Skip to main content

Advertisement

SpringerLink
Log in

The immunopathology of thymic GVHD

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

The clinical success of allogeneic hematopoietic stem cell transplantation (HSCT) depends on the appropriate reconstitution of the host’s immune system. While recovery of T-cell immunity may occur in transplant recipients via both thymus-dependent and thymus-independent pathways, the regeneration of a population of phenotypically naive T cells with a broad receptor repertoire relies entirely on the de novo generation of T-cells in the thymus. Preclinical models and clinical studies of allogeneic HSCT have identified the thymus as a target of graft-versus-host disease (GVHD), thus limiting T-cell regeneration. The present review focuses on recent insight into how GVHD affects thymic structure and function and how this knowledge may aid in the design of new strategies to improve T-cell reconstitution following allogeneic HSCT.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Mackall CL (2000) T-cell immunodeficiency following cytotoxic antineoplastic therapy: a review. Stem Cells 18:10–18. doi:10.1634/stemcells.18-1-10

    PubMed  CAS  Google Scholar 

  2. Haynes BF, Markert ML, Sempowski GD, Patel DD, Hale LP (2000) The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Annu Rev Immunol 18:529–560. doi:10.1146/annurev.immunol.18.1.529

    PubMed  CAS  Google Scholar 

  3. Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M, Koup RA, Betts MR, Collins RH, Douek DC (2001) Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 97:1458–166. doi:10.1182/blood.V97.5.1458

    PubMed  CAS  Google Scholar 

  4. Van den Brink MR, Alpdogan O, Boyd RL (2004) Strategies to enhance T-cell reconstitution in immunocompromised patients. Nat Rev Immunol 4:856–867. doi:10.1038/nri1484

    PubMed  Google Scholar 

  5. Auletta JJ, Lazarus HM (2005) Immune restoration following hematopoietic stem cell transplantation: an evolving target. Bone Marrow Transplant 35:835–857. doi:10.1038/sj.bmt.1704966

    PubMed  CAS  Google Scholar 

  6. Antin JH (2005) Immune reconstitution: the major barrier to successful stem cell transplantation. Biol Blood Marrow Transplant 11:43–45. doi:10.1016/j.bbmt.2004.11.010

    PubMed  Google Scholar 

  7. Muraro PA, Douek DC (2006) Renewing the T cell repertoire to arrest autoimmune aggression. Trends Immunol 27:61–67. doi:10.1016/j.it.2005.12.003

    PubMed  CAS  Google Scholar 

  8. Crooks GM, Weinberg K, Mackall C (2006) Immune reconstitution: from stem cells to lymphocytes. Biol Blood Marrow Transplant 12:42–46. doi:10.1016/j.bbmt.2005.10.015

    PubMed  Google Scholar 

  9. Peggs KS (2006) Reconstitution of adaptive and innate immunity following allogeneic hematopoietic stem cell transplantation in humans. Cytotherapy 8:427–436. doi:10.1080/14653240600851938

    PubMed  CAS  Google Scholar 

  10. Welniak LA, Blazar BR, Murphy WJ (2007) Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 25:139–170. doi:10.1146/annurev.immunol.25.022106.141606

    PubMed  CAS  Google Scholar 

  11. Chidgey A, Dudakov J, Seach N, Boyd R (2007) Impact of niche aging on thymic regeneration and immune reconstitution. Semin Immunol 19:331–340. doi:10.1016/j.smim.2007.10.006

    PubMed  CAS  Google Scholar 

  12. Zakrzewski JL, Goldberg GL, Smith OM, van den Brink MRM (2008) Enhancing T cell reconstitution after hematopoietic stem cell transplantation: a brief update of the latest trends. Blood Cells Mol Dis 40:44–47. doi:10.1016/j.bcmd.2007.07.015

    PubMed  CAS  Google Scholar 

  13. Toubert A (2008) Immune reconstitution after allogeneic HSCT. In Hematopoietic Stem Cell Transplantation. European School of Haematology, Paris

    Google Scholar 

  14. Krenger W, Holländer GA (2008) The thymus in GVHD pathophysiology. Best Pract Res Clin Haematol 21:119–128. doi:10.1016/j.beha.2008.02.001

    PubMed  CAS  Google Scholar 

  15. Storek J (2008) Immunological reconstitution after hematopoietic cell transplantation—its relation to the contents of the graft. Expert Opin Biol Ther 8:583–597. doi:10.1517/14712598.8.5.583

    PubMed  CAS  Google Scholar 

  16. 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 82:2585–2594

    PubMed  CAS  Google Scholar 

  17. Bahceci E, Epperson D, Douek DC, Melenhorst JJ, Childs RC, Barrett AJ (2003) Early reconstitution of the T-cell repertoire after non-myeloablative peripheral blood stem cell transplantation is from post-thymic T-cell expansion and is unaffected by graft-versus-host disease or mixed chimerism. Br J Haematol 122:934–943. doi:10.1046/j.1365-2141.2003.04522.x

