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Immune Reconstitution and Implications for Immunotherapy Following Hematopoeitic Stem Cell Transplantation

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Allogeneic Stem Cell Transplantation

Part of the book series: Contemporary Hematology ((CH))

Abstract

The innate immune system comprises a collection of cells that recognize and eradicate pathogens or aberrant cells without priming or antigen presentation. Natural killer cells, neutrophils, monocytes, dendritic cells, and macrophages contribute to innate immunity. Natural killer (NK) cells purge tumor or virus-infected cells. By one month post-transplant, natural killer cells circulate at normal levels and confer adept immune protection [1-6] (see Fig. 31-1). These donor derived NK cell clones effectively lyse recipient leukemia in vitro [7]. Studies have also shown that the number of natural killer cells, early posttransplant, correlate with remission rates, implicating the function of these early cells in the clearance of residual tumor [8-10]. Data also suggest that killer immunoglobulin-like receptor (KIR) mismatch may play a critical role in NK cell-mediated tumor eradication [7, 9]. Many, but not all, studies have associated NK cell KIR mismatch with protection from relapse and GVHD in HLA haplotype-mismatched and matched unrelated transplants for myeloid and acute lymphoid malignancies [9, 11, 12].

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References

  1. Eyrich M, Leiler C, Lang P, Schilbach K, Schumm M, Bader P et al (2003) A prospective comparison of immune reconstitution in pediatric recipients of positively selected CD34+ peripheral blood stem cells from unrelated donors vs recipients of unmanipulated bone marrow from related donors. Bone Marrow Transplant 32(4):379-390

    PubMed  CAS  Google Scholar 

  2. Martinez C, Urbano-Ispizua A, Rozman C, Marin P, Rovira M, Sierra J et al (1999) Immune reconstitution following allogeneic peripheral blood progenitor cell transplantation: comparison of recipients of positive CD34+ selected grafts with recipients of unmanipulated grafts. Exp Hematol 27(3):561-568

    PubMed  CAS  Google Scholar 

  3. Tayebi H, Tiberghien P, Ferrand C, Lienard A, Duperrier A, Cahn JY et al (2001) Allogeneic peripheral blood stem cell transplantation results in less alteration of early T cell compartment homeostasis than bone marrow transplantation. Bone Marrow Transplant 27(2):167-175

    PubMed  CAS  Google Scholar 

  4. Maris M, Boeckh M, Storer B, Dawson M, White K, Keng M et al (2003) Immunologic recovery after hematopoietic cell transplantation with nonmyeloablative conditioning. Exp Hematol 31(10):941-952

    PubMed  CAS  Google Scholar 

  5. Petersen SL, Ryder LP, Bjork P, Madsen HO, Heilmann C, Jacobsen N et al (2003) A comparison of T-, B- and NK-cell reconstitution following conventional or nonmyeloablative conditioning and transplantation with bone marrow or peripheral blood stem cells from human leucocyte antigen identical sibling donors. Bone Marrow Transplant 32(1):65-72

    PubMed  CAS  Google Scholar 

  6. Kalwak K, Gorczynska E, Toporski J, Turkiewicz D, Slociak M, Ussowicz M et al (2002) Immune reconstitution after haematopoietic cell transplantation in children: immunophenotype analysis with regard to factors affecting the speed of recovery. Br J Haematol 118(1):74-89

    PubMed  CAS  Google Scholar 

  7. Ruggeri L, Capanni M, Casucci M, Volpi I, Tosti A, Perruccio K et al (1999) Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood 94(1):333-339

    PubMed  CAS  Google Scholar 

  8. Savani BN, Rezvani K, Mielke S, Montero A, Kurlander R, Carter CS et al (2006) Factors associated with early molecular remission after T cell-depleted allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 107(4):1688-1695

    PubMed  CAS  Google Scholar 

  9. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295(5562):2097-2100

    PubMed  CAS  Google Scholar 

  10. Uharek L, Zeis M, Glass B, Steinmann J, Dreger P, Gassmann W et al (1996) High lytic activity against human leukemia cells after activation of allogeneic NK cells by IL-12 and IL-2. Leukemia 10(11):1758-1764

    PubMed  CAS  Google Scholar 

  11. Farag SS, Bacigalupo A, Eapen M, Hurley C, Dupont B, Caligiuri MA et al (2006) The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. Biol Blood Marrow Transplant 12(8):876-884

    PubMed  CAS  Google Scholar 

  12. Giebel S, Locatelli F, Lamparelli T, Velardi A, Davies S, Frumento G et al (2003) Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 102(3):814-819

