Skip to main content

Clinical Implications of Immune Reconstitution Following Hematopoietic Stem Cell Transplantation

  • Chapter
  • First Online:
Hematopoietic Stem Cell Transplantation

Part of the book series: Cancer Treatment and Research ((CTAR,volume 144))

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  10. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057–61.

    PubMed  CAS  Google Scholar 

  11. Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8:191–7.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  18. Krupica T Jr, Fry TJ, Mackall CL. Autoimmunity during lymphopenia: a two-hit model. Clin Immunol. 2006;120:121–8.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  24. LeBien TW. Fates of human B-cell precursors. Blood 2000;96:9–23.

    PubMed  CAS  Google Scholar 

  25. Lyons AB, Parish CR. Determination of lymphocyte division by flow cytometry. J Immunol Methods. 1994;171:131–7.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  27. Agenes F, Rosado MM, Freitas AA. Independent homeostatic regulation of B cell compartments. Eur J Immunol. 1997;27:1801–7.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  54. Manz RA, Thiel A, Radbruch A. Lifetime of plasma cells in the bone marrow. Nature 1997;388:133–4.

    PubMed  CAS  Google Scholar 

  55. Isaacs JD, Thiel A. Stem cell transplantation for autoimmune disorders. Immune reconstitution. Best Pract Res Clin Haematol. 2004;17:345–58.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  68. Kondo M, Weissman IL, Akashi K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 1997;91:661–72.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  72. Bhandoola A, Sambandam A. From stem cell to T cell: one route or many? Nat Rev Immunol. 2006;6:117–26.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  87. Sinha ML, Fry TJ, Fowler DH, Miller G, Mackall CL. Interleukin 7 worsens graft-versus-host disease. Blood 2002;100:2642–9.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  121. Prlic M, Blazar BR, Khoruts A, Zell T, Jameson SC. Homeostatic expansion occurs independently of costimulatory signals. J Immunol. 2001;167:5664–8.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Karl S. Peggs .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Peggs, K.S., Krauss, A.C., Mackall, C.L. (2009). Clinical Implications of Immune Reconstitution Following Hematopoietic Stem Cell Transplantation. In: Bishop, M. (eds) Hematopoietic Stem Cell Transplantation. Cancer Treatment and Research, vol 144. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-78580-6_6

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-78580-6_6

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-387-78579-0

  • Online ISBN: 978-0-387-78580-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics