UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Strategies for immune reconstitution following allogeneic hematopoietic cell transplantation

Authors
Marcel RM van den Brink, MD, PhD
Jarrod A Dudakov, PhD
Section Editor
Robert S Negrin, MD
Deputy Editor
Alan G Rosmarin, MD

INTRODUCTION

Allogeneic hematopoietic cell transplantation (HCT) is an important and potentially curative treatment option for a wide variety of malignant and nonmalignant diseases. Paradoxically, cytoreductive conditioning regimens designed to allow for successful allogeneic HCT are also detrimental to recovery of the immune system in general, and the production of lymphocytes in particular.

Delayed recovery of the immune system is associated with a high degree of morbidity and mortality [1-3]. Post-transplant immune depletion is particularly striking within the T cell compartment, which is exquisitely sensitive to negative regulation, evidenced by the profound decline in thymic function with age. As a consequence, regeneration of the immune system remains a significant unmet clinical need. Preclinical and clinical studies have revealed several promising therapeutic strategies to address ineffective lymphopoiesis and post-transplant immune deficiency.

Immune reconstitution following allogeneic HCT will be discussed here. Immunization following HCT and other supportive care issues surrounding HCT are presented separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients" and "Hematopoietic support after hematopoietic cell transplantation" and "Management of the hematopoietic cell transplant recipient in the immediate post-transplant period".)

The term "hematopoietic cell transplantation" (HCT) will be used throughout this review as a general term to cover transplantation of progenitor cells from any source (eg, bone marrow, peripheral blood, umbilical cord blood). Otherwise, the source of such cells will be specified (eg, peripheral blood progenitor cell transplantation).

OVERVIEW OF IMMUNE RECONSTITUTION

A critical component of allogeneic HCT is the administration of chemotherapy and/or radiation therapy as a conditioning (or preparative) regimen with the goal of providing adequate immunosuppression to prevent rejection of the transplanted graft. Both alkylating chemotherapeutics and irradiation target highly proliferative cells [4-6], including developing and naïve lymphocytes [1]. As a result, following transplant, there is severe depletion of all hematopoietic cells of the immune system, especially lymphocytes. (See "Preparative regimens for hematopoietic cell transplantation".)

                   

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Mon Jun 27 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Mackall CL, Fleisher TA, Brown MR, et al. Lymphocyte depletion during treatment with intensive chemotherapy for cancer. Blood 1994; 84:2221.
  2. Pizzo PA, Rubin M, Freifeld A, Walsh TJ. The child with cancer and infection. II. Nonbacterial infections. J Pediatr 1991; 119:845.
  3. Mackall CL. T-cell immunodeficiency following cytotoxic antineoplastic therapy: a review. Stem Cells 2000; 18:10.
  4. Brock N. The history of the oxazaphosphorine cytostatics. Cancer 1996; 78:542.
  5. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008; 8:59.
  6. Trobaugh FE Jr, Husseini S. Effects of radiation on hematopoietic tissue. Am J Med Technol 1973; 39:119.
  7. Bulek K, Swaidani S, Aronica M, Li X. Epithelium: the interplay between innate and Th2 immunity. Immunol Cell Biol 2010; 88:257.
  8. Metz-Boutigue MH, Shooshtarizadeh P, Prevost G, et al. Antimicrobial peptides present in mammalian skin and gut are multifunctional defence molecules. Curr Pharm Des 2010; 16:1024.
  9. Nochi T, Kiyono H. Innate immunity in the mucosal immune system. Curr Pharm Des 2006; 12:4203.
  10. Storek J, Geddes M, Khan F, et al. Reconstitution of the immune system after hematopoietic stem cell transplantation in humans. Semin Immunopathol 2008; 30:425.
  11. Zimmerli W, Zarth A, Gratwohl A, Speck B. Neutrophil function and pyogenic infections in bone marrow transplant recipients. Blood 1991; 77:393.
  12. Nakata K, Gotoh H, Watanabe J, et al. Augmented proliferation of human alveolar macrophages after allogeneic bone marrow transplantation. Blood 1999; 93:667.
  13. Cayeux S, Meuer S, Pezzutto A, et al. Allogeneic mixed lymphocyte reactions during a second round of ontogeny: normal accessory cells did not restore defective interleukin-2 (IL-2) synthesis in T cells but induced responsiveness to exogeneous IL-2. Blood 1989; 74:2278.
  14. Sahdev I, O'Reilly R, Black P, et al. Interleukin-1 production following T-cell-depleted and unmodified marrow grafts. Pediatr Hematol Oncol 1996; 13:55.