    PubMed  CAS  Google Scholar 

  13. Jimenez M, Martinez C, Ercilla G, Carreras E, Urbano-Ispizua A, Aymerich M et al (2005) Reduced-intensity conditioning regimen preserves thymic function in the early period after hematopoietic stem cell transplantation. Exp Hematol 33(10):1240-1248

    PubMed  CAS  Google Scholar 

  14. Larosa F, Marmier C, Robinet E, Ferrand C, Saas P, Deconinck E et al (2005) Peripheral T-cell expansion and low infection rate after reduced-intensity conditioning and allogeneic blood stem cell transplantation. Bone Marrow Transplant 35(9):859-868

    PubMed  CAS  Google Scholar 

  15. Oehler VG, Radich JP, Storer B, Blume KG, Chauncey T, Clift R et al (2005) Randomized trial of allogeneic related bone marrow transplantation versus peripheral blood stem cell transplantation for chronic myeloid leukemia. Biol Blood Marrow Transplant 11(2):85-92

    PubMed  Google Scholar 

  16. Powles R, Mehta J, Kulkarni S, Treleaven J, Millar B, Marsden J et al (2000) Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial. Lancet 355(9211):1231-1237

    PubMed  CAS  Google Scholar 

  17. Busca A, Lovisone E, Aliberti S, Locatelli F, Serra A, Scaravaglio P et al (2003) Immune reconstitution and early infectious complications following nonmyeloablative hematopoietic stem cell transplantation. Hematology 8(5):303-311

    PubMed  CAS  Google Scholar 

  18. Yu LC, Wall DA, Sandler E, Chan KW, Grayson G, Kletzel M (2001) Unrelated cord blood transplant experience by the pediatric blood and marrow transplant consortium. Pediatr Hematol Oncol 18(4):235-245

    PubMed  CAS  Google Scholar 

  19. Roux E, Dumont-Girard F, Starobinski M, Siegrist CA, Helg C, Chapuis B et al (2000) Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood 96(6):2299-2303

    PubMed  CAS  Google Scholar 

  20. Storek J, Dawson MA, Storer B, Stevens-Ayers T, Maloney DG, Marr KA et al (2001) Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 97(11):3380-3389

    PubMed  CAS  Google Scholar 

  21. Klangsinsirikul P, Carter GI, Byrne JL, Hale G, Russell NH (2002) Campath-1G causes rapid depletion of circulating host dendritic cells (DCs) before allogeneic transplantation but does not delay donor DC reconstitution. Blood 99(7):2586-2591

    PubMed  CAS  Google Scholar 

  22. Chklovskaia E, Nowbakht P, Nissen C, Gratwohl A, Bargetzi M, Wodnar-Filipowicz A (2004) Reconstitution of dendritic and natural killer-cell subsets after allogeneic stem cell transplantation: effects of endogenous flt3 ligand. Blood 103(10):3860-3868

    PubMed  CAS  Google Scholar 

  23. Bogunovic M, Ginhoux F, Wagers A, Loubeau M, Isola LM, Lubrano L et al (2006) Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men. J Exp Med 203(12):2627-2638

    PubMed  CAS  Google Scholar 

  24. Auffermann-Gretzinger S, Eger L, Bornhauser M, Schakel K, Oelschlaegel U, Schaich M et al (2006) Fast appearance of donor dendritic cells in human skin: dynamics of skin and blood dendritic cells after allogeneic hematopoietic cell transplantation. Transplantation 81(6):866-873

    PubMed  Google Scholar 

  25. Auffermann-Gretzinger S, Lossos IS, Vayntrub TA, Leong W, Grumet FC, Blume KG et al (2002) Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients. Blood 99(4):1442-1448

    PubMed  CAS  Google Scholar 

  26. Kumar D, Chen MH, Welsh B, Siegal D, Cobos I, Messner HA et al (2007) A randomized, double-blind trial of pneumococcal vaccination in adult allogeneic stem cell transplant donors and recipients. Clin Infect Dis 45(12):1576-1582

    PubMed  Google Scholar 

  27. Grigoleit GU, Kapp M, Hebart H, Fick K, Beck R, Jahn G et al (2007) Dendritic cell vaccination in allogeneic stem cell recipients: induction of human cytomegalovirus (HCMV)-specific cytotoxic T lymphocyte responses even in patients receiving a transplant from an HCMV-seronegative donor. J Infect Dis 196(5):699-704

    PubMed  Google Scholar 

  28. Nashida Y, Kumamoto T, Azuma E, Hirayama M, Araki M, Yamada H et al (2006) Development of a dendritic cell vaccine against measles for patients following hematopoietic cell transplantation. Transplantation 82(8):1104-1107

    PubMed  CAS  Google Scholar 

  29. Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F et al (1998) Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 339(17):1186-1193

    PubMed  CAS  Google Scholar 

  30. Mackall CL, Gress RE (1997) Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy. Immunol Rev 157:61-72

    PubMed  CAS  Google Scholar 

  31. Godthelp BC, van Tol MJ, Vossen JM, van Den Elsen PJ (1999) T-Cell immune reconstitution in pediatric leukemia patients after allogeneic bone marrow transplantation with T-cell-depleted or unmanipulated grafts: evaluation of overall and antigen-specific T-cell repertoires. Blood 94(12):4358-4369

    PubMed  CAS  Google Scholar 

  32. Storek J, Ferrara S, Ku N, Giorgi JV, Champlin RE, Saxon A (1993) B cell reconstitution after human bone marrow transplantation: recapitulation of ontogeny? Bone Marrow Transplant 12(4):387-398

    PubMed  CAS  Google Scholar 

  33. Shenoy S, Mohanakumar T, Todd G, Westhoff W, Dunnigan K, Adkins DR et al (1999) Immune reconstitution following allogeneic peripheral blood stem cell transplants. Bone Marrow Transplant 23(4):335-346

    PubMed  CAS  Google Scholar 

  34. Storek J, Joseph A, Espino G, Dawson MA, Douek DC, Sullivan KM et al (2001) Immunity of patients surviving 20 to 30 years after allogeneic or syngeneic bone marrow transplantation. Blood 98(13):3505-3512

    PubMed  CAS  Google Scholar 

  35. Suzuki I, Milner EC, Glas AM, Hufnagle WO, Rao SP, Pfister L et al (1996) Immunoglobulin heavy chain variable region gene usage in bone marrow transplant recipients: lack of somatic mutation indicates a maturational arrest. Blood 87(5):1873-1880

    PubMed  CAS  Google Scholar 

  36. Storek J, Witherspoon RP, Storb R (1997) Reconstitution of membrane IgD- (mIgD-) B cells after marrow transplantation lags behind the reconstitution of mIgD+ B cells. Blood 89(1):350-351

    PubMed  CAS  Google Scholar 

  37. Hajdu M, Puskas E, Sipos A, Barta A, Paloczi K, Uher F (2003) Homogeneous immunoglobulins following allogeneic bone marrow transplantation. Acta Haematol 109(3):124-128

    PubMed  CAS  Google Scholar 

  38. Griffith LM, McCoy JP Jr, Bolan CD, Stroncek DF, Pickett AC, Linton GF et al (2005) Persistence of recipient plasma cells and anti-donor isohaemagglutinins in patients with delayed donor erythropoiesis after major ABO incompatible non-myeloablative haematopoietic cell transplantation. Br J Haematol 128(5):668-675

    PubMed  CAS  Google Scholar 

  39. van Oosterhout M, Verburg RJ, Levarht EW, Moolenburgh JD, Barge RM, Fibbe WE et al (2005) High dose chemotherapy and syngeneic stem cell transplantation in a patient with refractory rheumatoid arthritis: poor response associated with persistence of host autoantibodies and synovial abnormalities. Ann Rheum Dis 64(12):1783-1785

    PubMed  Google Scholar 

  40. Omazic B, Lundkvist I, Mattsson J, Permert J, Nasman-Bjork I (2003) Memory B lymphocytes determine repertoire oligoclonality early after haematopoietic stem cell transplantation. Clin Exp Immunol 134(1):159-166

    PubMed  CAS  Google Scholar 

  41. Gokmen E, Raaphorst FM, Boldt DH, Teale JM (1998) Ig heavy chain third complementarity determining regions (H CDR3s) after stem cell transplantation do not resemble the developing human fetal H CDR3s in size distribution and Ig gene utilization. Blood 92(8):2802-2814

    PubMed  CAS  Google Scholar 

  42. Glas AM, van Montfort EH, Storek J, Green EG, Drissen RP, Bechtold VJ et al (2000) B-cell-autonomous somatic mutation deficit following bone marrow transplant. Blood 96(3):1064-1069

    PubMed  CAS  Google Scholar 

  43. Storek J, Espino G, Dawson MA, Storer B, Flowers ME, Maloney DG (2000) Low B-cell and monocyte counts on day 80 are associated with high infection rates between days 100 and 365 after allogeneic marrow transplantation. Blood 96(9):3290-3293

    PubMed  CAS  Google Scholar 

  44. Avanzini MA, Carra AM, Maccario R, Zecca M, Zecca G, Pession A et al (1998) Immunization with Haemophilus influenzae type b conjugate vaccine in children given bone marrow transplantation: comparison with healthy age-matched controls. J Clin Immunol 18(3):193-201

    PubMed  CAS  Google Scholar 

  45. Mackall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM et al (1995) Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 332(3):143-149

