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Immunologic Research

, Volume 57, Issue 1–3, pp 140–150 | Cite as

The evolving art of hematopoietic stem cell transplantation: translational research in post-transplant immune reconstitution and immunosuppression

  • Krishna V. Komanduri
  • Eric D. Wieder
  • Cara L. Benjamin
  • Robert B. Levy
Immunology & Microbiology in Miami

Abstract

Allogeneic hematopoietic stem cell transplantation (SCT) offers the best chance for cure and/or long-term survival for a broad range of diseases, including many high-risk hematologic malignancies, bone marrow failure states and subsets of inherited metabolic diseases and hemoglobinopathies. Clinical advances in allogeneic SCT have resulted in dramatically improved clinical outcomes over the past two decades, resulting in a significant expansion of transplant utilization to many recipients who would previously have been excluded from consideration, including elderly recipients and individuals lacking matched sibling or unrelated donors. Despite these advances, significant clinical challenges remain, including delayed immune reconstitution and the frequent occurrence of acute and chronic graft-versus-host disease, especially in the unrelated donor transplant setting. Translational laboratory efforts, facilitated by technical advances in our ability to measure thymopoiesis and functional T cell subsets in humans, have resulted in an improved understanding of immune recovery and have provided novel insights that may lead to more rational and selective immunosuppression.

Keywords

Hematopoietic stem cell transplantation T cell immunology Thymopoiesis Immune reconstitution Immunosuppression 

Notes

Acknowledgments

The authors thank Tae Kon Kim (Yale University) and Takero Shindo (Saga University) for their scientific contributions to the work discussed. The authors thank Marcos de Lima, Elizabeth Shpall, Ian McNiece and Richard Champlin (MD Anderson Cancer Center), Paul Szabolcs and Joanne Kurtzberg (Duke) for their collaborative clinical and laboratory efforts. This work was supported, in part by the generous funding from the National Institutes of Health (NCI RO1 CA109326 to K. V. K. and NHLBI RO1 HL091749 to K. V. K. and Paul Szabolcs) and the Kalish Family Foundation (to K. V. K.).