  15. Hokland M, Jacobsen N, Ellegaard J, Hokland P. Natural killer function following allogeneic bone marrow transplantation. Very early reemergence but strong dependence of cytomegalovirus infection. Transplantation 1988; 45:1080.
  16. Jacobs R, Stoll M, Stratmann G, et al. CD16- CD56+ natural killer cells after bone marrow transplantation. Blood 1992; 79:3239.
  17. Vitale C, Pitto A, Benvenuto F, et al. Phenotypic and functional analysis of the HLA-class I-specific inhibitory receptors of natural killer cells isolated from peripheral blood of patients undergoing bone marrow transplantation from matched unrelated donors. Hematol J 2000; 1:136.
  18. Weinberg K, Annett G, Kashyap A, et al. The effect of thymic function on immunocompetence following bone marrow transplantation. Biol Blood Marrow Transplant 1995; 1:18.
  19. Roux E, Helg C, Dumont-Girard F, et al. Analysis of T-cell repopulation after allogeneic bone marrow transplantation: significant differences between recipients of T-cell depleted and unmanipulated grafts. Blood 1996; 87:3984.
  20. Dumont-Girard F, Roux E, van Lier RA, et al. Reconstitution of the T-cell compartment after bone marrow transplantation: restoration of the repertoire by thymic emigrants. Blood 1998; 92:4464.
  21. Ault KA, Antin JH, Ginsburg D, et al. Phenotype of recovering lymphoid cell populations after marrow transplantation. J Exp Med 1985; 161:1483.
  22. Gratama JW, Naipal A, Oljans P, et al. T lymphocyte repopulation and differentiation after bone marrow transplantation. Early shifts in the ratio between T4+ and T8+ T lymphocytes correlate with the occurrence of acute graft-versus-host disease. Blood 1984; 63:1416.
  23. Roosnek EE, Brouwer MC, Vossen JM, et al. The role of interleukin-2 in proliferative responses in vitro of T cells from patients after bone marrow transplantation. Evidence that minor defects can lead to in vitro unresponsiveness. Transplantation 1987; 43:855.
  24. Roux E, Dumont-Girard F, Starobinski M, et al. Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood 2000; 96:2299.
  25. Soiffer RJ, Bosserman L, Murray C, et al. Reconstitution of T-cell function after CD6-depleted allogeneic bone marrow transplantation. Blood 1990; 75:2076.
  26. Atkinson K, Hansen JA, Storb R, et al. T-cell subpopulations identified by monoclonal antibodies after human marrow transplantation. I. Helper-inducer and cytotoxic-suppressor subsets. Blood 1982; 59:1292.
  27. Mackall CL, Fleisher TA, Brown MR, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995; 332:143.
  28. Hakim FT, Memon SA, Cepeda R, et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 2005; 115:930.
  29. Rodewald HR. The thymus in the age of retirement. Nature 1998; 396:630.
  30. Storek J, Witherspoon RP, Storb R. T cell reconstitution after bone marrow transplantation into adult patients does not resemble T cell development in early life. Bone Marrow Transplant 1995; 16:413.
  31. Mackall CL, Fleisher TA, Brown MR, et al. Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy. Blood 1997; 89:3700.
  32. Fagnoni FF, Lozza L, Zibera C, et al. T-cell dynamics after high-dose chemotherapy in adults: elucidation of the elusive CD8+ subset reveals multiple homeostatic T-cell compartments with distinct implications for immune competence. Immunology 2002; 106:27.
  33. Heitger A, Neu N, Kern H, et al. Essential role of the thymus to reconstitute naive (CD45RA+) T-helper cells after human allogeneic bone marrow transplantation. Blood 1997; 90:850.
  34. Sfikakis PP, Gourgoulis GM, Moulopoulos LA, et al. Age-related thymic activity in adults following chemotherapy-induced lymphopenia. Eur J Clin Invest 2005; 35:380.
  35. Storek J, Gooley T, Witherspoon RP, et al. Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol 1997; 54:131.
  36. Storek J, Espino G, Dawson MA, et al. 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 2000; 96:3290.
  37. Fry TJ, Mackall CL. Immune reconstitution following hematopoietic progenitor cell transplantation: challenges for the future. Bone Marrow Transplant 2005; 35 Suppl 1:S53.
  38. MacLean GD, Reddish MA, Koganty RR, Longenecker BM. Antibodies against mucin-associated sialyl-Tn epitopes correlate with survival of metastatic adenocarcinoma patients undergoing active specific immunotherapy with synthetic STn vaccine. J Immunother Emphasis Tumor Immunol 1996; 19:59.
