Seminars in Hematology
Volume 47, Issue 1 , Pages 22-36 , January 2010

Unrelated Umbilical Cord Blood Transplantation and Immune Reconstitution

  • Paul Szabolcs

      Affiliations

    • Department of Pediatrics, Division of Pediatric Bone Marrow Transplantation, Duke University Medical Center, Durham, NC
    • Department of Immunology, Duke University Medical Center, Durham, NC
  • ,
  • Mitchell S. Cairo

      Affiliations

    • Division of Pediatric Blood and Marrow Transplantation, Morgan Stanley Children's Hospital, NewYork-Presbyterian, Columbia University, New York, NY
    • Corresponding Author InformationAddress correspondence to Mitchell S. Cairo, MD, Division of Pediatric Blood and Marrow Transplantation, Morgan Stanley Children's Hospital of New York-Presbyterian Hospital, Columbia University, 3959 Broadway, CHN 10-03, New York, NY 10032

References 

  1. Schwinger W, Weber-Mzell D, Zois B, Rojacher T, Benesch M, Lackner H, et al. Immune reconstitution after purified autologous and allogeneic blood stem cell transplantation compared with unmanipulated bone marrow transplantation in children. Br J Haematol. 2006;135:76–84
  2. Storek J, Geddes M, Khan F, Huard B, Helg C, Chalandon Y, et al. Reconstitution of the immune system after hematopoietic stem cell transplantation in humans. Semin Immunopathol. 2008;30:425–437
  3. Crooks GM, Weinberg K, Mackall C. Immune reconstitution: from stem cells to lymphocytes. Biol Blood Marrow Transplant. 2006;12:42–46
  4. Fry TJ, Mackall CL. Immune reconstitution following hematopoietic progenitor cell transplantation: challenges for the future. Bone Marrow Transplant. 2005;35(Suppl 1):S53–S57
  5. Parkman R, Weinberg KI. Immunological reconstitution following bone marrow transplantation. Immunol Rev. 1997;157:73–78
  6. Mackall CL, Bare CV, Granger LA, Sharrow SO, Titus JA, Gress RE. Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing. J Immunol. 1996;156:4609–4616
  7. Garderet L, Dulphy N, Douay C, Chalumeau N, Schaeffer V, Zilber MT, et al. The umbilical cord blood alphabeta T-cell repertoire: characteristics of a polyclonal and naive but completely formed repertoire. Blood. 1998;91:340–346
  8. Broxmeyer HE. American Association of Blood Banks. Cord blood: biology, immunology, banking and clinical transplantation. Bethesda, MD: AABB Press; 2004;
  9. Koh LP, Chao NJ. Umbilical cord blood transplantation in adults using myeloablative and nonmyeloablative preparative regimens. Biol Blood Marrow Transplant. 2004;10:1–22
  10. Talvensaari K, Clave E, Douay C, Rabian C, Garderet L, Busson M, et al. A broad T-cell repertoire diversity and an efficient thymic function indicate a favorable long-term immune reconstitution after cord blood stem cell transplantation. Blood. 2002;99:1458–1464
  11. Klein AK, Patel DD, Gooding ME, Sempowski GD, Chen BJ, Liu C, et al. T-cell recovery in adults and children following umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2001;7:454–466
  12. Komanduri KV, St John LS, de Lima M, McMannis J, Rosinski S, McNiece I, et al. Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing. Blood. 2007;110:4543–4551
  13. Brahmi Z, Hommel-Berrey G, Smith F, Thomson B. NK cells recover early and mediate cytotoxicity via perforin/granzyme and Fas/FasL pathways in umbilical cord blood recipients. Hum Immunol. 2001;62:782–790
  14. Moretta A, Maccario R, Fagioli F, Giraldi E, Busca A, Montagna D, et al. Analysis of immune reconstitution in children undergoing cord blood transplantation. Exp Hematol. 2001;29:371–379