    PubMed  CAS  Google Scholar 

  46. Mackall CL, Granger L, Sheard MA, Cepeda R, Gress RE (1993) T-cell regeneration after bone marrow transplantation: differential CD45 isoform expression on thymic-derived versus thymic-independent progeny. Blood 82(8):2585-2594

    PubMed  CAS  Google Scholar 

  47. Hakim FT, Memon SA, Cepeda R, Jones EC, Chow CK, Kasten-Sportes C et al (2005) Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 115(4):930-939

    PubMed  CAS  Google Scholar 

  48. Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L et al (2000) Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355(9218):1875-1881

    PubMed  CAS  Google Scholar 

  49. Wu CJ, Chillemi A, Alyea EP, Orsini E, Neuberg D, Soiffer RJ et al (2000) Reconstitution of T-cell receptor repertoire diversity following T-cell depleted allogeneic bone marrow transplantation is related to hematopoietic chimerism. Blood 95(1):352-359

    PubMed  CAS  Google Scholar 

  50. Fry TJ, Mackall CL (2005) The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J Immunol 174(11):6571-6576

    PubMed  CAS  Google Scholar 

  51. Fry TJ, Moniuszko M, Creekmore S, Donohue SJ, Douek DC, Giardina S et al (2003) IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. Blood 101(6):2294-2299

    PubMed  CAS  Google Scholar 

  52. Rosenberg SA, Sportes C, Ahmadzadeh M, Fry TJ, Ngo LT, Schwarz SL et al (2006) IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells. J Immunother 29(3):313-319

    PubMed  CAS  Google Scholar 

  53. Bolotin E, Annett G, Parkman R, Weinberg K (1999) Serum levels of IL-7 in bone marrow transplant recipients: relationship to clinical characteristics and lymphocyte count. Bone Marrow Transplant 23(8):783-788

    PubMed  CAS  Google Scholar 

  54. Fry TJ, Connick E, Falloon J, Lederman MM, Liewehr DJ, Spritzler J et al (2001) A potential role for interleukin-7 in T-cell homeostasis. Blood 97(10):2983-2990

    PubMed  CAS  Google Scholar 

  55. Li Y, Zhi W, Wareski P, Weng NP (2005) IL-15 activates telomerase and minimizes telomere loss and may preserve the replicative life span of memory CD8+ T cells in vitro. J Immunol 174(7):4019-4024

    PubMed  CAS  Google Scholar 

  56. Anichini A, Scarito A, Molla A, Parmiani G, Mortarini R (2003) Differentiation of CD8+ T cells from tumor-invaded and tumor-free lymph nodes of melanoma patients: role of common gamma-chain cytokines. J Immunol 171(4):2134-2141

    PubMed  CAS  Google Scholar 

  57. Cooley S, June CH, Schoenberger SP, Miller JS (2007) Adoptive therapy with T Cells/NK cells. Biol Blood Marrow Transplant 13(Suppl 1):33-42

    CAS  Google Scholar 

  58. Hakim FT, Cepeda R, Kaimei S, Mackall CL, McAtee N, Zujewski J et al (1997) Constraints on CD4 recovery postchemotherapy in adults: thymic insufficiency and apoptotic decline of expanded peripheral CD4 cells. Blood 90(9):3789-3798

    PubMed  CAS  Google Scholar 

  59. Mackall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM et al (1997) Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy. Blood 89(10):3700-3707

    PubMed  CAS  Google Scholar 

  60. Ferrari V, Cacere CR, Machado CM, Pannuti CS, Dulley FL, Barros JC et al (2006) Distinct patterns of regeneration of central memory, effector memory and effector TCD8+ cell subsets after different hematopoietic cell transplant types: possible influence in the recovery of anti-cytomegalovirus immune response and risk for its reactivation. Clin Immunol 119(3):261-271

    PubMed  CAS  Google Scholar 

  61. Tan JT, Dudl E, LeRoy E, Murray R, Sprent J, Weinberg KI et al (2001) IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad Sci USA 98(15):8732-8737

    PubMed  CAS  Google Scholar 

  62. Schluns KS, Williams K, Ma A, Zheng XX, Lefrancois L (2002) Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol 168(10):4827-4831

    PubMed  CAS  Google Scholar 

  63. Geginat J, Lanzavecchia A, Sallusto F (2003) Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood 101(11):4260-4266

    PubMed  CAS  Google Scholar 

  64. Lucas PJ, Kim SJ, Melby SJ, Gress RE (2000) Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor beta II receptor. J Exp Med 191(7):1187-1196

    PubMed  CAS  Google Scholar 

  65. Lucas PJ, McNeil N, Hilgenfeld E, Choudhury B, Kim SJ, Eckhaus MA et al (2004) Transforming growth factor-beta pathway serves as a primary tumor suppressor in CD8+ T cell tumorigenesis. Cancer Res 64(18):6524-6529