    PubMed  Google Scholar 

  18. Fallen PR, McGreavey L, Madrigal JA, Potter M, Ethell M, Prentice HG, Guimaraes A, Travers PJ (2003) Factors affecting reconstitution of the T-cell compartment in allogeneic hematopoietic cell transplant recipients. Bone Marrow Transplant 32:1001–1014. doi:10.1038/sj.bmt.1704235

    PubMed  CAS  Google Scholar 

  19. Hakim FT, Memon SA, Cepeda R, Jones EC, Chow CK, Kasten-Sportes C, Odom J, Vance BA, Christensen BL, Mackall CL, Gress RE (2005) Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 115:930–939

    PubMed  CAS  Google Scholar 

  20. Gill J, Malin M, Sutherland J, Gray DHD, Holländer GA, Boyd RL (2003) Thymic generation and regeneration. Immunol Rev 195:28–50. doi:10.1034/j.1600-065X.2003.00077.x

    PubMed  CAS  Google Scholar 

  21. Guidos C (2006) Thymus and T-lymphocyte development: what is new in the 21st century? Immunol Rev 209:5–9. doi:10.1111/j.0105-2896.2006.00368.x

    PubMed  Google Scholar 

  22. Holländer G, Gill J, Zuklys S, Iwanami N, Liu C, Takahama Y (2006) Cellular and molecular events during early thymus development. Immunol Rev 209:28–46. doi:10.1111/j.0105-2896.2006.00357.x

    PubMed  Google Scholar 

  23. Boehm T (2008) Thymus development and function. Curr Opin Immunol 20:1–7. doi:10.1016/j.coi.2008.03.001

    Google Scholar 

  24. Rothenberg EV, Moore JE, Yui MA (2008) Launching the T-cell-lineage developmental programme. Nat Rev Immunol 8:9–21. doi:10.1038/nri2232

    PubMed  CAS  Google Scholar 

  25. Petrie HT, Zúñiga-Pflücker JC (2007) Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu Rev Immunol 25:649–679. doi:10.1146/annurev.immunol.23.021704.115715

    PubMed  CAS  Google Scholar 

  26. Anderson G, Lane PJ, Jenkinson EJ (2007) Generating intrathymic microenvironments to establish T-cell tolerance. Nat Rev Immunol 7:954–963. doi:10.1038/nri2187

    PubMed  CAS  Google Scholar 

  27. Rodewald HR (2008) Thymus organogenesis. Annu Rev Immunol 26:355–388. doi:10.1146/annurev.immunol.26.021607.090408

    PubMed  CAS  Google Scholar 

  28. Van Ewijk W, Wang B, Holländer G, Kawamoto H, Spanopoulou E, Itoi M, Amagai T, Jiang YF, Germeraad WT, Chen WF, Katsura Y (1999) Thymic microenvironments, 3-D versus 2-D? Semin Immunol 11:57–64. doi:10.1006/smim.1998.0158

    PubMed  Google Scholar 

  29. Rodewald HR, Paul S, Haller C, Bluethmann H, Blum C (2001) Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414:763–768. doi:10.1038/414763a

    PubMed  CAS  Google Scholar 

  30. Rossi SW, Jenkinson WE, Anderson G, Jenkinson EJ (2006) Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441:988–991. doi:10.1038/nature04813

    PubMed  CAS  Google Scholar 

  31. Bleul CC, Corbeaux T, Reuter A, Fisch P, Mönting JS, Boehm T (2006) Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441:992–996. doi:10.1038/nature04850

    PubMed  CAS  Google Scholar 

  32. Jenkinson WE, Rossi SW, Jenkinson EJ, Anderson G (2005) Development of functional thymic epithelial cells occurs independently of lymphostromal interactions. Mech Dev 122:1294–1299. doi:10.1016/j.mod.2005.08.003

    PubMed  CAS  Google Scholar 

  33. Revest JM, Suniara RK, Kerr K, Owen JJ, Dickson C (2001) Development of the thymus requires signaling through the fibroblast growth factor receptor r2-iiib. J Immunol 167:1954–161

    PubMed  CAS  Google Scholar 

  34. Alpdogan O, Hubbard VM, Smith OM, Patel N, Lu SX, Goldberg GL, Gray DH, Feinman J, Kochman AA, Eng JM, Muriglan SJ, Suh D, Boyd RL, van den Brink MR (2006) Keratinocyte growth factor (KGF) Is required for post-natal thymic regeneration. Blood 107:2453–2460. doi:10.1182/blood-2005-07-2831