  15. Niehues T, Rocha V, Filipovich AH, Chan KW, Porcher R, Michel G, et al. Factors affecting lymphocyte subset reconstitution after either related or unrelated cord blood transplantation in children -- a Eurocord analysis. Br J Haematol. 2001;114:42–48
  16. Thomson BG, Robertson KA, Gowan D, Heilman D, Broxmeyer HE, Emanuel D, et al. Analysis of engraftment, graft-versus-host disease, and immune recovery following unrelated donor cord blood transplantation. Blood. 2000;96:2703–2711
  17. Barker JN, Hough RE, van Burik JA, 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;11:362–370
  18. Cohen G, Carter SL, Weinberg KI, Masinsin B, Guinan E, Kurtzberg J, et al. Antigen-specific T-lymphocyte function after cord blood transplantation. Biol Blood Marrow Transplant. 2006;12:1335–1342
  19. Parkman R, Cohen G, Carter SL, Weinberg KI, Masinsin B, Guinan E, et al. Successful immune reconstitution decreases leukemic relapse and improves survival in recipients of unrelated cord blood transplantation. Biol Blood Marrow Transplant. 2006;12:919–927
  20. Cairo MS, Wagner EL, Fraser J, Cohen G, van de Ven C, Carter SL, et al. Characterization of banked umbilical cord blood hematopoietic progenitor cells and lymphocyte subsets and correlation with ethnicity, birth weight, sex, and type of delivery: a Cord Blood Transplantation (COBLT) study report. Transfusion. 2005;45:856–866
  21. Kurtzberg J, Cairo MS, Fraser JK, Baxter-Lowe L, Cohen G, Carter SL, et al. Results of the Cord Blood Transplantation (COBLT) study unrelated donor banking program. Transfusion. 2005;45:842–855
  22. Bradley MB, Satwani P, Baldinger L, Morris E, van de Ven C, Del Toro GD, et al. Reduced intensity allogeneic umbilical cord blood transplantation in children and adolescent recipients with malignant and non-malignant diseases. Bone Marrow Transplant. 2007;40:621–631
  23. Cairo MS, Jin Z, van de Ven C, Tallamy B, Schonfeld T, Moore V, et al. Reduced intensity conditioning (RIC) is associated with a significant decrease in day +100 non-relapse mortality (NRM), grade II-IV AGVHD and overall survival (OS) in pediatric recipients following cord blood transplantation (CBT) [abstract]. Biol Blood Marrow Transplant. 2009;15:77
  24. Kurtzberg J, Carter SL, Baxter-Lowe L, Feig SA, Guinan EC, Kamani NR, et al. Results of the Cord Blood Transplantation Study (COBLT): Clinical outcomes of 193 unrelated donor umbilical cord blood transplantation in pediatric patients with malignant conditions [abstract]. Biol Blood Marrow Transplant. 2005;2:6
  25. Rocha V, Gluckman E. Clinical use of umbilical cord blood hematopoietic stem cells. Biol Blood Marrow Transplant. 2006;12:34–41
  26. 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
  27. Rubinstein P, Carrier C, Scaradavou A, Arcese W, Schwerdtfeger R, Bosi A, et al. Outcomes among 562 recipients of ‘placental-blood transplants from unrelated donors. N Engl J Med. 1998;339:1565–1577
  28. 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
  29. Parody R, Martino R, Rovira M, Vazquez L, Vazquez MJ, de la Camara 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;12:734–748
  30. Szabolcs P, Niedzwiecki D, Chao N, Kurtzberg J. Multivariate analysis of patient and graft specific factors among 330 recipients of unrelated cord blood transplant (UCBT) to predict risk of death from opportunistic infections in the first 6 months after UCBT [abstract]. Blood. 2006;108:2860a
  31. Szabolcs P, Park KD, Marti L, Reese M, Lee M, Deoliveria D, et al. The impact of immune reconstitution in the early post grafting period on the development of opportunistic infections after unrelated cord blood transplantation: a multivariate analysis of host, graft, and day +50 immune profile [abstract]. Biol Blood Marrow Transplant. 2004;10:24
