F, Moretti S et al. Analysis of the activating receptors and cytolytic function of human natural killer cells undergoing in vivo differentiation after allogeneic bone marrow transplantation. Eur J Immunol 2004; 34: 455–460.

    Article  CAS  PubMed  Google Scholar 

  34. Nguyen S, Beziat V, Dhedin N, Kuentz M, Vernant JP, Debre P et al. HLA-E upregulation on IFN-γ-activated AML blasts impairs CD94-dependent NK cytolysis after haplo-mismatched hematopoietic SCT. Bone Marrow Transplant 2008 Nov 17 (e-pub-ahead of print).

  35. Savani BN, Rezvani K, Mielke S, Montero A, Kurlander R, Carter CS et al. Factors associated with early molecular remission after T cell-depleted allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 2006; 107: 1688–1695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Vago L, Forno B, Sormani MP, Crocchiolo R, Zino E, Di Terlizzi S et al. Temporal, quantitative, and functional characteristics of single-KIR-positive alloreactive natural killer cell recovery account for impaired graft-versus-leukemia activity after haploidentical hematopoietic stem cell transplantation. Blood 2008; 112: 3488–3499.

    Article  CAS  PubMed  Google Scholar 

  37. Fan YY, Yang BY, Wu CY . Phenotypic and functional heterogeneity of natural killer cells from umbilical cord blood mononuclear cells. Immunol Invest 2008; 37: 79–96.

    Article  CAS  PubMed  Google Scholar 

  38. Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A . Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 2007; 26: 503–517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fehniger TA, Cooper MA, Nuovo GJ, Cella M, Facchetti F, Colonna M et al. CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 2003; 101: 3052–3057.

    Article  CAS  PubMed  Google Scholar 

  40. Cooper MA, Fehniger TA, Fuchs A, Colonna M, Caligiuri MA . NK cell and DC interactions. Trends Immunol 2004; 25: 47–52.

    Article  CAS  PubMed  Google Scholar 

  41. Long EO . Ready for prime time: NK cell priming by dendritic cells. Immunity 2007; 26: 385–387.

    Article  CAS  PubMed  Google Scholar 

  42. Ferlazzo G, Thomas D, Lin SL, Goodman K, Morandi B, Muller WA et al. The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic. J Immunol 2004; 172: 1455–1462.

    Article  CAS  PubMed  Google Scholar 

  43. Borg C, Jalil A, Laderach D, Maruyama K, Wakasugi H, Charrier S et al. NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs. Blood 2004; 104: 3267–3275.

    Article  CAS  PubMed  Google Scholar 

  44. Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E . Natural-killer cells and dendritic cells: ‘l'union fait la force’. Blood 2005; 106: 2252–2258.

    Article  CAS  PubMed  Google Scholar 

  45. Bethge WA, Faul C, Bornhäuser M, Stuhler G, Beelen DW, Lang P et al. Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: an update. Blood Cells Mol Dis 2008; 40: 13–19.

    Article  CAS  PubMed  Google Scholar 

  46. Lowe EJ, Turner V, Handgretinger R, Horwitz EM, Benaim E, Hale GA et al. T-cell alloreactivity dominates natural killer cell alloreactivity in minimally T-cell-depleted HLA-non-identical paediatric bone marrow transplantation. Br J Haematol 2003; 123: 323–326.

    Article  PubMed  Google Scholar 

  47. Kloosterboer FM, van Luxemburg-Heijs SA, Willemze R, Falkenburg JH . Similar potential to become activated and proliferate but differential kinetics and profiles of cytokine production of umbilical cord blood T cells and adult blood naive and memory T cells. Hum Immunol 2006; 67: 874–883.

    Article  CAS  PubMed  Google Scholar 

  48. Szabolcs P, Niedzwiecki D . Immune reconstitution after unrelated cord blood transplantation. Cytotherapy 2007; 9: 111–122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fan YY, Yang BY, Wu CY . Phenotypic and functional heterogeneity of natural killer cells from umbilical cord blood mononuclear cells. Immunol Invest 2008; 37: 79–96.

    Article  CAS  PubMed  Google Scholar 

  50. Ballen KK, Haley NR, Kurtzberg J, Lane TA, Lindgren BR, Miller JP et al. Outcomes of 122 diverse adult and pediatric cord blood transplant recipients from a large cord blood bank. Transfusion 2006; 46: 2063–2070.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank E Recchia (Hôtel Dieu, Paris, France) and A Achour (INSERM U543, Paris, France) for their excellent technical assistance, M Legarff-Tarvernier and J Decocq (Department of Hématologie Biologique, AP-HP, Paris, France) for providing RituxiMab and all the personnel from the Etablissement français du Sang (EFS) and from the Department of Gynécologie-Obstétrique at the Pitié-Salpêtrière hospital (Paris, France) for healthy adult and cord blood samples. We also thank I Theodorou (Department of Immunologie Cellulaire et Tissulaire, AP-HP, Paris, France) for his input. This project has been funded in part by national funds from the Institut National de la Santé et de la Recherche Médicale (INSERM) under contract PHRC ‘Minicord’ (P060206-AOM06206), by the associations Cent pour Sang la Vie and the Agence de la BioMédecine.

Author information

Authors and Affiliations

  1. INSERM U543, Hôpital Pitié-Salpêtrière, Paris, France

    V Beziat, B Hervier, P Debre & V Vieillard

  2. UPMC, Université Paris, Paris, France

    V Beziat, B Hervier, P Debre & V Vieillard

  3. Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, Paris, France

    S Nguyen, N Dhedin, M Uzunov & J-P Vernant

  4. Département d'Hématologie et d'Oncologie Médicale, Hôtel Dieu, Paris, France

    S Lapusan, Z Marjanovic, J-P Marie & B Rio

  5. Unité d'Hématologie Moléculaire, Hôpital Henri-Mondor, Créteil, France

    D Bories

  6. Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris, France

    A Boudifa & P Debre

  7. Laboratoire de Thérapie Cellulaire, Hôpital Pitié-Salpêtrière, Paris, France

    H Trebeden-Negre & F Norol

Authors
  1. V Beziat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Lapusan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B Hervier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N Dhedin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Bories
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Uzunov
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Boudifa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H Trebeden-Negre
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F Norol
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Z Marjanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J-P Marie
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J-P Vernant
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. P Debre
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. B Rio
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. V Vieillard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V Vieillard.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Beziat, V., Nguyen, S., Lapusan, S. et al. Fully functional NK cells after unrelated cord blood transplantation. Leukemia 23, 721–728 (2009). https://doi.org/10.1038/leu.2008.343

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.343

Keywords

This article is cited by

Search

Advanced search

Quick links