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Cell Selection

CD3+ and/or CD14+ depletion from cord blood mononuclear cells before ex vivo expansion culture improves total nucleated cell and CD34+ cell yields

Bone Marrow Transplantation volume 45, pages 1000–1007 (2010)Cite this article

Abstract

Cord blood (CB) is used increasingly in transplant patients lacking sibling or unrelated donors. A major hurdle in the use of CB is its low cell dose, which is largely responsible for an elevated risk of graft failure and a significantly delayed neutrophil and platelet engraftment. As a positive correlation has been shown between the total nucleated cell (TNC) and CD34+ cell dose transplanted and time to neutrophil and platelet engraftment, strategies to increase these measures are under development. One strategy includes the ex vivo expansion of CB mononuclear cells (MNC) with MSC in a cytokine cocktail. We show that this strategy can be further improved if CD3+ and/or CD14+ cells are first depleted from the CB MNC before ex vivo expansion. Ready translation of this depletion strategy to improve ex vivo CB expansion in the clinic is feasible as clinical-grade devices and reagents are available. Ultimately, the aim of improving TNC and CD34+ transplant doses is to further improve the rate of neutrophil and platelet engraftment in CB recipients.

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References

  1. Barker JN, Davies SM, Defor T, Ramsay NK, Weisdorf DJ, Wagner JE . Survival after transplantation of unrelated donor umbilical cord blood is comparable to that of human leukocyte antigen-matched unrelated donor bone marrow: results of a matched-pair analysis. Blood 2001; 97: 2957–2961.

    Article  CAS  PubMed  Google Scholar 

  2. Barker JN, Weisdorf DJ, Defor TE, Blazar BR, Miller JS, Wagner JE . Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood 2003; 102: 1915–1919.

    Article  CAS  PubMed  Google Scholar 

  3. Barker JN, Weisdorf DJ, Defor TE, Blazar BR, McGlave PB, Miller JS et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 2005; 105: 1343–1347.

    Article  CAS  PubMed  Google Scholar 

  4. Brunstein CG, Barker JN, Weisdorf DJ, Defor TE, Miller JS, Blazar BR et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood 2007; 110: 3064–3070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med 1997; 337: 373–381.

    Article  CAS  PubMed  Google Scholar 

  6. Gluckman E, Rocha V, Chevret S . Results of unrelated umbilical cord blood hematopoietic stem cell transplantation. Rev Clin Exp Hematol 2001; 5: 87–99.

    Article  CAS  PubMed  Google Scholar 

  7. Gluckman E, Rocha V, Arcese W, Michel G, Sanz G, Chan KW et al. Factors associated with outcomes of unrelated cord blood transplant: guidelines for donor choice. Exp Hematol 2004; 32: 397–407.

    Article  CAS  PubMed  Google Scholar 

  8. Kurtzberg J, Laughlin M, Graham ML, Smith C, Olson JF, Halperin EC et al. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med 1996; 335: 157–166.

    Article  CAS  PubMed  Google Scholar 

  9. Laughlin MJ, Barker J, Bambach B, Koc ON, Rizzieri DA, Wagner JE et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med 2001; 344: 1815–1822.

    Article  CAS  PubMed  Google Scholar 

  10. 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 

  11. Rubinstein P, Carrier C, Scaradavou A, Kurtzberg J, Adamson J, Migliaccio AR et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med 1998; 339: 1565–1577.

    Article  CAS  PubMed  Google Scholar 

  12. Wagner JE, Barker JN, Defor TE, Baker KS, Blazar BR, Eide C et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 2002; 100: 1611–1618.

    CAS  PubMed  Google Scholar 

  13. Barker JN, Weisdorf DJ, Wagner JE . Creation of a double chimera after the transplantation of umbilical-cord blood from two partially matched unrelated donors. N Engl J Med 2001; 344: 1870–1871.