References

  1. 1.
    Appelbaum FR. Hematopoietic-cell transplantation at 50. N Engl J Med. 2007;357(15):1472–5. doi: 10.1056/NEJMp078166.CrossRefPubMedGoogle Scholar
  2. 2.
    Pasquini MC, Wang Z, Horowitz MM, Gale RP. Report from the Center for International Blood and Marrow Transplant Research (CIBMTR): current uses and outcomes of hematopoietic cell transplants for blood and bone marrow disorders. Clin Transpl. 2010;2010:87–105.Google Scholar
  3. 3.
  4. 4.
    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(22):1565–77.CrossRefPubMedGoogle Scholar
  5. 5.
    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(3):795–802.PubMedGoogle Scholar
  6. 6.
    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(10):2962–71.CrossRefPubMedGoogle Scholar
  7. 7.
    Broxmeyer HE, Cooper S, Hass DM, Hathaway JK, Stehman FB, Hangoc G. Experimental basis of cord blood transplantation. Bone Marrow Transpl. 2009;. doi: 10.1038/bmt.2009.285.Google Scholar
  8. 8.
    Gluckman E. History of cord blood transplantation. Bone Marrow Transpl. 2009;. doi: 10.1038/bmt.2009.280.Google Scholar
  9. 9.
    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(17):1174–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Kurtzberg J, Graham M, Casey J, Olson J, Stevens CE, Rubinstein P. The use of umbilical cord blood in mismatched related and unrelated hemopoietic stem cell transplantation. Blood Cells. 1994;20(2–3):275–283, discussion 84.Google Scholar
  11. 11.
    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(3):1343–7. doi: 10.1182/blood-2004-07-2717.CrossRefPubMedGoogle Scholar
  12. 12.
    Sanz GF, Saavedra S, Planelles D, Senent L, Cervera J, Barragan E, et al. Standardized, unrelated donor cord blood transplantation in adults with hematologic malignancies. Blood. 2001;98(8):2332–8.CrossRefPubMedGoogle Scholar
  13. 13.
    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(24):1815–22.CrossRefPubMedGoogle Scholar
  14. 14.
    Rocha V, Kabbara N, Ionescu I, Ruggeri A, Purtill D, Gluckman E. Pediatric related and unrelated cord blood transplantation for malignant diseases. Bone Marrow Transpl. 2009;. doi: 10.1038/bmt.2009.291.Google Scholar
  15. 15.
    Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood. 2013;122(4):491–8. doi: 10.1182/blood-2013-02-453175.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    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(5):1915–9.CrossRefPubMedGoogle Scholar
  17. 17.
    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(3):157–66.CrossRefPubMedGoogle Scholar
  18. 18.
    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(5):1611–8.PubMedGoogle Scholar
  19. 19.
    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 Transpl. 2008;41(9):771–8.Google Scholar
  20. 20.
    Shpall EJ, Quinones R, Giller R, Zeng C, Baron AE, Jones RB, et al. Transplantation of ex vivo expanded cord blood. Biol Blood Marrow Transpl. 2002;8(7):368–76.CrossRefGoogle Scholar
  21. 21.
    Kelly SS, Sola CB, de Lima M, Shpall E. Ex vivo expansion of cord blood. Bone Marrow Transpl. 2009;. doi: 10.1038/bmt.2009.284.Google Scholar
  22. 22.
    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(4):311–7.CrossRefPubMedGoogle Scholar
  23. 23.
    de Lima M. Mesenchymal stromal cell expansion for cord-blood engraftment. Clin Adv Hematol Oncol. 2013;11(4):248–50.PubMedGoogle Scholar
  24. 24.
    Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med. 2010;16(2):232–6. doi: 10.1038/nm.2080.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Zakrzewski JL, Kochman AA, Lu SX, Terwey TH, Kim TD, Hubbard VM, et al. Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation. Nat Med. 2006;12(9):1039–47.CrossRefPubMedGoogle Scholar
  26. 26.
    de Lima M, John LS, 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(3):773–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Haspel RL, Kao G, Yeap BY, Cutler C, Soiffer RJ, Alyea EP, et al. Preinfusion variables predict the predominant unit in the setting of reduced-intensity double cord blood transplantation. Bone Marrow Transpl. 2008;41(6):523–9. doi: 10.1038/sj.bmt.1705933.CrossRefGoogle Scholar
  28. 28.
    Gutman JA, Turtle CJ, Manley TJ, Heimfeld S, Bernstein ID, Riddell SR, et al. Single unit dominance following double unit umbilical cord blood transplantation coincides with a specific CD8+ T cell response against the non-engrafted unit. Blood. 2009;. doi: 10.1182/blood-2009-07-228999.Google Scholar
  29. 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 Transpl. 2006;12(7):734–48. doi: 10.1016/j.bbmt.2006.03.007.CrossRefGoogle Scholar