  39. von Mensdorff-Pouilly S, Verstraeten AA, Kenemans P, et al. Survival in early breast cancer patients is favorably influenced by a natural humoral immune response to polymorphic epithelial mucin. J Clin Oncol 2000; 18:574.
  40. White CA, Weaver RL, Grillo-López AJ. Antibody-targeted immunotherapy for treatment of malignancy. Annu Rev Med 2001; 52:125.
  41. Storek J. B-cell immunity after allogeneic hematopoietic cell transplantation. Cytotherapy 2002; 4:423.
  42. Li F, Jin F, Freitas A, et al. Impaired regeneration of the peripheral B cell repertoire from bone marrow following lymphopenia in old mice. Eur J Immunol 2001; 31:500.
  43. Storek J, Wells D, Dawson MA, et al. Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation. Blood 2001; 98:489.
  44. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 2009; 15:1143.
  45. Kim DH, Sohn SK, Won DI, et al. Rapid helper T-cell recovery above 200 x 10 6/l at 3 months correlates to successful transplant outcomes after allogeneic stem cell transplantation. Bone Marrow Transplant 2006; 37:1119.
  46. Seggewiss R, Einsele H. Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood 2010; 115:3861.
  47. Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 2007; 25:139.
  48. Hamza NS, Lisgaris M, Yadavalli G, et al. Kinetics of myeloid and lymphocyte recovery and infectious complications after unrelated umbilical cord blood versus HLA-matched unrelated donor allogeneic transplantation in adults. Br J Haematol 2004; 124:488.
  49. van Kraaij MG, Verdonck LF, Rozenberg-Arska M, Dekker AW. Early infections in adults undergoing matched related and matched unrelated/mismatched donor stem cell transplantation: a comparison of incidence. Bone Marrow Transplant 2002; 30:303.
  50. Yoo JH, Lee DG, Choi SM, et al. Infectious complications and outcomes after allogeneic hematopoietic stem cell transplantation in Korea. Bone Marrow Transplant 2004; 34:497.
  51. Luznik L, O'Donnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol 2012; 39:683.
  52. Lang P, Teltschik HM, Feuchtinger T, et al. Transplantation of CD3/CD19 depleted allografts from haploidentical family donors in paediatric leukaemia. Br J Haematol 2014; 165:688.
  53. Guerrettaz LM, Johnson SA, Cambier JC. Acquired hematopoietic stem cell defects determine B-cell repertoire changes associated with aging. Proc Natl Acad Sci U S A 2008; 105:11898.
  54. Muller-Sieburg CE, Cho RH, Karlsson L, et al. Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness. Blood 2004; 103:4111.
  55. Signer RA, Montecino-Rodriguez E, Witte ON, et al. Age-related defects in B lymphopoiesis underlie the myeloid dominance of adult leukemia. Blood 2007; 110:1831.
  56. Rossi DJ, Bryder D, Zahn JM, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 2005; 102:9194.
  57. Kamminga LM, van Os R, Ausema A, et al. Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging. Stem Cells 2005; 23:82.
  58. Kim M, Moon HB, Spangrude GJ. Major age-related changes of mouse hematopoietic stem/progenitor cells. Ann N Y Acad Sci 2003; 996:195.
  59. Liang Y, Van Zant G, Szilvassy SJ. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 2005; 106:1479.
  60. Carreras E, Jiménez M, Gómez-García V, et al. Donor age and degree of HLA matching have a major impact on the outcome of unrelated donor haematopoietic cell transplantation for chronic myeloid leukaemia. Bone Marrow Transplant 2006; 37:33.
  61. Harrison DE, Astle CM. Loss of stem cell repopulating ability upon transplantation. Effects of donor age, cell number, and transplantation procedure. J Exp Med 1982; 156:1767.
  62. Mehta J, Gordon LI, Tallman MS, et al. Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially? Bone Marrow Transplant 2006; 38:95.
  63. Goldberg GL, Dudakov JA, Reiseger JJ, et al. Sex steroid ablation enhances immune reconstitution following cytotoxic antineoplastic therapy in young mice. J Immunol 2010; 184:6014.
  64. Fredrickson GG, Basch RS. Early thymic regeneration after irradiation. Dev Comp Immunol 1994; 18:251.
  65. Hauri-Hohl MM, Zuklys S, Keller MP, et al. TGF-beta signaling in thymic epithelial cells regulates thymic involution and postirradiation reconstitution. Blood 2008; 112:626.
  66. Popa I, Zubkova I, Medvedovic M, et al. Regeneration of the adult thymus is preceded by the expansion of K5+K8+ epithelial cell progenitors and by increased expression of Trp63, cMyc and Tcf3 transcription factors in the thymic stroma. Int Immunol 2007; 19:1249.
