Clinical Implications of Immune Reconstitution Following Hematopoietic Stem Cell Transplantation

  • Karl S. Peggs
  • Aviva C. Krauss
  • Crystal L. Mackall
Part of the Cancer Treatment and Research book series (CTAR, volume 144)


Hematopoietic Stem Cell Transplantation Allogeneic Hematopoietic Stem Cell Transplantation Immune Reconstitution Keratinocyte Growth Factor Autologous Hematopoietic Stem Cell Transplantation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Storek J, Gooley T, Witherspoon RP, Sullivan KM, Storb R. Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol. 1997;54:131–8.PubMedGoogle Scholar
  2. 2.
    Anderson KC, Ritz J, Takvorian T, Coral F, Daley H, Gorgone BC, et al. Hematologic engraftment and immune reconstitution posttransplantation with anti-B1 purged autologous bone marrow. Blood 1987;69:597–604.PubMedGoogle Scholar
  3. 3.
    Storek J, Dawson MA, Storer B, Stevens-Ayers T, Maloney DG, Marr KA, et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 2001;97:3380–9.PubMedGoogle Scholar
  4. 4.
    Hakim FT, Memon SA, Cepeda R, Jones EC, Chow CK, Kasten-Sportes C, et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest. 2005;115:930–9.PubMedGoogle Scholar
  5. 5.
    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;156:4609–16.PubMedGoogle Scholar
  6. 6.
    Dumont-Girard F, Roux E, van Lier RA, Hale G, Helg C, Chapuis B, et al. Reconstitution of the T-cell compartment after bone marrow transplantation: restoration of the repertoire by thymic emigrants. Blood 1998;92:4464–71.PubMedGoogle Scholar
  7. 7.
    Weinberg K, Annett G, Kashyap A, Lenarsky C, Forman SJ, Parkman R. The effect of thymic function on immunocompetence following bone marrow transplantation. Biol Blood Marrow Transplant. 1995;1:18–23.PubMedGoogle Scholar
  8. 8.
    Kalwak K, Moson I, Cwian J, Gorczynska E, Toporski J, Turkiewicz D, et al. A prospective analysis of immune recovery in children following allogeneic transplantation of T-cell-depleted or non-T-cell-depleted hematopoietic cells from HLA-disparate family donors. Transplant Proc. 2003;35:1551–5.PubMedGoogle Scholar
  9. 9.
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–6.PubMedGoogle Scholar
  10. 10.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057–61.PubMedGoogle Scholar
  11. 11.
    Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8:191–7.PubMedGoogle Scholar
  12. 12.
    Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 2002;420:502–7.PubMedGoogle Scholar
  13. 13.
    Mendez S, Reckling SK, Piccirillo CA, Sacks D, Belkaid Y. Role for CD4(+) CD25(+) regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity. J Exp Med. 2004;200:201–10.PubMedGoogle Scholar
  14. 14.
    Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res. 1999;59:3128–33.PubMedGoogle Scholar
  15. 15.
    Zhang H, Chua KS, Guimond M, Kapoor V, Brown MV, Fleisher TA, et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med. 2005;11:1238–43.PubMedGoogle Scholar
  16. 16.
    Powell DJ Jr, de Vries CR, Allen T, Ahmadzadeh M, Rosenberg SA. Inability to mediate prolonged reduction of regulatory T Cells after transfer of autologous CD25-depleted PBMC and interleukin-2 after lymphodepleting chemotherapy. J Immunother (1997). 2007;30:438–47.Google Scholar
  17. 17.
    Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, et al. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol. 2005;174:2591–601.PubMedGoogle Scholar
  18. 18.
    Krupica T Jr, Fry TJ, Mackall CL. Autoimmunity during lymphopenia: a two-hit model. Clin Immunol. 2006;120:121–8.PubMedGoogle Scholar
  19. 19.
    Rezvani K, Mielke S, Ahmadzadeh M, Kilical Y, Savani BN, Zeilah J, et al. High donor FOXP3–positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood 2006;108:1291–7.PubMedGoogle Scholar
  20. 20.