  32. Szabolcs P, Park KD, Marti L, Deoliveria D, Lee YA, Colvin MO, et al. Superior depletion of alloreactive T cells from peripheral blood stem cell and umbilical cord blood grafts by the combined use of trimetrexate and interleukin-2 immunotoxin. Biol Blood Marrow Transplant. 2004;10:772–783
  33. Szabolcs P, Park KD, Reese M, Marti L, Broadwater G, Kurtzberg J. Coexistent naive phenotype and higher cycling rate of cord blood T cells as compared to adult peripheral blood. Exp Hematol. 2003;31:708–714
  34. Szabolcs P, Park KD, Reese M, Marti L, Broadwater G, Kurtzberg J. Absolute values of dendritic cell subsets in bone marrow, cord blood, and peripheral blood enumerated by a novel method. Stem Cells. 2003;21:296–303
  35. Cairo MS, Wagner JE. Placental and/or umbilical cord blood: an alternative source of hematopoietic stem cells for transplantation. Blood. 1997;90:4665–4678
  36. 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
  37. 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
  38. 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
  39. 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
  40. Kurtzberg J, Prasad VK, Carter SL, Wagner JE, Baxter-Lowe LA, Wall D, et al. Results of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies. Blood. 2008;112:4318–4327
  41. Michel G, Rocha V, Chevret S, Arcese W, Chan KW, Filipovich A, et al. Unrelated cord blood transplantation for childhood acute myeloid leukemia: a Eurocord group analysis. Blood. 2003;102:4290–4297
  42. 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;97:2962–2971
  43. Wall DA, Carter SL, Kernan NA, Kapoor N, Kamani NR, Brochstein JA, et al. Busulfan/melphalan/antithymocyte globulin followed by unrelated donor cord blood transplantation for treatment of infant leukemia and leukemia in young children: the Cord Blood Transplantation study (COBLT) experience. Biol Blood Marrow Transplant. 2005;11:637–646
  44. 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
  45. Ooi J, Takahashi S, Tomonari A, Tsukada N, Konuma T, Kato S, et al. Unrelated cord blood transplantation after myeloablative conditioning in adults with acute myelogenous leukemia. Biol Blood Marrow Transplant. 2008;14:1341–1347
  46. Takahashi S, Iseki T, Ooi J, Tomonari A, Takasugi K, Shimohakamada Y, et al. Single-institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adult patients with hematologic malignancies. Blood. 2004;104:3813–3820
  47. Brunstein CG, Cantero S, Cao Q, Majhail N, McClune B, Burns LJ, et al. Promising progression-free survival for patients low and intermediate grade lymphoid malignancies after nonmyeloablative umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2009;15:214–222
  48. Majhail NS, Weisdorf DJ, Wagner JE, Defor TE, Brunstein CG, Burns LJ. Comparable results of umbilical cord blood and HLA-matched sibling donor hematopoietic stem cell transplantation after reduced-intensity preparative regimen for advanced Hodgkin lymphoma. Blood. 2006;107:3804–3807
  49. Rodrigues CA, Sanz G, Brunstein CG, Sanz J, Wagner JE, Renaud M, et al. Analysis of risk factors for outcomes after unrelated cord blood transplantation in adults with lymphoid malignancies: a study by the Eurocord-Netcord and Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2009;27:256–263
  50. Yuji K, Miyakoshi S, Kato D, Miura Y, Myojo T, Murashige N, et al. Reduced-intensity unrelated cord blood transplantation for patients with advanced malignant lymphoma. Biol Blood Marrow Transplant. 2005;11:314–318