  67. Min D, Taylor PA, Panoskaltsis-Mortari A, 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.
  68. 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.
  69. Kelly RM, Highfill SL, Panoskaltsis-Mortari A, et al. Keratinocyte growth factor and androgen blockade work in concert to protect against conditioning regimen-induced thymic epithelial damage and enhance T-cell reconstitution after murine bone marrow transplantation. Blood 2008; 111:5734.
  70. Kelly RM, Goren EM, Taylor PA, et al. Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation. Blood 2010; 115:1088.
  71. Williams KM, Mella H, Lucas PJ, et al. Single cell analysis of complex thymus stromal cell populations: rapid thymic epithelia preparation characterizes radiation injury. Clin Transl Sci 2009; 2:279.
  72. Gray DH, Seach N, Ueno T, et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 2006; 108:3777.
  73. Sykes M, Szot GL, Swenson K, et al. Separate regulation of peripheral hematopoietic and thymic engraftment. Exp Hematol 1998; 26:457.
  74. Dudakov JA, Goldberg GL, Reiseger JJ, et al. Sex steroid ablation enhances hematopoietic recovery following cytotoxic antineoplastic therapy in aged mice. J Immunol 2009; 183:7084.
  75. Flores KG, Li J, Sempowski GD, et al. Analysis of the human thymic perivascular space during aging. J Clin Invest 1999; 104:1031.
  76. Savage WJ, Bleesing JJ, Douek D, et al. Lymphocyte reconstitution following non-myeloablative hematopoietic stem cell transplantation follows two patterns depending on age and donor/recipient chimerism. Bone Marrow Transplant 2001; 28:463.
  77. Suessmuth Y, Mukherjee R, Watkins B, et al. CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire. Blood 2015; 125:3835.
  78. Storek J, Dawson MA, Storer B, et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 2001; 97:3380.
  79. Russell NH, Gratwohl A, Schmitz N. Developments in allogeneic peripheral blood progenitor cell transplantation. Br J Haematol 1998; 103:594.
  80. Körbling M, Anderlini P. Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter? Blood 2001; 98:2900.
  81. Szilvassy SJ, Meyerrose TE, Ragland PL, Grimes B. Differential homing and engraftment properties of hematopoietic progenitor cells from murine bone marrow, mobilized peripheral blood, and fetal liver. Blood 2001; 98:2108.
  82. Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 2005; 105:1343.
  83. Avery S, Shi W, Lubin M, et al. Influence of infused cell dose and HLA match on engraftment after double-unit cord blood allografts. Blood 2011; 117:3277.
  84. Gutman JA, Turtle CJ, Manley TJ, et al. Single-unit dominance after double-unit umbilical cord blood transplantation coincides with a specific CD8+ T-cell response against the nonengrafted unit. Blood 2010; 115:757.
  85. Delaney C, Gutman JA, Appelbaum FR. Cord blood transplantation for haematological malignancies: conditioning regimens, double cord transplant and infectious complications. Br J Haematol 2009; 147:207.
  86. Smith AR, Wagner JE. Alternative haematopoietic stem cell sources for transplantation: place of umbilical cord blood. Br J Haematol 2009; 147:246.
  87. Kanda J, Chiou LW, Szabolcs P, et al. Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 18:1664.
  88. Chen BJ, Cui X, Sempowski GD, et al. Hematopoietic stem cell dose correlates with the speed of immune reconstitution after stem cell transplantation. Blood 2004; 103:4344.
  89. Neven B, Leroy S, Decaluwe H, et al. Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency. Blood 2009; 113:4114.
  90. Cavazzana-Calvo M, Carlier F, Le Deist F, et al. Long-term T-cell reconstitution after hematopoietic stem-cell transplantation in primary T-cell-immunodeficient patients is associated with myeloid chimerism and possibly the primary disease phenotype. Blood 2007; 109:4575.
  91. Müller SM, Kohn T, Schulz AS, et al. Similar pattern of thymic-dependent T-cell reconstitution in infants with severe combined immunodeficiency after human leukocyte antigen (HLA)-identical and HLA-nonidentical stem cell transplantation. Blood 2000; 96:4344.
  92. Torelli GF, Lucarelli B, Iori AP, et al. The immune reconstitution after an allogeneic stem cell transplant correlates with the risk of graft-versus-host disease and cytomegalovirus infection. Leuk Res 2011; 35:1124.