    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;196:389–99.PubMedGoogle Scholar
  21. 21.
    Nguyen VH, Shashidhar S, Chang DS, Ho L, Kambham N, Bachmann M, et al. The impact of regulatory T cells on T cell immunity following hematopoeitic cell transplantation. Blood 2007;111:945–53.Google Scholar
  22. 22.
    Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9:1144–50.PubMedGoogle Scholar
  23. 23.
    Zeiser R, Nguyen VH, Beilhack A, Buess M, Schulz S, Baker J, et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006;108:390–9.PubMedGoogle Scholar
  24. 24.
    LeBien TW. Fates of human B-cell precursors. Blood 2000;96:9–23.PubMedGoogle Scholar
  25. 25.
    Lyons AB, Parish CR. Determination of lymphocyte division by flow cytometry. J Immunol Methods. 1994;171:131–7.PubMedGoogle Scholar
  26. 26.
    Agenes F, Freitas AA. Transfer of small resting B cells into immunodeficient hosts results in the selection of a self-renewing activated B cell population. J Exp Med. 1999;189:319–30.PubMedGoogle Scholar
  27. 27.
    Agenes F, Rosado MM, Freitas AA. Independent homeostatic regulation of B cell compartments. Eur J Immunol. 1997;27:1801–7.PubMedGoogle Scholar
  28. 28.
    Cabatingan MS, Schmidt MR, Sen R, Woodland RT. Naive B lymphocytes undergo homeostatic proliferation in response to B cell deficit. J Immunol. 2002;169:6795–805.PubMedGoogle Scholar
  29. 29.
    van Zelm MC, Szczepanski T, van der Burg M, van Dongen JJ. Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion. J Exp Med. 2007;204:645–55.PubMedGoogle Scholar
  30. 30.
    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;396:690–5.PubMedGoogle Scholar
  31. 31.
    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;190:479–86.PubMedGoogle Scholar
  32. 32.
    Takeshita S, Toda M, Yamagishi H. Excision products of the T cell receptor gene support a progressive rearrangement model of the alpha/delta locus. Embo J. 1989;8:3261–70.PubMedGoogle Scholar
  33. 33.
    Ribeiro RM, Perelson AS. Determining thymic output quantitatively: using models to interpret experimental T-cell receptor excision circle (TREC) data. Immunol Rev. 2007;216:21–34.PubMedGoogle Scholar
  34. 34.
    Geenen V, Poulin JF, Dion ML, Martens H, Castermans E, Hansenne I, et al. Quantification of T cell receptor rearrangement excision circles to estimate thymic function: an important new tool for endocrine-immune physiology. J Endocrinol. 2003;176:305–11.PubMedGoogle Scholar
  35. 35.
    Mackall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med. 1995;332:143–9.PubMedGoogle Scholar
  36. 36.
    Shand JC, Mansky PJ, Brown MV, Fleisher TA, Mackall CL. Adolescents and young adults successfully restore lymphocyte homeostasis after intensive T-cell depleting therapy for cancer. Br J Haematol. 2006;135:270–1.PubMedGoogle Scholar
  37. 37.
    Buckley RH, Schiff SE, Schiff RI, Roberts JL, Markert ML, Peters W, et al. Haploidentical bone marrow stem cell transplantation in human severe combined immunodeficiency. Semin Hematol. 1993;30 Suppl 4:92–101; discussion 2–4.PubMedGoogle Scholar
  38. 38.
    Chung B, Barbara-Burnham L, Barsky L, Weinberg K. Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation. Blood 2001;98:1601–6.PubMedGoogle Scholar
  39. 39.
    Desbarats J, Lapp WS. Thymic selection and thymic major histocompatibility complex class II expression are abnormal in mice undergoing graft-versus-host reactions. J Exp Med. 1993;178:805–14.PubMedGoogle Scholar
  40. 40.
    Storek J, Joseph A, Dawson MA, Douek DC, Storer B, Maloney DG. Factors influencing T-lymphopoiesis after allogeneic hematopoietic cell transplantation. Transplantation 2002;73:1154–8.PubMedGoogle Scholar
  41. 41.