    PubMed  CAS  Google Scholar 

  66. Lucas PJ, Kim SJ, Mackall CL, Telford WG, Chu YW, Hakim FT et al (2006) Dysregulation of IL-15-mediated T-cell homeostasis in TGF-beta dominant-negative receptor transgenic mice. Blood 108(8):2789-2795

    PubMed  CAS  Google Scholar 

  67. Ahmadzadeh M, Rosenberg SA (2005) TGF-beta 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol 174(9):5215-5223

    PubMed  CAS  Google Scholar 

  68. Shen S, Ding Y, Tadokoro CE, Olivares-Villagomez D, Camps-Ramirez M, Curotto de Lafaille MA et al (2005) Control of homeostatic proliferation by regulatory T cells. J Clin Invest 115(12):3517-3526

    PubMed  CAS  Google Scholar 

  69. Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S et al (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203(7):1701-1711

    PubMed  CAS  Google Scholar 

  70. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z et al (2006) Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212:8-27

    PubMed  CAS  Google Scholar 

  71. Rezvani K, Mielke S, Ahmadzadeh M, Kilical Y, Savani BN, Zeilah J et al (2006) High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood 108(4):1291-1297

    PubMed  CAS  Google Scholar 

  72. Zhang H, Chua KS, Guimond M, Kapoor V, Brown MV, Fleisher TA et al (2005) Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med 11(11):1238-1243

    PubMed  CAS  Google Scholar 

  73. Mackall CL, Bare CV, Granger LA, Sharrow SO, Titus JA, Gress RE (1996) 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 156(12):4609-4616

    PubMed  CAS  Google Scholar 

  74. Min B, McHugh R, Sempowski GD, Mackall C, Foucras G, Paul WE (2003) Neonates support lymphopenia-induced proliferation. Immunity 18(1):131-140

    PubMed  CAS  Google Scholar 

  75. Min B, Paul WE (2005) Endogenous proliferation: burst-like CD4 T cell proliferation in lymphopenic settings. Semin Immunol 17(3):201-207

    PubMed  CAS  Google Scholar 

  76. Chalandon Y, Degermann S, Villard J, Arlettaz L, Kaiser L, Vischer S et al (2006) Pretransplantation CMV-specific T cells protect recipients of T-cell-depleted grafts against CMV-related complications. Blood 107(1):389-396

    PubMed  CAS  Google Scholar 

  77. Ganepola S, Gentilini C, Hilbers U, Lange T, Rieger K, Hofmann J et al (2007) Patients at high risk for CMV infection and disease show delayed CD8+ T-cell immune recovery after allogeneic stem cell transplantation. Bone Marrow Transplant 39(5):293-299

    PubMed  CAS  Google Scholar 

  78. Hazenberg MD, Otto SA, de Pauw ES, Roelofs H, Fibbe WE, Hamann D et al (2002) T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events. Blood 99(9):3449-3453

    PubMed  CAS  Google Scholar 

  79. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ et al (2005) Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med 202(7):907-912

    PubMed  CAS  Google Scholar 

  80. Borrello I, Sotomayor EM, Rattis FM, Cooke SK, Gu L, Levitsky HI (2000) Sustaining the graft-versus-tumor effect through posttransplant immunization with granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing tumor vaccines. Blood 95(10):3011-3019

    PubMed  CAS  Google Scholar 

  81. Wrzesinski C, Paulos CM, Gattinoni L, Palmer DC, Kaiser A, Yu Z et al (2007) Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest 117(2):492-501

    PubMed  CAS  Google Scholar 

  82. Antony PA, Paulos CM, Ahmadzadeh M, Akpinarli A, Palmer DC, Sato N et al (2006) Interleukin-2-dependent mechanisms of tolerance and immunity in vivo. J Immunol 176(9):5255-5266

    PubMed  CAS  Google Scholar 

  83. Zhou G, Drake CG, Levitsky HI (2006) Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood 107(2):628-636

    PubMed  CAS  Google Scholar 

  84. Mirmonsef P, Tan G, Zhou G, Morino T, Noonan K, Borrello I et al (2008) Escape from suppression: tumor-specific effector cells outcompete regulatory T cells following stem-cell transplantation. Blood 111(4):2112-2121

    PubMed  CAS  Google Scholar 

  85. Kochenderfer JN, Chien CD, Simpson JL, Gress RE (2006) Synergism between CpG-containing oligodeoxynucleotides and IL-2 causes dramatic enhancement of vaccine-elicited CD8+ T cell responses. J Immunol 177(12):8860-8873