  93. Rezvani K, Mielke S, Ahmadzadeh M, 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.
  94. Gaidot A, Landau DA, Martin GH, et al. Immune reconstitution is preserved in hematopoietic stem cell transplantation coadministered with regulatory T cells for GVHD prevention. Blood 2011; 117:2975.
  95. Winstead CJ, Reilly CS, Moon JJ, et al. CD4+CD25+Foxp3+ regulatory T cells optimize diversity of the conventional T cell repertoire during reconstitution from lymphopenia. J Immunol 2010; 184:4749.
  96. Soderling CC, Song CW, Blazar BR, Vallera DA. A correlation between conditioning and engraftment in recipients of MHC-mismatched T cell-depleted murine bone marrow transplants. J Immunol 1985; 135:941.
  97. Gardner RV, McKinnon E, Astle CM. Analysis of the stem cell sparing properties of cyclophosphamide. Eur J Haematol 2001; 67:14.
  98. Gardner RV, McKinnon E, Poretta C, Leiva L. Hemopoietic function after use of IL-1 with chemotherapy or irradiation. J Immunol 2003; 171:1202.
  99. Meng A, Wang Y, Brown SA, et al. Ionizing radiation and busulfan inhibit murine bone marrow cell hematopoietic function via apoptosis-dependent and -independent mechanisms. Exp Hematol 2003; 31:1348.
  100. Meng A, Wang Y, Van Zant G, Zhou D. Ionizing radiation and busulfan induce premature senescence in murine bone marrow hematopoietic cells. Cancer Res 2003; 63:5414.
  101. Wang Y, Schulte BA, LaRue AC, et al. Total body irradiation selectively induces murine hematopoietic stem cell senescence. Blood 2006; 107:358.
  102. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11:945.
  103. Mielcarek M, Martin PJ, Leisenring W, et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003; 102:756.
  104. Keever-Taylor. Immune reconstitution after allogeneic transplantation. In: Hematopoietic Stem Cell Transplantation, Soiffer RJ. (Ed), Humana Press, Totowa, New Jersey 2008. p.377.
  105. Wingard JR, Hsu J, Hiemenz JW. Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology. Infect Dis Clin North Am 2010; 24:257.
  106. Fletcher AL, Lowen TE, Sakkal S, et al. Ablation and regeneration of tolerance-inducing medullary thymic epithelial cells after cyclosporine, cyclophosphamide, and dexamethasone treatment. J Immunol 2009; 183:823.
  107. Purton JF, Monk JA, Liddicoat DR, et al. Expression of the glucocorticoid receptor from the 1A promoter correlates with T lymphocyte sensitivity to glucocorticoid-induced cell death. J Immunol 2004; 173:3816.
  108. Na IK, Lu SX, Yim NL, et al. The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease. J Clin Invest 2010; 120:343.
  109. Krenger W, Holländer GA. The immunopathology of thymic GVHD. Semin Immunopathol 2008; 30:439.
  110. Krenger W, Rossi S, Holländer GA. Apoptosis of thymocytes during acute graft-versus-host disease is independent of glucocorticoids. Transplantation 2000; 69:2190.
  111. Zakrzewski JL, Kochman AA, Lu SX, et al. Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation. Nat Med 2006; 12:1039.
  112. Alpdogan O, Hubbard VM, Smith OM, et al. Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood 2006; 107:2453.
  113. Goldberg GL, Alpdogan O, Muriglan SJ, et al. Enhanced immune reconstitution by sex steroid ablation following allogeneic hemopoietic stem cell transplantation. J Immunol 2007; 178:7473.
  114. Wada H, Masuda K, Satoh R, et al. Adult T-cell progenitors retain myeloid potential. Nature 2008; 452:768.
  115. Bell JJ, Bhandoola A. The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature 2008; 452:764.
  116. Schwarz BA, Bhandoola A. Circulating hematopoietic progenitors with T lineage potential. Nat Immunol 2004; 5:953.
  117. Serwold T, Ehrlich LI, Weissman IL. Reductive isolation from bone marrow and blood implicates common lymphoid progenitors as the major source of thymopoiesis. Blood 2009; 113:807.
  118. Martin CH, Aifantis I, Scimone ML, et al. Efficient thymic immigration of B220+ lymphoid-restricted bone marrow cells with T precursor potential. Nat Immunol 2003; 4:866.
  119. Arber C, BitMansour A, Sparer TE, et al. Common lymphoid progenitors rapidly engraft and protect against lethal murine cytomegalovirus infection after hematopoietic stem cell transplantation. Blood 2003; 102:421.