    Atkinson K, Hansen JA, Storb R, Goehle S, Goldstein G, Thomas ED. T-cell subpopulations identified by monoclonal antibodies after human marrow transplantation. I. Helper-inducer and cytotoxic-suppressor subsets. Blood 1982;59:1292–8.PubMedGoogle Scholar
  42. 42.
    Fry TJ, Christensen BL, Komschlies KL, Gress RE, Mackall CL. Interleukin-7 restores immunity in athymic T-cell-depleted hosts. Blood 2001;97:1525–33.PubMedGoogle Scholar
  43. 43.
    Daley JP, Rozans MK, Smith BR, Burakoff SJ, Rappeport JM, Miller RA. Retarded recovery of functional T cell frequencies in T cell-depleted bone marrow transplant recipients. Blood 1987;70:960–4.PubMedGoogle Scholar
  44. 44.
    Dey BR, Shaffer J, Yee AJ, McAfee S, Caron M, Power K, et al. Comparison of outcomes after transplantation of peripheral blood stem cells versus bone marrow following an identical nonmyeloablative conditioning regimen. Bone Marrow Transplant. 2007;40:19–27.PubMedGoogle Scholar
  45. 45.
    Koehl U, Bochennek K, Zimmermann SY, Lehrnbecher T, Sorensen J, Esser R, et al. Immune recovery in children undergoing allogeneic stem cell transplantation: absolute CD8+ CD3+ count reconstitution is associated with survival. Bone Marrow Transplant. 2007;39:269–78.PubMedGoogle Scholar
  46. 46.
    Powles R, Mehta J, Kulkarni S, Treleaven J, Millar B, Marsden J, et al. Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial. Lancet 2000;355:1231–7.PubMedGoogle Scholar
  47. 47.
    Roberts MM, To LB, Gillis D, Mundy J, Rawling C, Ng K, et al. Immune reconstitution following peripheral blood stem cell transplantation, autologous bone marrow transplantation and allogeneic bone marrow transplantation. Bone Marrow Transplant. 1993;12:469–75.PubMedGoogle Scholar
  48. 48.
    Dulude G, Roy DC, Perreault C. The effect of graft-versus-host disease on T cell production and homeostasis. J Exp Med. 1999;189:1329–42.PubMedGoogle Scholar
  49. 49.
    Gorski J, Chen X, Gendelman M, Yassai M, Krueger A, Tivol E, et al. Homeostatic expansion and repertoire regeneration of donor T cells during graft versus host disease is constrained by the host environment. Blood 2007;109:5502–10.PubMedGoogle Scholar
  50. 50.
    Small TN, Keever CA, Weiner-Fedus S, Heller G, O’Reilly RJ, Flomenberg N. B-cell differentiation following autologous, conventional, or T-cell depleted bone marrow transplantation: a recapitulation of normal B-cell ontogeny. Blood 1990;76:1647–56.PubMedGoogle Scholar
  51. 51.
    Storek J, Witherspoon RP, Storb R. Reconstitution of membrane IgD- (mIgD-) B cells after marrow transplantation lags behind the reconstitution of mIgD+ B cells. Blood 1997;89:350–1.PubMedGoogle Scholar
  52. 52.
    Hakim FT, Sharrow SO, Payne S, Shearer GM. Repopulation of host lymphohematopoietic systems by donor cells during graft-versus-host reaction in unirradiated adult F1 mice injected with parental lymphocytes. J Immunol. 1991;146:2108–15.PubMedGoogle Scholar
  53. 53.
    Storek J, Wells D, Dawson MA, Storer B, Maloney DG. Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation. Blood 2001;98:489–91.PubMedGoogle Scholar
  54. 54.
    Manz RA, Thiel A, Radbruch A. Lifetime of plasma cells in the bone marrow. Nature 1997;388:133–4.PubMedGoogle Scholar
  55. 55.