    PubMed  CAS  Google Scholar 

  86. Moyer JS, Maine G, Mule JJ (2006) Early vaccination with tumor-lysate-pulsed dendritic cells after allogeneic bone marrow transplantation has antitumor effects. Biol Blood Marrow Transplant 12(10):1010-1019

    PubMed  CAS  Google Scholar 

  87. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ et al (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298(5594):850-854

    PubMed  CAS  Google Scholar 

  88. Robbins PF, Dudley ME, Wunderlich J, El-Gamil M, Li YF, Zhou J et al (2004) Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J Immunol 173(12):7125-7130

    PubMed  CAS  Google Scholar 

  89. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314(5796):126-129

    PubMed  CAS  Google Scholar 

  90. Thurner B, Haendle I, Roder C, Dieckmann D, Keikavoussi P, Jonuleit H et al (1999) Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 190(11):1669-1678

    PubMed  CAS  Google Scholar 

  91. Fay JW, Palucka AK, Paczesny S, Dhodapkar M, Johnston DA, Burkeholder S et al (2006) Long-term outcomes in patients with metastatic melanoma vaccinated with melanoma peptide-pulsed CD34(+) progenitor-derived dendritic cells. Cancer Immunol Immunother 55(10):1209-1218

    PubMed  CAS  Google Scholar 

  92. Banchereau J, Ueno H, Dhodapkar M, Connolly J, Finholt JP, Klechevsky E et al (2005) Immune and clinical outcomes in patients with stage IV melanoma vaccinated with peptide-pulsed dendritic cells derived from CD34+ progenitors and activated with type I interferon. J Immunother 28(5):505-516

    PubMed  CAS  Google Scholar 

  93. Reichardt VL, Okada CY, Liso A, Benike CJ, Stockerl-Goldstein KE, Engleman EG et al (1999) Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma - a feasibility study. Blood 93(7):2411-2419

    PubMed  CAS  Google Scholar 

  94. Bendandi M, Rodriguez-Calvillo M, Inoges S, Lopez-Diaz de Cerio A, Perez-Simon JA, Rodriguez-Caballero A, Rodriguez-Caballero A et al (2006) Combined vaccination with idiotype-pulsed allogeneic dendritic cells and soluble protein idiotype for multiple myeloma patients relapsing after reduced-intensity conditioning allogeneic stem cell transplantation. Leuk Lymphoma 47(1):29-3

    PubMed  CAS  Google Scholar 

  95. Kitawaki T, Kadowaki N, Kondo T, Ishikawa T, Ichinohe T, Teramukai S et al (2008) Potential of dendritic cell immunotherapy for relapse after allogeneic hematopoietic stem cell transplantation, shown by WT1 peptide- and keyhole limpet hemocyanin-pulsed, donor-derived dendritic cell vaccine for acute myeloid leukemia. Am J Hematol 83(4):315-317

    PubMed  CAS  Google Scholar 

  96. Bellucci R, Alyea EP, Weller E, Chillemi A, Hochberg E, Wu CJ et al (2002) Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma. Blood 99(12):4610-4617

    PubMed  CAS  Google Scholar 

  97. Hochberg EP, Chillemi AC, Wu CJ, Neuberg D, Canning C, Hartman K et al (2001) Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults. Blood 98(4):1116-1121

    PubMed  CAS  Google Scholar 

  98. Klein AK, Patel DD, Gooding ME, Sempowski GD, Chen BJ, Liu C et al (2001) T-Cell recovery in adults and children following umbilical cord blood transplantation. Biol Blood Marrow Transplant 7(8):454-466

    PubMed  CAS  Google Scholar 

  99. Dumont-Girard F, Roux E, van Lier RA, Hale G, Helg C, Chapuis B et al (1998) Reconstitution of the T-cell compartment after bone marrow transplantation: restoration of the repertoire by thymic emigrants. Blood 92(11):4464-4471

    PubMed  CAS  Google Scholar 

  100. Sarzotti M, Patel DD, Li X, Ozaki DA, Cao S, Langdon S et al (2003) T cell repertoire development in humans with SCID after nonablative allogeneic marrow transplantation. J Immunol 170(5):2711-2718

    PubMed  CAS  Google Scholar 

  101. Yager EJ, Ahmed M, Lanzer K, Randall TD, Woodland DL, Blackman MA (2008) Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med 205(3):711-723

    PubMed  CAS  Google Scholar 

  102. Zoller M, Rajasagi M, Vitacolonna M, Luft T (2007) Thymus repopulation after allogeneic reconstitution in hematological malignancies. Exp Hematol 35(12):1891-1905

    PubMed  Google Scholar 

  103. Parkman R, Cohen G, Carter SL, Weinberg KI, Masinsin B, Guinan E et al (2006) Successful immune reconstitution decreases leukemic relapse and improves survival in recipients of unrelated cord blood transplantation. Biol Blood Marrow Transplant 12(9):919-927