    Article  CAS  PubMed  Google Scholar 

  14. de Lima M, St John L, Wieder ED, Lee MS, McMannis J, Karandish S et al. Double-chimaerism after transplantation of two human leucocyte antigen mismatched, unrelated cord blood units. Br J Haematol 2002; 119: 773–776.

    Article  PubMed  Google Scholar 

  15. McNiece IK, meida-Porada G, Shpall EJ, Zanjani E . Ex vivo expanded cord blood cells provide rapid engraftment in fetal sheep but lack long-term engrafting potential. Exp Hematol 2002; 30: 612–616.

    Article  PubMed  Google Scholar 

  16. McNiece I, Harrington J, Turney J, Kellner J, Shpall EJ . Ex vivo expansion of cord blood mononuclear cells on mesenchymal stem cells. Cytotherapy 2004; 6: 311–317.

    Article  CAS  PubMed  Google Scholar 

  17. McNiece I, Kubegov D, Kerzic P, Shpall EJ, Gross S . Increased expansion and differentiation of cord blood products using a two-step expansion culture. Exp Hematol 2000; 28: 1181–1186.

    Article  CAS  PubMed  Google Scholar 

  18. Shpall EJ, Quinones R, Giller R, Zeng C, Baron AE, Jones RB et al. Transplantation of ex vivo expanded cord blood. Biol Blood Marrow Transplant 2002; 8: 368–376.

    Article  PubMed  Google Scholar 

  19. Robinson SN, Ng J, Niu T, Yang H, McMannis JD, Karandish S et al. Superior ex vivo cord blood expansion following co-culture with bone marrow-derived mesenchymal stem cells. Bone Marrow Transplant 2006; 37: 359–366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. de Lima M, McMannis J, Gee A, Komanduri K, Couriel D, Andersson BS et al. Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial. Bone Marrow Transplant 2008; 41: 771–778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Briddell RA, Kern BP, Zilm KL, Stoney GB, McNiece IK . Purification of CD34+ cells is essential for optimal ex vivo expansion of umbilical cord blood cells. J Hematother 1997; 6: 145–150.

    Article  CAS  PubMed  Google Scholar 

  22. Harada M, Odaka K, Kondo K, Nakao S, Ueda M, Matsue K et al. Effect of activated lymphocytes on the regulation of hematopoiesis: suppression of in vitro granulopoiesis and erythropoiesis by OKT8+ Ia- T cells induced by concanavalin-A stimulation. Exp Hematol 1985; 13: 963–967.

    CAS  PubMed  Google Scholar 

  23. Harada M, Nakao S, Kondo K, Odaka K, Ueda M, Shiobara S et al. Effect of activated lymphocytes on the regulation of hematopoiesis: enhancement and suppression of in vitro BFU-E growth by T cells stimulated by autologous non-T cells. Blood 1986; 67: 1143–1147.

    CAS  PubMed  Google Scholar 

  24. Degliantoni G, Perussia B, Mangoni L, Trinchieri G . Inhibition of bone marrow colony formation by human natural killer cells and by natural killer cell-derived colony-inhibiting activity. J Exp Med 1985; 161: 1152–1168.

    Article  CAS  PubMed  Google Scholar 

  25. Degliantoni G, Murphy M, Kobayashi M, Francis MK, Perussia B, Trinchieri G . Natural killer (NK) cell-derived hematopoietic colony-inhibiting activity and NK cytotoxic factor. Relationship with tumor necrosis factor and synergism with immune interferon. J Exp Med 1985; 162: 1512–1530.

    Article  CAS  PubMed  Google Scholar 

  26. Landoni VI, Vermeulen M, van RN, Gomez S, Palermo M, Isturiz MA et al. Macrophage derived signalling regulates negatively the megakaryocyte compartment. Cell Mol Biol 2004; 50: 667–675.