    Isaacs JD, Thiel A. Stem cell transplantation for autoimmune disorders. Immune reconstitution. Best Pract Res Clin Haematol. 2004;17:345–58.PubMedGoogle Scholar
  56. 56.
    Bolan CD, Leitman SF, Griffith LM, Wesley RA, Procter JL, Stroncek DF, et al. Delayed donor red cell chimerism and pure red cell aplasia following major ABO-incompatible nonmyeloablative hematopoietic stem cell transplantation. Blood 2001;98:1687–94.PubMedGoogle Scholar
  57. 57.
    Chalandon Y, Degermann S, Villard J, Arlettaz L, Kaiser L, Vischer S, et al. Pretransplantation CMV-specific T cells protect recipients of T-cell-depleted grafts against CMV-related complications. Blood 2006;107:389–96.PubMedGoogle Scholar
  58. 58.
    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;110:4543–51.Google Scholar
  59. 59.
    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;114:42–8.PubMedGoogle Scholar
  60. 60.
    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;96:2703–11.PubMedGoogle Scholar
  61. 61.
    Theilgaard-Monch K, Raaschou-Jensen K, Palm H, Schjodt K, Heilmann C, Vindelov L, et al. Flow cytometric assessment of lymphocyte subsets, lymphoid progenitors, and hematopoietic stem cells in allogeneic stem cell grafts. Bone Marrow Transplant. 2001;28:1073–82.PubMedGoogle Scholar
  62. 62.
    Goldrath AW, Bevan MJ. Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 1999;11:183–90.PubMedGoogle Scholar
  63. 63.
    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;12:1335–42.PubMedGoogle Scholar
  64. 64.
    Robin C, Bennaceur-Griscelli A, Louache F, Vainchenker W, Coulombel L. Identification of human T-lymphoid progenitor cells in CD34+ CD38low and CD34+ CD38+ subsets of human cord blood and bone marrow cells using NOD-SCID fetal thymus organ cultures. Br J Haematol. 1999;104:809–19.PubMedGoogle Scholar
  65. 65.
    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;100:1611–8.PubMedGoogle Scholar
  66. 66.
    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;29:371–9.PubMedGoogle Scholar
  67. 67.
    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;99:1458–64.PubMedGoogle Scholar
  68. 68.
    Kondo M, Weissman IL, Akashi K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 1997;91:661–72.PubMedGoogle Scholar
  69. 69.
    Arber C, BitMansour A, Sparer TE, Higgins JP, Mocarski ES, Weissman IL, et al. Common lymphoid progenitors rapidly engraft and protect against lethal murine cytomegalovirus infection after hematopoietic stem cell transplantation. Blood 2003;102:421–8.PubMedGoogle Scholar
  70. 70.
    Allman D, Sambandam A, Kim S, Miller JP, Pagan A, Well D, et al. Thymopoiesis independent of common lymphoid progenitors. Nat Immunol. 2003;4:168–74.PubMedGoogle Scholar
  71. 71.
    Sambandam A, Maillard I, Zediak VP, Xu L, Gerstein RM, Aster JC, et al. Notch signaling controls the generation and differentiation of early T lineage progenitors. Nat Immunol. 2005;6:663–70.PubMedGoogle Scholar
  72. 72.
    Bhandoola A, Sambandam A. From stem cell to T cell: one route or many? Nat Rev Immunol. 2006;6:117–26.PubMedGoogle Scholar
  73. 73.
    Ohishi K, Varnum-Finney B, Bernstein ID. Delta-1 enhances marrow and thymus repopulating ability of human CD34(+)CD38(–) cord blood cells. J Clin Invest. 2002;110:1165–74.PubMedGoogle Scholar
  74. 74.
    Schmitt TM, de Pooter RF, Gronski MA, Cho SK, Ohashi PS, Zuniga-Pflucker JC. Induction of T cell development and establishment of T cell competence from embryonic stem cells differentiated in vitro. Nat Immunol. 2004;5:410–7.PubMedGoogle Scholar
  75. 75.