  30. 30.
    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 Transpl. 2005;11(5):362–70. doi: 10.1016/j.bbmt.2005.02.004.CrossRefGoogle Scholar
  31. 31.
    Safdar A, Rodriguez GH, De Lima MJ, Petropoulos D, Chemaly RF, Worth LL, et al. Infections in 100 cord blood transplantations: spectrum of early and late posttransplant infections in adult and pediatric patients 1996–2005. Medicine (Baltimore). 2007;86(6):324–33. doi: 10.1097/MD.0b013e31815c52b0.CrossRefPubMedGoogle Scholar
  32. 32.
    Tomonari A, Iseki T, Takahashi S, Ooi J, Takasugi K, Shimohakamada Y, et al. Varicella-zoster virus infection in adult patients after unrelated cord blood transplantation: a single institute experience in Japan. Br J Haematol. 2003;122(5):802–5.CrossRefPubMedGoogle Scholar
  33. 33.
    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 Transpl. 2008;14(8):867–71. doi: 10.1016/j.bbmt.2008.05.006.CrossRefGoogle Scholar
  34. 34.
    de Pagter PJ, 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 Transpl. 2008;14(7):831–9. doi: 10.1016/j.bbmt.2008.04.016.CrossRefGoogle Scholar
  35. 35.
    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(6):2005–11.PubMedGoogle Scholar
  36. 36.
    El-Zimaity M, Saliba R, Chan K, Shahjahan M, Carrasco A, Khorshid O, et al. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: donor type matters. Blood. 2004;103(12):4674–80. doi: 10.1182/blood-2003-08-2815.CrossRefPubMedGoogle Scholar
  37. 37.
    Waldrop SL, Pitcher CJ, Peterson DM, Maino VC, Picker LJ. Determination of antigen-specific memory/effector CD4+ T cell frequencies by flow cytometry: evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency. J Clin Invest. 1997;99(7):1739–50.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Komanduri KV, Viswanathan MN, Wieder ED, Schmidt DK, Bredt BM, Jacobson MA, et al. Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nat Med. 1998;4(8):953–6.CrossRefPubMedGoogle Scholar
  39. 39.
    Mackall CL, Gress RE. Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy. Immunol Rev. 1997;157:61–72.CrossRefPubMedGoogle Scholar
  40. 40.
    Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998;396(6712):690–5.CrossRefPubMedGoogle Scholar
  41. 41.
    Poulin JF, Viswanathan MN, Harris JM, Komanduri KV, Wieder E, Ringuette N, et al. Direct evidence for thymic function in adult humans. J Exp Med. 1999;190(4):479–86.PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Komanduri KV, 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(13):4543–51.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Szabolcs P, Niedzwiecki D. Immune reconstitution in children after unrelated cord blood transplantation. Biol Blood Marrow Transpl. 2008;14(1 Suppl 1):66–72. doi: 10.1016/j.bbmt.2007.10.016.CrossRefGoogle Scholar
  44. 44.
    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(3):371–9.CrossRefPubMedGoogle Scholar
  45. 45.
    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 Transpl. 2001;7(8):454–66.CrossRefGoogle Scholar
  46. 46.
    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 Transpl. 2006;12(9):919–27.CrossRefGoogle Scholar
  47. 47.
    Kim TK, John LS, Wieder ED, Khalili J, Ma Q, Komanduri KV, et al. Human late memory CD8+ T cells have a distinct cytokine signature characterized by CC chemokine production without IL-2 production. J Immunol. 2009;. doi: 10.4049/jimmunol.0902068.Google Scholar
  48. 48.
    Komanduri KV, Donahoe SM, Moretto WJ, Schmidt DK, Gillespie G, Ogg GS, et al. Direct measurement of CD4+ and CD8+ T-cell responses to CMV in HIV-1-infected subjects. Virology. 2001;279(2):459–70. doi: 10.1006/viro2000.0697.CrossRefPubMedGoogle Scholar
  49. 49.
    Komanduri KV, Feinberg J, Hutchins RK, Frame RD, Schmidt DK, Viswanathan MN, et al. Loss of cytomegalovirus-specific CD4+ T cell responses in human immunodeficiency virus type 1-infected patients with high CD4+ T cell counts and recurrent retinitis. J Infect Dis. 2001;183(8):1285–9. doi: 10.1086/319683.CrossRefPubMedGoogle Scholar
  50. 50.
    Ozdemir E, John LS, Gillespie G, Rowland-Jones S, Champlin RE, Molldrem JJ, et al. Cytomegalovirus reactivation following allogeneic stem cell transplantation is associated with the presence of dysfunctional antigen-specific CD8+ T cells. Blood. 2002;100(10):3690–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Stanzani M, Orciuolo E, Lewis R, Kontoyiannis DP, Martins SL, John LS, et al. Aspergillus fumigatus suppresses the human cellular immune response via gliotoxin-mediated apoptosis of monocytes. Blood. 2005;105(6):2258–65. doi: 10.1182/blood-2004-09-3421.CrossRefPubMedGoogle Scholar