  51. Styczynski J, Cheung YK, Garvin J, Savage DG, Billote GB, Harrison L, et al. Outcomes of unrelated cord blood transplantation in pediatric recipients. Bone Marrow Transplant. 2004;34:129–136
  52. 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
  53. Fujita Y, Rooney CM, Heslop HE. Adoptive cellular immunotherapy for viral diseases. Bone Marrow Transplant. 2008;41:193–198
  54. Chalmers IM, Janossy G, Contreras M, Navarrete C. Intracellular cytokine profile of cord and adult blood lymphocytes. Blood. 1998;92:11–18
  55. Risdon G, Gaddy J, Stehman FB, Broxmeyer HE. Proliferative and cytotoxic responses of human cord blood T lymphocytes following allogeneic stimulation. Cell Immunol. 1994;154:14–24
  56. Szabolcs P, Niedzwiecki D. Immune reconstitution after unrelated cord blood transplantation. Cytotherapy. 2007;9:111–122
  57. 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
  58. Parmar S, Robinson SN, Komanduri K, St John L, 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
  59. June CH, Ledbetter JA, Linsley PS, Thompson CB. Role of the CD28 receptor in T-cell activation. Immunol Today. 1990;11:211–216
  60. Laport GG, Levine BL, Stadtmauer EA, Schuster SJ, Luger SM, Grupp S, et al. Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation. Blood. 2003;102:2004–2013
  61. Levine BL, Bernstein WB, Aronson NE, Schlienger K, Cotte J, Perfetto S, et al. Adoptive transfer of costimulated CD4+ T cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV infection. Nat Med. 2002;8:47–53
  62. Porter DL, Levine BL, Bunin N, Stadtmauer EA, Luger SM, Goldstein S, et al. A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation. Blood. 2006;107:1325–1331
  63. Taylor PA, Noelle RJ, Blazar BR. CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J Exp Med. 2001;193:1311–1318
  64. Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL. CD4(+)CD25(+) immunoregulatory T Cells: new therapeutics for graft-versus-host disease. J Exp Med. 2002;196:401–406
  65. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med. 2002;196:389–399
  66. Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood. 2002;99:3493–3499
  67. Taylor PA, Panoskaltsis-Mortari A, Swedin JM, Lucas PJ, Gress RE, Levine BL, et al. L-selectin(hi) but not the L-selectin(lo) CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. Blood. 2004;104:3804–3812
  68. Brunstein CG HK, McKenna DH, Cao Q, Curtsinger J, Sumstad D, Levine BL, et al. Adoptive transfer of umbilical cord blood (UCB)-derived regulatory T cells (Tregs) to recipients of nonmyeloablative unrelated double UCB transplantation [abstract]. American Society of Hematology Annual Meeting. Orlando, FL, May 29–June 12, 2009.
  69. Godfrey WR, Spoden DJ, Ge YG, Baker SR, Liu B, Levine BL, et al. Cord blood CD4(+)CD25(+)-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function. Blood. 2005;105:750–758
  70. June CH, Blazar BR. Clinical application of expanded CD4+25+ cells. Semin Immunol. 2006;18:78–88
  71. Hanley PJ, Cruz CR, Savoldo B, Leen AM, Stanojevic M, Khalil M, et al. Functionally active virus-specific T-cells that target CMV, adenovirus and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes. Blood. 2009;114:1958–1967
  72. Park KD, Marti L, Kurtzberg J, Szabolcs P. In vitro priming and expansion of cytomegalovirus-specific Th1 and Tc1 T cells from naive cord blood lymphocytes. Blood. 2006;108:1770–1773
  73. Serrano LM, Pfeiffer T, Olivares S, Numbenjapon T, Bennitt J, Kim D, et al. Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy. Blood. 2006;107:2643–2652