    PubMed  Google Scholar 

  104. Powles R, Singhal S, Treleaven J, Kulkarni S, Horton C, Mehta J (1998) Identification of patients who may benefit from prophylactic immunotherapy after bone marrow transplantation for acute myeloid leukemia on the basis of lymphocyte recovery early after transplantation. Blood 91(9):3481-3486

    PubMed  CAS  Google Scholar 

  105. Fallen PR, McGreavey L, Madrigal JA, Potter M, Ethell M, Prentice HG et al (2003) Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients. Bone Marrow Transplant 32(10):1001-1014

    PubMed  CAS  Google Scholar 

  106. Lewin SR, Heller G, Zhang L, Rodrigues E, Skulsky E, van den Brink MR et al (2002) Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantations. Blood 100(6):2235-2242

    PubMed  CAS  Google Scholar 

  107. Jimenez M, Martinez C, Ercilla G, Carreras E, Urbano-Ispizua A, Aymerich M et al (2006) Clinical factors influencing T-cell receptor excision circle (TRECs) counts following allogeneic stem cell transplantation in adults. Transpl Immunol 16(1):52-59

    PubMed  CAS  Google Scholar 

  108. Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M et al (2001) Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 97(5):1458-1466

    PubMed  CAS  Google Scholar 

  109. Olkinuora H, Talvensaari K, Kaartinen T, Siitonen S, Saarinen-Pihkala U, Partanen J et al (2007) T cell regeneration in pediatric allogeneic stem cell transplantation. Bone Marrow Transplant 39(3):149-156

    PubMed  CAS  Google Scholar 

  110. Desbarats J, Lapp WS (1993) Thymic selection and thymic major histocompatibility complex class II expression are abnormal in mice undergoing graft-versus-host reactions. J Exp Med 178(3):805-814

    PubMed  CAS  Google Scholar 

  111. Ghayur T, Seemayer TA, Xenocostas A, Lapp WS (1988) Complete sequential regeneration of graft-vs-host-induced severely dysplastic thymuses. Implications for the pathogenesis of chronic graft-vs-host disease. Am J Pathol 133(1):39-46

    PubMed  CAS  Google Scholar 

  112. Hauri-Hohl MM, Keller MP, Gill J, Hafen K, Pachlatko E, Boulay T et al (2007) Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation. Blood

    Google Scholar 

  113. Blaser BW, Roychowdhury S, Kim DJ, Schwind NR, Bhatt D, Yuan W et al (2005) Donor-derived IL-15 is critical for acute allogeneic graft-versus-host disease. Blood 105(2):894-901

    PubMed  CAS  Google Scholar 

  114. Alpdogan O, Eng JM, Muriglan SJ, Willis LM, Hubbard VM, Tjoe KH et al (2005) Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. Blood 105(2):865-873

    PubMed  CAS  Google Scholar 

  115. Chung B, Dudl E, Toyama A, Barsky L, Weinberg KI (2008) Importance of interleukin-7 in the development of experimental graft-versus-host disease. Biol Blood Marrow Transplant 14(1):16-27

    PubMed  CAS  Google Scholar 

  116. Kumaki S, Minegishi M, Fujie H, Sasahara Y, Ohashi Y, Tsuchiya S et al (1998) Prolonged secretion of IL-15 in patients with severe forms of acute graft-versus-host disease after allogeneic bone marrow transplantation in children. Int J Hematol 67(3):307-312

    PubMed  CAS  Google Scholar 

  117. Chik KW, Li K, Pong H, Shing MM, Li CK, Yuen PM (2003) Elevated serum interleukin-15 level in acute graft-versus-host disease after hematopoietic cell transplantation. J Pediatr Hematol Oncol 25(12):960-964

    PubMed  Google Scholar 

  118. Taylor PA, Lees CJ, Blazar BR (2002) The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99(10):3493-3499

    PubMed  CAS  Google Scholar 

  119. de Vries E, van Tol MJ, van den Bergh RL, Waaijer JL, ten Dam MM, Hermans J et al (2000) Reconstitution of lymphocyte subpopulations after paediatric bone marrow transplantation. Bone Marrow Transplant 25(3):267-275

    PubMed  Google Scholar 

  120. Nordoy T, Kolstad A, Endresen P, Holte H, Kvaloy S, Kvalheim G et al (1999) Persistent changes in the immune system 4-10 years after ABMT. Bone Marrow Transplant 24(8):873-878

    PubMed  CAS  Google Scholar 

  121. Chao NJ, Liu CX, Rooney B, Chen BJ, Long GD, Vredenburgh JJ et al (2002) Nonmyeloablative regimen preserves “niches” allowing for peripheral expansion of donor T-cells. Biol Blood Marrow Transplant 8(5):249-256