  120. Geiger H, Rudolph KL. Aging in the lympho-hematopoietic stem cell compartment. Trends Immunol 2009; 30:360.
  121. Dudakov JA, Khong DM, Boyd RL, Chidgey AP. Feeding the fire: the role of defective bone marrow function in exacerbating thymic involution. Trends Immunol 2010; 31:191.
  122. Mackall CL, Gress RE. Thymic aging and T-cell regeneration. Immunol Rev 1997; 160:91.
  123. Gui J, Zhu X, Dohkan J, et al. The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells. Int Immunol 2007; 19:1201.
  124. Min D, Panoskaltsis-Mortari A, Kuro-O M, et al. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 2007; 109:2529.
  125. Rossi S, Blazar BR, Farrell CL, et al. Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease. Blood 2002; 100:682.
  126. Rossi SW, Jeker LT, Ueno T, 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.
  127. Alpdogan O, Muriglan SJ, Eng JM, et al. IL-7 enhances peripheral T cell reconstitution after allogeneic hematopoietic stem cell transplantation. J Clin Invest 2003; 112:1095.
  128. Lu H, Zhao Z, Kalina T, et al. Interleukin-7 improves reconstitution of antiviral CD4 T cells. Clin Immunol 2005; 114:30.
  129. Sempowski GD, Gooding ME, Liao HX, et al. T cell receptor excision circle assessment of thymopoiesis in aging mice. Mol Immunol 2002; 38:841.
  130. Fry TJ, Moniuszko M, Creekmore S, et al. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. Blood 2003; 101:2294.
  131. Chu YW, Memon SA, Sharrow SO, et al. Exogenous IL-7 increases recent thymic emigrants in peripheral lymphoid tissue without enhanced thymic function. Blood 2004; 104:1110.
  132. Andrew D, Aspinall R. Il-7 and not stem cell factor reverses both the increase in apoptosis and the decline in thymopoiesis seen in aged mice. J Immunol 2001; 166:1524.
  133. Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol 2011; 11:330.
  134. Perales MA, Goldberg JD, Yuan J, et al. Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation. Blood 2012; 120:4882.
  135. Fry TJ, Sinha M, Milliron M, et al. Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution. Blood 2004; 104:2794.
  136. Kenins L, Gill JW, Boyd RL, et al. Intrathymic expression of Flt3 ligand enhances thymic recovery after irradiation. J Exp Med 2008; 205:523.
  137. Wils EJ, Braakman E, Verjans GM, et al. Flt3 ligand expands lymphoid progenitors prior to recovery of thymopoiesis and accelerates T cell reconstitution after bone marrow transplantation. J Immunol 2007; 178:3551.
  138. Balciunaite G, Ceredig R, Massa S, Rolink AG. A B220+ CD117+ CD19- hematopoietic progenitor with potent lymphoid and myeloid developmental potential. Eur J Immunol 2005; 35:2019.
  139. Ceredig R, Rauch M, Balciunaite G, Rolink AG. Increasing Flt3L availability alters composition of a novel bone marrow lymphoid progenitor compartment. Blood 2006; 108:1216.
  140. Dixit VD, Yang H, Sun Y, et al. Ghrelin promotes thymopoiesis during aging. J Clin Invest 2007; 117:2778.
  141. Taub DD, Longo DL. Insights into thymic aging and regeneration. Immunol Rev 2005; 205:72.
  142. Carlo-Stella C, Di Nicola M, Milani R, et al. Age- and irradiation-associated loss of bone marrow hematopoietic function in mice is reversed by recombinant human growth hormone. Exp Hematol 2004; 32:171.
  143. Herasimtschuk AA, Westrop SJ, Moyle GJ, et al. Effects of recombinant human growth hormone on HIV-1-specific T-cell responses, thymic output and proviral DNA in patients on HAART: 48-week follow-up. J Immune Based Ther Vaccines 2008; 6:7.
  144. Napolitano LA, Schmidt D, Gotway MB, et al. Growth hormone enhances thymic function in HIV-1-infected adults. J Clin Invest 2008; 118:1085.
  145. Napolitano LA, Lo JC, Gotway MB, et al. Increased thymic mass and circulating naive CD4 T cells in HIV-1-infected adults treated with growth hormone. AIDS 2002; 16:1103.
  146. Plana M, Garcia F, Darwich L, et al. The reconstitution of the thymus in immunosuppressed individuals restores CD4-specific cellular and humoral immune responses. Immunology 2011; 133:318.
  147. Dudakov JA, Hanash AM, Jenq RR, et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science 2012; 336:91.
  148. Pan B, Liu J, Zhang Y, et al. Acute ablation of DP thymocytes induces up-regulation of IL-22 and Foxn1 in TECs. Clin Immunol 2014; 150:101.