    Schmitt TM, Zuniga-Pflucker JC. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 2002;17:749–56.PubMedGoogle Scholar
  76. 76.
    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;12:1039–47.PubMedGoogle Scholar
  77. 77.
    Hao QL, Zhu J, Price MA, Payne KJ, Barsky LW, Crooks GM. Identification of a novel, human multilymphoid progenitor in cord blood. Blood 2001;97:3683–90.PubMedGoogle Scholar
  78. 78.
    Fry TJ, Sinha M, Milliron M, Chu YW, Kapoor V, Gress RE, et al. Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution. Blood 2004;104:2794–800.PubMedGoogle Scholar
  79. 79.
    von Freeden-Jeffry U, Vieira P, Lucian LA, McNeil T, Burdach SE, Murray R. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med. 1995;181:1519–26.Google Scholar
  80. 80.
    Plum J, De Smedt M, Leclercq G, Verhasselt B, Vandekerckhove B. Interleukin-7 is a critical growth factor in early human T-cell development. Blood 1996;88:4239–45.PubMedGoogle Scholar
  81. 81.
    Alpdogan O, Muriglan SJ, Eng JM, Willis LM, Greenberg AS, Kappel BJ, et al. IL-7 enhances peripheral T cell reconstitution after allogeneic hematopoietic stem cell transplantation. J Clin Invest. 2003;112:1095–107.PubMedGoogle Scholar
  82. 82.
    Boerman OC, Gregorio TA, Grzegorzewski KJ, Faltynek CR, Kenny JJ, Wiltrout RH, et al. Recombinant human IL-7 administration in mice affects colony-forming units-spleen and lymphoid precursor cell localization and accelerates engraftment of bone marrow transplants. J Leukoc Biol. 1995;58:151–8.PubMedGoogle Scholar
  83. 83.
    Bolotin E, Smogorzewska M, Smith S, Widmer M, Weinberg K. Enhancement of thymopoiesis after bone marrow transplant by in vivo interleukin-7. Blood 1996;88:1887–94.PubMedGoogle Scholar
  84. 84.
    Mackall CL, Fry TJ, Bare C, Morgan P, Galbraith A, Gress RE. IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation. Blood 2001;97:1491–7.PubMedGoogle Scholar
  85. 85.
    Storek J, Gillespy T, 3rd, Lu H, Joseph A, Dawson MA, Gough M, et al. Interleukin-7 improves CD4 T-cell reconstitution after autologous CD34 cell transplantation in monkeys. Blood 2003;101:4209–18.PubMedGoogle Scholar
  86. 86.
    Fry TJ, Moniuszko M, Creekmore S, Donohue SJ, Douek DC, Giardina S, et al. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. Blood 2003;101:2294–9.PubMedGoogle Scholar
  87. 87.
    Sinha ML, Fry TJ, Fowler DH, Miller G, Mackall CL. Interleukin 7 worsens graft-versus-host disease. Blood 2002;100:2642–9.PubMedGoogle Scholar
  88. 88.
    Blazar BR, McKenna HJ, Panoskaltsis-Mortari A, Taylor PA. Flt3 ligand (FL) treatment of murine donors does not modify graft-versus-host disease (GVHD) but FL treatment of recipients post-bone marrow transplantation accelerates GVHD lethality. Biol Blood Marrow Transplant. 2001;7:197–207.PubMedGoogle Scholar
  89. 89.
    Alpdogan O, Schmaltz C, Muriglan SJ, Kappel BJ, Perales MA, Rotolo JA, et al. Administration of interleukin-7 after allogeneic bone marrow transplantation improves immune reconstitution without aggravating graft-versus-host disease. Blood 2001;98:2256–65.PubMedGoogle Scholar
  90. 90.
    Alpdogan O, Eng JM, Muriglan SJ, Willis LM, Hubbard VM, Tjoe KH, et al. Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. Blood 2005;105:865–73.PubMedGoogle Scholar
  91. 91.