    PubMed  Google Scholar 

  122. Chen X, Hale GA, Barfield R, Benaim E, Leung WH, Knowles J et al (2006) Rapid immune reconstitution after a reduced-intensity conditioning regimen and a CD3-depleted haploidentical stem cell graft for paediatric refractory haematological malignancies. Br J Haematol 135(4):524-532

    PubMed  Google Scholar 

  123. Chen BJ, Cui X, Sempowski GD, Domen J, Chao NJ (2004) Hematopoietic stem cell dose correlates with the speed of immune reconstitution after stem cell transplantation. Blood 103(11):4344-4352

    PubMed  CAS  Google Scholar 

  124. Zakrzewski JL, Kochman AA, Lu SX, Terwey TH, Kim TD, Hubbard VM et al (2006) Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation. Nat Med 12(9):1039-1047

    PubMed  CAS  Google Scholar 

  125. Talvensarri K, Clave E, Douay C, Rabian C, Garderet L, Busson M et al (2002) 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 99(4):1458-1464

    Google Scholar 

  126. Bolotin E, Smogorzewska M, Smith S, Widmer M, Weinberg K (1996) Enhancement of thymopoiesis after bone marrow transplant by in vivo interleukin-7. Blood 88(5):1887-1894

    PubMed  CAS  Google Scholar 

  127. Mackall CL, Fry TJ, Bare C, Morgan P, Galbraith A, Gress RE (2001) IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation. Blood 97(5):1491-1497

    PubMed  CAS  Google Scholar 

  128. Alpdogan O, Hubbard VM, Smith OM, Patel N, Lu S, Goldberg GL et al (2006) Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood 107(6):2453-2460

    PubMed  CAS  Google Scholar 

  129. Rossi S, Blazar BR, Farrell CL, Danilenko DM, Lacey DL, Weinberg KI et al (2002) Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease. Blood 100(2):682-691

    PubMed  CAS  Google Scholar 

  130. Blazar BR, Weisdorf DJ, Defor T, Goldman A, Braun T, Silver S et al (2006) Phase 1/2 randomized, placebo-control trial of palifermin to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Blood 108(9):3216-3222

    PubMed  CAS  Google Scholar 

  131. Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS et al (2005) Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 175(4):2741-2753

    PubMed  CAS  Google Scholar 

  132. Napolitano LA, Lo JC, Gotway MB, Mulligan K, Barbour JD, Schmidt D et al (2002) Increased thymic mass and circulating naive CD4 T cells in HIV-1-infected adults treated with growth hormone. AIDS 16(8):1103-1111

    PubMed  CAS  Google Scholar 

  133. Savino W, Postel-Vinay MC, Smaniotto S, Dardenne M (2002) The thymus gland: a target organ for growth hormone. Scand J Immunol 55(5):442-452

    PubMed  CAS  Google Scholar 

  134. Polgreen L, Steiner M, Dietz CA, Manivel JC, Petryk A (2006) Thymic hyperplasia in a child treated with growth hormone. Growth Horm IGF Res

    Google Scholar 

  135. Goldberg GL, Sutherland JS, Hammet MV, Milton MK, Heng TS, Chidgey AP et al (2005) Sex steroid ablation enhances lymphoid recovery following autologous hematopoietic stem cell transplantation. Transplantation 80(11):1604-1613

    PubMed  Google Scholar 

  136. Sutherland JS, Spyroglou L, Muirhead JL, Heng TS, Prieto-Hinojosa A, Prince HM et al (2008) Enhanced immune system regeneration in humans following allogeneic or autologous hemopoietic stem cell transplantation by temporary sex steroid blockade. Clin Cancer Res 14(4):1138-1149

    PubMed  CAS  Google Scholar 

  137. Rizzieri DA, Koh LP, Long GD, Gasparetto C, Sullivan KM, Horwitz M et al (2007) Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution. J Clin Oncol 25(6):690-697

    PubMed  CAS  Google Scholar 

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  1. Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Kirsten M. Williams & Ronald E. Gress

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  1. University Hospitals Case Medical Center, Cleveland, OH, USA

    Hillard M. Lazarus

  2. Case Western Reserve University, Cleveland, OH, USA

    Mary J. Laughlin

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Williams, K.M., Gress, R.E. (2010). Immune Reconstitution and Implications for Immunotherapy Following Hematopoeitic Stem Cell Transplantation. In: Lazarus, H.M., Laughlin, M.J. (eds) Allogeneic Stem Cell Transplantation. Contemporary Hematology. Humana Press. https://doi.org/10.1007/978-1-59745-478-0_31

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