    Google Scholar 

  27. Zuckerman KS . Human erythroid burst-forming units. Growth in vitro is dependent on monocytes, but not T lymphocytes. J Clin Invest 1981; 67: 702–709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cicuttini FM, Loudovaris M, Boyd AW . Interactions between purified human cord blood haemopoietic progenitor cells and accessory cells. Br J Haematol 1993; 84: 365–373.

    Article  CAS  PubMed  Google Scholar 

  29. Flores-Guzman P, Martinez-Jaramillo G, Montesinos JJ, Valencia I, Mayani H . Growth kinetics of progenitor cell-enriched hematopoietic cell populations in long-term liquid cultures under continuous removal of mature cells. Cytotherapy 2006; 8: 299–307.

    Article  CAS  PubMed  Google Scholar 

  30. Parmar S, Robinson SN, Komanduri K, St JL, Decker W, Xing D et al. Ex vivo expanded umbilical cord blood T cells maintain naive phenotype and TCR diversity. Cytotherapy 2006; 8: 149–157.

    Article  CAS  PubMed  Google Scholar 

  31. Robinson KL, Ayello J, Hughes R, van de Ven C, Issitt L, Kurtzberg J et al. Ex vivo expansion, maturation, and activation of umbilical cord blood-derived T lymphocytes with IL-2, IL-12, anti-CD3, and IL-7. Potential for adoptive cellular immunotherapy post-umbilical cord blood transplantation. Exp Hematol 2002; 30: 245–251.

    Article  CAS  PubMed  Google Scholar 

  32. Mazur MA, Davis CC, Szabolcs P . Ex vivo expansion and Th1/Tc1 maturation of umbilical cord blood T cells by CD3/CD28 costimulation. Biol Blood Marrow Transplant 2008; 14: 1190–1196.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Graham GJ, Wright EG, Hewick R, Wolpe SD, Wilkie NM, Donaldson D et al. Identification and characterization of an inhibitor of haemopoietic stem cell proliferation. Nature 1990; 344: 442–444.

    Article  CAS  PubMed  Google Scholar 

  34. Graham GJ, Freshney MG, Donaldson D, Pragnell IB . Purification and biochemical characterisation of human and murine stem cell inhibitors (SCI). Growth Factors 1992; 7: 151–160.

    Article  CAS  PubMed  Google Scholar 

  35. Wright EG, Garland JM, Lord BI . Specific inhibition of haemopoietic stem cell proliferation: characteristics of the inhibitor producing cells. Leuk Res 1980; 4: 537–545.

    Article  CAS  PubMed  Google Scholar 

  36. Lord BI, Wright EG . Sources of haemopoietic stem cell proliferation: stimulators and inhibitors. Blood Cells 1980; 6: 581–593.

    CAS  PubMed  Google Scholar 

  37. Majhail NS, Mothukuri JM, Brunstein CG, Weisdorf DJ . Costs of hematopoietic cell transplantation: comparison of umbilical cord blood and matched related donor transplantation and the impact of posttransplant complications. Biol Blood Marrow Transplant 2009; 15: 564–573.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by NCI R01 CA061508-16. The authors gratefully acknowledge the provision of MPC by Angioblast Systems, Inc., New York, NY.

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Author notes

  1. H Yang and S N Robinson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    H Yang, S N Robinson, J Lu, W K Decker, D Xing, D Steiner, S Parmar, N Shah, R E Champlin & E J Shpall

  2. Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M Munsell

  3. The Baylor College of Medicine Center for Cell and Gene Therapy, Houston, TX, USA

    A Leen & C Bollard

  4. The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX, USA

    P J Simmons

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Correspondence to S N Robinson.

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Yang, H., Robinson, S., Lu, J. et al. CD3+ and/or CD14+ depletion from cord blood mononuclear cells before ex vivo expansion culture improves total nucleated cell and CD34+ cell yields. Bone Marrow Transplant 45, 1000–1007 (2010). https://doi.org/10.1038/bmt.2009.289

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