    Katsanis E, Xu Z, Panoskaltsis-Mortari A, Weisdorf DJ, Widmer MB, Blazar BR. IL-15 administration following syngeneic bone marrow transplantation prolongs survival of lymphoma bearing mice. Transplantation 1996;62:872–5.PubMedGoogle Scholar
  92. 92.
    Chen X, Barfield R, Benaim E, Leung W, Knowles J, Lawrence D, et al. Prediction of T-cell reconstitution by assessment of T-cell receptor excision circle before allogeneic hematopoietic stem cell transplantation in pediatric patients. Blood 2005;105:886–93.PubMedGoogle Scholar
  93. 93.
    Tomita Y, Khan A, Sykes M. Role of intrathymic clonal deletion and peripheral anergy in transplantation tolerance induced by bone marrow transplantation in mice conditioned with a nonmyeloablative regimen. J Immunol. 1994;153:1087–98.PubMedGoogle Scholar
  94. 94.
    Hollander GA, Wang B, Nichogiannopoulou A, Platenburg PP, van Ewijk W, Burakoff SJ, et al. Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 1995;373:350–3.PubMedGoogle Scholar
  95. 95.
    Lind EF, Prockop SE, Porritt HE, Petrie HT. Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J Exp Med. 2001;194:127–34.PubMedGoogle Scholar
  96. 96.
    Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M, et al. Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 2001;97:1458–66.PubMedGoogle Scholar
  97. 97.
    Rubin JS, Osada H, Finch PW, Taylor WG, Rudikoff S, Aaronson SA. Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci USA. 1989;86:802–6.PubMedGoogle Scholar
  98. 98.
    Min D, Taylor PA, Panoskaltsis-Mortari A, Chung B, Danilenko DM, Farrell C, et al. Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood 2002;99:4592–600.PubMedGoogle Scholar
  99. 99.
    Rossi S, Blazar BR, Farrell CL, Danilenko DM, Lacey DL, Weinberg KI, et al. Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease. Blood 2002;100:682–91.PubMedGoogle Scholar
  100. 100.
    Alpdogan O, Hubbard VM, Smith OM, Patel N, Lu S, Goldberg GL, et al. Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood 2006;107:2453–60.PubMedGoogle Scholar
  101. 101.
    Rossi SW, Jeker LT, Ueno T, Kuse S, Keller MP, Zuklys S, et al. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood 2007;109:3803–11.PubMedGoogle Scholar
  102. 102.
    Min D, Panoskaltsis-Mortari A, Kuro OM, Hollander GA, Blazar BR, Weinberg KI. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 2007;109:2529–37.PubMedGoogle Scholar
  103. 103.
    Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202:907–12.PubMedGoogle Scholar
  104. 104.
    Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP. Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005;26:111–7.PubMedGoogle Scholar
  105. 105.
    Wrzesinski C, Paulos CM, Gattinoni L, Palmer DC, Kaiser A, Yu Z, et al. Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest. 2007;117:492–501.PubMedGoogle Scholar
  106. 106.
    Heslop HE, Ng CY, Li C, Smith CA, Loftin SK, Krance RA, et al. Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat Med. 1996;2:551–5.PubMedGoogle Scholar
  107. 107.
    Peggs KS, Verfuerth S, Pizzey A, Khan N, Guiver M, Moss PA, et al. Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet 2003;362:1375–7.PubMedGoogle Scholar
  108. 108.
    Feuchtinger T, Matthes-Martin S, Richard C, Lion T, Fuhrer M, Hamprecht K, et al. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br J Haematol. 2006;134:64–76.PubMedGoogle Scholar
  109. 109.
    Leen AM, Myers GD, Sili U, Huls MH, Weiss H, Leung KS, et al. Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat Med. 2006;12:1160–6.PubMedGoogle Scholar
  110. 110.
    Rauser G, Einsele H, Sinzger C, Wernet D, Kuntz G, Assenmacher M, et al. Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants. Blood 2004;103:3565–72.PubMedGoogle Scholar
  111. 111.