    PubMed  CAS  Google Scholar 

  35. Rossi SW, Jeker LT, Ueno T, Kuse S, Keller MP, Zuklys S, Gudkov AV, Takahama Y, Krenger W, Blazar BR, Holländer GA (2007) Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood 109:3803–3811. doi:10.1182/blood-2006-10-049767

    PubMed  CAS  Google Scholar 

  36. Chu JW, Hakim FT (2007) KGF boosts thymic architecture. Blood 109:3613–3614. doi:10.1182/blood-2007-02-072637

    CAS  Google Scholar 

  37. Van Ewijk W, Shores EW, Singer A (1994) Crosstalk in the mouse thymus. Immunol Today 15:214–217. doi:10.1016/0167-5699(94)90246-1

    PubMed  Google Scholar 

  38. Gray D, Seach N, Ueno T, Milton MK, Liston A, Lew AM, Goodnow CC, Boyd RL (2006) Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108:3777–3785. doi:10.1182/blood-2006-02-004531

    PubMed  CAS  Google Scholar 

  39. Gray D, Abramson J, Benoist C, Mathis D (2007) Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J Exp Med 204:2521–2528. doi:10.1084/jem.20070795

    PubMed  CAS  Google Scholar 

  40. Steinmann GG (1986) Changes in the human thymus during aging. Curr Top Pathol 75:43–88

    PubMed  CAS  Google Scholar 

  41. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690–695. doi:10.1038/25374

    PubMed  CAS  Google Scholar 

  42. Taub DD, Longo DL (2005) Insights into thymic aging and regeneration. Immunol Rev 205:72–93. doi:10.1111/j.0105-2896.2005.00275.x

    PubMed  CAS  Google Scholar 

  43. Gray DH, Tull D, Ueno T, Seach N, Classon BJ, Chidgey A, McConville MJ, Boyd RL (2007) A unique thymic fibroblast population revealed by the monoclonal antibody MTS-15. J Immunol 178:4956–4965

    PubMed  CAS  Google Scholar 

  44. Rossi S, Blazar BR, Farrell CL, Danilenko DM, Lacey DL, Weinberg KI, Krenger W, Holländer GA (2002) Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease. Blood 100:682–691. doi:10.1182/blood.V100.2.682

    PubMed  CAS  Google Scholar 

  45. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immunological self shadow within the thymus by the Aire protein. Science 298:1395–1401. doi:10.1126/science.1075958

    PubMed  CAS  Google Scholar 

  46. Derbinski J, Gabler J, Brors B, Tierling S, Jonnakuty S, Hergenhahn M, Peltonen L, Walter J, Kyewski B (2005) Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 202:33–45. doi:10.1084/jem.20050471

    PubMed  CAS  Google Scholar 

  47. Kyewski B, Klein L (2006) A central role for central tolerance. Annu Rev Immunol 24:571–606. doi:10.1146/annurev.immunol.23.021704.115601

    PubMed  CAS  Google Scholar 

  48. Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D (2005) The cellular mechanism of Aire control of T cell tolerance. Immunity 23:227–239. doi:10.1016/j.immuni.2005.07.005

    PubMed  CAS  Google Scholar 

  49. Pereira LE, Bostik P, Ansari AA (2005) The development of mouse APECED models provides new insight into the role of AIRE in immune regulation. Clin Dev Immunol 12:211–216. doi:10.1080/17402520500212589

    PubMed  CAS  Google Scholar 

  50. Park Y, Moon Y, Chung HY (2003) AIRE-1 (autoimmune regulator type 1) as a regulator of the thymic induction of negative selection. Ann N Y Acad Sci 1005:431–435. doi:10.1196/annals.1288.073

    PubMed  CAS  Google Scholar 

  51. Liston A, Gray DH, Lesage S, Fletcher AL, Wilson J, Webster KE, Scott HS, Boyd RL, Peltonen L, Goodnow CC (2004) Gene dosage-limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity. J Exp Med 200:1015–1026. doi:10.1084/jem.20040581

    PubMed  CAS  Google Scholar 

  52. Fontenot JD, Rudensky AY (2005) A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 6:331–337. doi:10.1038/ni1179

    PubMed  CAS  Google Scholar 

  53. Von Boehmer H (2005) Mechanisms of suppression by suppressor T cells. Nat Immunol 6:338–344. doi:10.1038/ni1180

    Google Scholar 

  54. Miyara M, Sakaguchi S (2007) Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 13:108–116. doi:10.1016/j.molmed.2007.01.003

    PubMed  CAS  Google Scholar 

  55. Aschenbrenner K, D'Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, Rolink A, Klein L (2007) Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire(+) medullary thymic epithelial cells. Nat Immunol 8:351–358. doi:10.1038/ni1444