  149. Alpdogan O, Muriglan SJ, Kappel BJ, et al. Insulin-like growth factor-I enhances lymphoid and myeloid reconstitution after allogeneic bone marrow transplantation. Transplantation 2003; 75:1977.
  150. Chu YW, Schmitz S, Choudhury B, et al. Exogenous insulin-like growth factor 1 enhances thymopoiesis predominantly through thymic epithelial cell expansion. Blood 2008; 112:2836.
  151. Taguchi T, Takenouchi H, Matsui J, et al. Involvement of insulin-like growth factor-I and insulin-like growth factor binding proteins in pro-B-cell development. Exp Hematol 2006; 34:508.
  152. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 2011; 365:2055.
  153. Alpdogan O, Eng JM, Muriglan SJ, et al. Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. Blood 2005; 105:865.
  154. Alpdogan O, van den Brink MR. IL-7 and IL-15: therapeutic cytokines for immunodeficiency. Trends Immunol 2005; 26:56.
  155. Chen J, Wang J, Li J, et al. Enhancement of cytotoxic T-lymphocyte response in aged mice by a novel treatment with recombinant AdIL-12 and wild-type adenovirus in rapid succession. Mol Ther 2008; 16:1500.
  156. Chen T, Burke KA, Zhan Y, et al. IL-12 facilitates both the recovery of endogenous hematopoiesis and the engraftment of stem cells after ionizing radiation. Exp Hematol 2007; 35:203.
  157. Li L, Hsu HC, Stockard CR, et al. IL-12 inhibits thymic involution by enhancing IL-7- and IL-2-induced thymocyte proliferation. J Immunol 2004; 172:2909.
  158. Eisenring M, vom Berg J, Kristiansen G, et al. IL-12 initiates tumor rejection via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46. Nat Immunol 2010; 11:1030.
  159. Satoh-Takayama N, Lesjean-Pottier S, Vieira P, et al. IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors. J Exp Med 2010; 207:273.
  160. Adams GB, Martin RP, Alley IR, et al. Therapeutic targeting of a stem cell niche. Nat Biotechnol 2007; 25:238.
  161. Chen X, Esplin BL, Garrett KP, et al. Retinoids accelerate B lineage lymphoid differentiation. J Immunol 2008; 180:138.
  162. Olsen NJ, Kovacs WJ. Effects of androgens on T and B lymphocyte development. Immunol Res 2001; 23:281.
  163. Zoller AL, Kersh GJ. Estrogen induces thymic atrophy by eliminating early thymic progenitors and inhibiting proliferation of beta-selected thymocytes. J Immunol 2006; 176:7371.
  164. Grimaldi CM, Jeganathan V, Diamond B. Hormonal regulation of B cell development: 17 beta-estradiol impairs negative selection of high-affinity DNA-reactive B cells at more than one developmental checkpoint. J Immunol 2006; 176:2703.
  165. Kincade PW, Medina KL, Payne KJ, et al. Early B-lymphocyte precursors and their regulation by sex steroids. Immunol Rev 2000; 175:128.
  166. Viselli SM, Reese KR, Fan J, et al. Androgens alter B cell development in normal male mice. Cell Immunol 1997; 182:99.
  167. Igarashi H, Kouro T, Yokota T, et al. Age and stage dependency of estrogen receptor expression by lymphocyte precursors. Proc Natl Acad Sci U S A 2001; 98:15131.
  168. Medina KL, Garrett KP, Thompson LF, et al. Identification of very early lymphoid precursors in bone marrow and their regulation by estrogen. Nat Immunol 2001; 2:718.
  169. Heng TS, Goldberg GL, Gray DH, et al. Effects of castration on thymocyte development in two different models of thymic involution. J Immunol 2005; 175:2982.
  170. Sutherland JS, Goldberg GL, Hammett MV, et al. Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 2005; 175:2741.
  171. Williams KM, Lucas PJ, Bare CV, et al. CCL25 increases thymopoiesis after androgen withdrawal. Blood 2008; 112:3255.
  172. Greenstein BD, Fitzpatrick FT, Kendall MD, Wheeler MJ. Regeneration of the thymus in old male rats treated with a stable analogue of LHRH. J Endocrinol 1987; 112:345.
  173. Olsen NJ, Watson MB, Henderson GS, Kovacs WJ. Androgen deprivation induces phenotypic and functional changes in the thymus of adult male mice. Endocrinology 1991; 129:2471.
  174. Roden AC, Moser MT, Tri SD, et al. Augmentation of T cell levels and responses induced by androgen deprivation. J Immunol 2004; 173:6098.