    Szmania S, Galloway A, Bruorton M, Musk P, Aubert G, Arthur A, et al. Isolation and expansion of cytomegalovirus-specific cytotoxic T lymphocytes to clinical scale from a single blood draw using dendritic cells and HLA-tetramers. Blood 2001;98:505–12.PubMedGoogle Scholar
  112. 112.
    Cobbold M, Khan N, Pourgheysari B, Tauro S, McDonald D, Osman H, et al. Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J Exp Med. 2005;202:379–86.PubMedGoogle Scholar
  113. 113.
    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;108:1770–3.PubMedGoogle Scholar
  114. 114.
    Rosenberg SA, Sportes C, Ahmadzadeh M, Fry TJ, Ngo LT, Schwarz SL, et al. IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells. J Immunother (1997). 2006;29:313–9.Google Scholar
  115. 115.
    Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002;298:850–4.PubMedGoogle Scholar
  116. 116.
    Becker C, Pohla H, Frankenberger B, Schuler T, Assenmacher M, Schendel DJ, et al. Adoptive tumor therapy with T lymphocytes enriched through an IFN-gamma capture assay. Nat Med. 2001;7:1159–62.PubMedGoogle Scholar
  117. 117.
    Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006;314:126–9.PubMedGoogle Scholar
  118. 118.
    Stanislawski T, Voss RH, Lotz C, Sadovnikova E, Willemsen RA, Kuball J, et al. Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat Immunol. 2001;2:962–70.PubMedGoogle Scholar
  119. 119.
    Bozza S, Perruccio K, Montagnoli C, Gaziano R, Bellocchio S, Burchielli E, et al. A dendritic cell vaccine against invasive aspergillosis in allogeneic hematopoietic transplantation. Blood 2003;102:3807–14.PubMedGoogle Scholar
  120. 120.
    Rapoport AP, Stadtmauer EA, Aqui N, Badros A, Cotte J, Chrisley L, et al. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med. 2005;11:1230–7.PubMedGoogle Scholar
  121. 121.
    Prlic M, Blazar BR, Khoruts A, Zell T, Jameson SC. Homeostatic expansion occurs independently of costimulatory signals. J Immunol. 2001;167:5664–8.PubMedGoogle Scholar
  122. 122.
    Amrolia PJ, Muccioli-Casadei G, Huls H, Adams S, Durett A, Gee A, et al. Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. Blood 2006;108:1797–808.PubMedGoogle Scholar
  123. 123.
    Andre-Schmutz I, Le Deist F, Hacein-Bey-Abina S, Vitetta E, Schindler J, Chedeville G, et al. Immune reconstitution without graft-versus-host disease after haemopoietic stem-cell transplantation: a phase 1/2 study. Lancet 2002;360:130–7.PubMedGoogle Scholar
  124. 124.
    Solomon SR, Mielke S, Savani BN, Montero A, Wisch L, Childs R, et al. Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation. Blood 2005;106:1123–9.PubMedGoogle Scholar
  125. 125.
    Amrolia PJ, Muccioli-Casadei G, Yvon E, Huls H, Sili U, Wieder ED, et al. Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses. Blood 2003;102:2292–9.PubMedGoogle Scholar
  126. 126.
    Martins SL, St 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;104:3429–36.PubMedGoogle Scholar
  127. 127.
    Michalek J, Collins RH, Durrani HP, Vaclavkova P, Ruff LE, Douek DC, et al. Definitive separation of graft-versus-leukemia- and graft-versus-host-specific CD4+ T cells by virtue of their receptor beta loci sequences. Proc Natl Acad Sci USA. 2003;100:1180–4.PubMedGoogle Scholar
  128. 128.
    Mielke S, Rezvani K, Savani BN, Nunes R, Yong AS, Schindler J, et al. Reconstitution of FOXP3+ regulatory T cells (Tregs) after CD25-depleted allotransplantation in elderly patients and association with acute graft-versus-host disease. Blood 2007 Sep 1;110(5):1689–97.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Karl S. Peggs
    • 1
  • Aviva C. Krauss
  • Crystal L. Mackall
  1. 1.Royal Free and University College London Medical SchoolsLondonUK

Personalised recommendations