  74. Lee SM, Suen Y, Chang L, Bruner V, Qian J, Indes J, et al. Decreased interleukin-12 (IL-12) from activated cord versus adult peripheral blood mononuclear cells and upregulation of interferon-gamma, natural killer, and lymphokine-activated killer activity by IL-12 in cord blood mononuclear cells. Blood. 1996;88:945–954
  75. Qian JX, Lee SM, Suen Y, Knoppel E, van de Ven C, Cairo MS. Decreased interleukin-15 from activated cord versus adult peripheral blood mononuclear cells and the effect of interleukin-15 in upregulating antitumor immune activity and cytokine production in cord blood. Blood. 1997;90:3106–3117
  76. Satwani P, Ayello J, Ven C, O'Neill AF, Simpson LL, Baxi L, et al. Immaturity of IL-18 gene expression and protein production in cord blood (CB) versus peripheral blood (PB) mononuclear cells and differential effects in natural killer (NK) cell development and function. Br J Haematol. 2005;130:284–292
  77. Lee SM, Suen Y, Qian J, Knoppel E, Cairo MS. The regulation and biological activity of interleukin 12. Leuk Lymphoma. 1998;29:427–438
  78. Dunbar EM, Buzzeo MP, Levine JB, Schold JD, Meier-Kriesche HU, Reddy V. The relationship between circulating natural killer cells after reduced intensity conditioning hematopoietic stem cell transplantation and relapse-free survival and graft-versus-host disease. Haematologica. 2008;93:1852–1858
  79. Willemze R, Rodrigues CA, Labopin M, Sanz G, Michel G, Socie G, et al. KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia. Leukemia. 2009;23:492–500
  80. Jaroscak J, Goltry K, Smith A, Waters-Pick B, Martin PL, Driscoll TA, et al. Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase 1 trial using the AastromReplicell System. Blood. 2003;101:5061–5067
  81. 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
  82. Ayello J, van de Ven C, Cairo E, Hochberg J, Baxi L, Satwani P, et al. Characterization of natural killer (NK) and natural killer-like T (NKT) cells derived from ex-vivo expanded and activated cord blood mononuclear cells: implications for adoptive cellular immunotherapy (ACI). Exp Hematol. 2009;37:1216–1229
  83. Ayello J, van de Ven C, Fortino W, Wade-Harris C, Satwani P, Baxi L, et al. Characterization of cord blood natural killer and lymphokine activated killer lymphocytes following ex vivo cellular engineering. Biol Blood Marrow Transplant. 2006;12:608–622
  84. Condiotti R, Zakai YB, Barak V, Nagler A. Ex vivo expansion of CD56+ cytotoxic cells from human umbilical cord blood. Exp Hematol. 2001;29:104–113
  85. Frias AM, Porada CD, Crapnell KB, Cabral JM, Zanjani ED, Almeida-Porada G. Generation of functional natural killer and dendritic cells in a human stromal-based serum-free culture system designed for cord blood expansion. Exp Hematol. 2008;36:61–68
  86. 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
  87. Hochberg J, Mar B, Ayello J, Day N, van de Ven C, Ricci A, et al. Genetic engineering and significant ex-vivo expansion of cord blood natural killer cells: implications for post-transplant adoptive cellular immunotherapy [abstract]. Blood. 2008;112:209

 M.S.C. was supported in part by grants from National Heart, Lung and Blood Institute (NIH N01-HB-67136), National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21 AR49330), Pediatric Cancer Research Foundation, BevanMar Foundation, Marisa Fund, Sonia Scaramella Fund, Paul Luisi Foundation, and the Brittany Barron Fund. P.S. was supported in part by Grant No. R01-CA132110, The Childrens' Miracle Network, The National Marrow Donor Program-Marrow Transplant Research grant, and 1PO1-HL-67314-01A1 (Principal Investigator: N. Chao).

PII: S0037-1963(09)00140-1

doi: 10.1053/j.seminhematol.2009.10.009

Seminars in Hematology
Volume 47, Issue 1 , Pages 22-36 , January 2010