  52. 52.
    Martins SL, John LS, Champlin RE, Wieder ED, McMannis J, Molldrem JJ, et al. Functional assessment and specific depletion of alloreactive human T cells using flow cytometry. Blood. 2004;104(12):3429–36. doi: 10.1182/blood-2004-05-1918.CrossRefPubMedGoogle Scholar
  53. 53.
    Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401(6754):708–12.CrossRefPubMedGoogle Scholar
  54. 54.
    Champagne P, Ogg GS, King AS, Knabenhans C, Ellefsen K, Nobile M, et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature. 2001;410(6824):106–11.CrossRefPubMedGoogle Scholar
  55. 55.
    Chen BJ, Cui X, Sempowski GD, Liu C, Chao NJ. Transfer of allogeneic CD62L–memory T cells without graft-versus-host disease. Blood. 2004;103(4):1534–41. doi: 10.1182/blood-2003-08-2987.CrossRefPubMedGoogle Scholar
  56. 56.
    Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat Med. 2005;11(12):1299–305. doi: 10.1038/nm1326.CrossRefPubMedGoogle Scholar
  57. 57.
    Anderson BE, McNiff J, Yan J, Doyle H, Mamula M, Shlomchik MJ, et al. Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest. 2003;112(1):101–8.PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Zheng H, Matte-Martone C, Jain D, McNiff J, Shlomchik WD. Central memory CD8+ T cells induce graft-versus-host disease and mediate graft-versus-leukemia. J Immunol. 2009;182(10):5938–48. doi: 10.4049/jimmunol.0802212.CrossRefPubMedGoogle Scholar
  59. 59.
    Zheng H, Matte-Martone C, Li H, Anderson BE, Venketesan S, Tan HS, et al. Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood. 2008;111(4):2476–84. doi: 10.1182/blood-2007-08-109678.PubMedCentralCrossRefPubMedGoogle Scholar
  60. 60.
    Chen BJ, Deoliveira D, Cui X, Le NT, Son J, Whitesides JF, et al. Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse. Blood. 2007;109(7):3115–23.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Krutzik PO, Crane JM, Clutter MR, Nolan GP. High-content single-cell drug screening with phosphospecific flow cytometry. Nat Chem Biol. 2008;4(2):132–42. doi: 10.1038/nchembio.2007.59.CrossRefPubMedGoogle Scholar
  62. 62.
    Kim TK, Billard MJ, Wieder ED, McIntyre BW, Komanduri KV. Co-engagement of alpha(4)beta(1) integrin (VLA-4) and CD4 or CD8 is necessary to induce maximal Erk1/2 phosphorylation and cytokine production in human T cells. Hum Immunol. 2010;71(1):23–8. doi: 10.1016/j.humimm.2009.09.360.PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Shindo T, Kim TK, Benjamin CL, Wieder ED, Levy RB, Komanduri KV. MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner. Blood. 2013;121(23):4617–26. doi: 10.1182/blood-2012-12-476218.PubMedCentralCrossRefPubMedGoogle Scholar
  64. 64.
    Lu SX, Alpdogan O, Lin J, Balderas R, Campos-Gonzalez R, Wang X, et al. STAT-3 and ERK 1/2 phosphorylation are critical for T-cell alloactivation and graft-versus-host disease. Blood. 2008;112(13):5254–8.PubMedCentralCrossRefPubMedGoogle Scholar
  65. 65.
    Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703. doi: 10.1056/NEJMoa1210093.PubMedCentralCrossRefPubMedGoogle Scholar
  66. 66.
    Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–14. doi: 10.1056/NEJMoa1203421.CrossRefPubMedGoogle Scholar
  67. 67.
    Ross D, Jones M, Komanduri K, Levy RB. Antigen and lymphopenia-driven donor T cells are differentially diminished by post-transplantation administration of cyclophosphamide after hematopoietic cell transplantation. Biol Blood Marrow Transpl. 2013;19(10):1430–8. doi: 10.1016/j.bbmt.2013.06.019.CrossRefGoogle Scholar
  68. 68.
    Luznik L, Engstrom LW, Iannone R, Fuchs EJ. Posttransplantation cyclophosphamide facilitates engraftment of major histocompatibility complex-identical allogeneic marrow in mice conditioned with low-dose total body irradiation. Biol Blood Marrow Transpl. 2002;8(3):131–8.CrossRefGoogle Scholar
  69. 69.
    Luznik L, Bolanos-Meade J, Zahurak M, Chen AR, Smith BD, Brodsky R, et al. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010;115(16):3224–30. doi: 10.1182/blood-2009-11-251595.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Krishna V. Komanduri
    • 1
    • 2
  • Eric D. Wieder
    • 1
  • Cara L. Benjamin
    • 1
  • Robert B. Levy
    • 1
    • 2
  1. 1.Adult Stem Cell Transplant Program, Department of MedicineUniversity of Miami Sylvester Comprehensive Cancer CenterMiamiUSA
  2. 2.Department of Microbiology and ImmunologyUniversity of Miami Miller School of MedicineMiamiUSA

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