  175. Goldberg GL, King CG, Nejat RA, et al. Luteinizing hormone-releasing hormone enhances T cell recovery following allogeneic bone marrow transplantation. J Immunol 2009; 182:5846.
  176. Erben RG, Eberle J, Stangassinger M. B lymphopoiesis is upregulated after orchiectomy and is correlated with estradiol but not testosterone serum levels in aged male rats. Horm Metab Res 2001; 33:491.
  177. Ellis TM, Moser MT, Le PT, et al. Alterations in peripheral B cells and B cell progenitors following androgen ablation in mice. Int Immunol 2001; 13:553.
  178. Erben RG, Raith S, Eberle J, Stangassinger M. Ovariectomy augments B lymphopoiesis and generation of monocyte-macrophage precursors in rat bone marrow. Am J Physiol 1998; 274:E476.
  179. Masuzawa T, Miyaura C, Onoe Y, et al. Estrogen deficiency stimulates B lymphopoiesis in mouse bone marrow. J Clin Invest 1994; 94:1090.
  180. Dudakov JA, Goldberg GL, Reiseger JJ, et al. Withdrawal of sex steroids reverses age- and chemotherapy-related defects in bone marrow lymphopoiesis. J Immunol 2009; 182:6247.
  181. Goldberg GL, Sutherland JS, Hammet MV, et al. Sex steroid ablation enhances lymphoid recovery following autologous hematopoietic stem cell transplantation. Transplantation 2005; 80:1604.
  182. Schmitt TM, Zúñiga-Pflücker JC. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 2002; 17:749.
  183. Awong G, Herer E, Surh CD, et al. Characterization in vitro and engraftment potential in vivo of human progenitor T cells generated from hematopoietic stem cells. Blood 2009; 114:972.
  184. Reimann C, Dal Cortivo L, Hacein-Bey-Abina S, et al. Advances in adoptive immunotherapy to accelerate T-cellular immune reconstitution after HLA-incompatible hematopoietic stem cell transplantation. Immunotherapy 2010; 2:481.
  185. Zakrzewski JL, Suh D, Markley JC, et al. Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors. Nat Biotechnol 2008; 26:453.
  186. Holland AM, Zakrzewski JL, Goldberg GL, et al. Adoptive precursor cell therapy to enhance immune reconstitution after hematopoietic stem cell transplantation in mouse and man. Semin Immunopathol 2008; 30:479.
  187. Vago L, Oliveira G, Bondanza A, et al. T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation. Blood 2012; 120:1820.
  188. Gill J, Malin M, Holländer GA, Boyd R. Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat Immunol 2002; 3:635.
  189. Bennett AR, Farley A, Blair NF, et al. Identification and characterization of thymic epithelial progenitor cells. Immunity 2002; 16:803.
  190. Depreter MG, Blair NF, Gaskell TL, et al. Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells. Proc Natl Acad Sci U S A 2008; 105:961.
  191. Rossi SW, Chidgey AP, Parnell SM, et al. Redefining epithelial progenitor potential in the developing thymus. Eur J Immunol 2007; 37:2411.
  192. Jenkinson WE, Bacon A, White AJ, et al. An epithelial progenitor pool regulates thymus growth. J Immunol 2008; 181:6101.
  193. Bleul CC, Corbeaux T, Reuter A, et al. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 2006; 441:992.
  194. Bonfanti P, Claudinot S, Amici AW, et al. Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature 2010; 466:978.
  195. Chidgey AP, Seach N, Dudakov J, et al. Strategies for reconstituting and boosting T cell-based immunity following haematopoietic stem cell transplantation: pre-clinical and clinical approaches. Semin Immunopathol 2008; 30:457.
  196. Seach N, Layton D, Lim J, et al. Thymic generation and regeneration: a new paradigm for establishing clinical tolerance of stem cell-based therapies. Curr Opin Biotechnol 2007; 18:441.
  197. Ott HC, Matthiesen TS, Goh SK, et al. Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart. Nat Med 2008; 14:213.
  198. Uygun BE, Soto-Gutierrez A, Yagi H, et al. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 2010; 16:814.
  199. Ott HC, Clippinger B, Conrad C, et al. Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med 2010; 16:927.
  200. Petersen TH, Calle EA, Zhao L, et al. Tissue-engineered lungs for in vivo implantation. Science 2010; 329:538.
  201. Seach N, Mattesich M, Abberton K, et al. Vascularized tissue engineering mouse chamber model supports thymopoiesis of ectopic thymus tissue grafts. Tissue Eng Part C Methods 2010; 16:543.