    PubMed  CAS  Google Scholar 

  56. Gabor MJ, Scollay R, Godfrey DI (1997) Thymic T cell export is not influenced by the peripheral T cell pool. Eur J Immunol 27:2986–2993. doi:10.1002/eji.1830271135

    PubMed  CAS  Google Scholar 

  57. Michie CA, McLean A, Alcock C, Beverley PC (1992) Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 360:264–265. doi:10.1038/360264a0

    PubMed  CAS  Google Scholar 

  58. Picker LJ, Treer JR, Ferguson-Darnell B, Collins PA, Buck D, Terstappen LW (1993) Control of lymphocyte recirculation in man. I. Differential regulation of the peripheral lymph node homing receptor L-selectin on T cells during the virgin to memory cell transition. J Immunol 150:1105–1121

    PubMed  CAS  Google Scholar 

  59. McFarland RD, Douek DC, Koup RA, Picker LJ (2000) Identification of a human recent thymic emigrant phenotype. Proc Natl Acad Sci USA 97:4215–4220. doi:10.1073/pnas.070061597

    PubMed  CAS  Google Scholar 

  60. Peggs KS, Mackinnon S (2004) Immune reconstitution following hematopoietic stem cell transplantation. Br J Haematol 124:407–420. doi:10.1046/j.1365-2141.2003.04767.x

    PubMed  Google Scholar 

  61. Douek DC, Koup RA, McFarland RD, Sullivan JL, Luzuriaga K (2000) Effect of HIV on thymic function before and after antiretroviral therapy in children. J Infect Dis 181:1479–1482. doi:10.1086/315398

    PubMed  CAS  Google Scholar 

  62. Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L, Berenson JR, Collins RH, Koup RA (2000) Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355:1875–1881. doi:10.1016/S0140-6736(00)02293-5

    PubMed  CAS  Google Scholar 

  63. Patel DD, Gooding ME, Parrott RE, Curtis KM, Haynes BF, Buckley RH (2000) Thymic function after hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 342:1325–1332. doi:10.1056/NEJM200005043421804

    PubMed  CAS  Google Scholar 

  64. Markert ML, Hicks CB, Bartlett JA, Harmon JL, Hale LP, Greenberg ML, Ferrari G, Ottinger J, Boeck A, Kloster AL, McLaughlin TM, Bleich KB, Ungerleider RM, Lyerly HK, Wilkinson WE, Rousseau FS, Heath-Chiozzi ME, Leonard JM, Haase AT, Shaw GM, Bucy RP, Douek DC, Koup RA, Haynes BF, Bolognesi DP, Weinhold KJ (2000) Effect of highly active antiretroviral therapy and thymic transplantation on immunoreconstitution in HIV infection. AIDS Res Hum Retroviruses 16:403–413. doi:10.1089/088922200309061

    PubMed  CAS  Google Scholar 

  65. Steffens CM, Al-Harthi L, Shott S, Yogev R, Landay A (2000) Evaluation of thymopoiesis using T cell receptor excision circles (TRECs): differential correlation between adult and pediatric TRECs and naive phenotypes. Clin Immunol 97:95–101. doi:10.1006/clim.2000.4938

    PubMed  CAS  Google Scholar 

  66. Storek J, Joseph A, Dawson MA, Douek DC, Storer B, Maloney DG (2002) Factors influencing T-lymphopoiesis after allogeneic hematopoietic cell transplantation. Transplantation 73:1154–1158. doi:10.1097/00007890-200204150-00026

    PubMed  Google Scholar 

  67. Hochberg EP, Chillemi AC, Wu CJ (2001) Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation. Blood 98:1116–1121. doi:10.1182/blood.V98.4.1116

    PubMed  CAS  Google Scholar 

  68. Lewin SR, Heller G, Zhang L, Rodrigues E, Skulsky E, van den Brink MR, Small TN, Kernan NA, O'Reilly RJ, Ho DD, Young JW (2002) Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantation. Blood 100:2235–2242

    PubMed  CAS  Google Scholar 

  69. Hakim FT, Gress RE (2002) Reconstitution of thymic function after stem cell transplantation in humans. Curr Opin Hematol 9:490–496. doi:10.1097/00062752-200211000-00004

    PubMed  Google Scholar 

  70. Hazenberg MD, Otto SA, de Pauw ES, Roelofs H, Fibbe WE, Hamann D, Miedema F (2002) T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events. Blood 99:3449–353. doi:10.1182/blood.V99.9.3449

    PubMed  CAS  Google Scholar 

  71. Ye P, Kirschner DE (2002) Reevaluation of T cell receptor excision circles as a measure of human recent thymic emigrants. J Immunol 169:4968–4979

    Google Scholar 

  72. Svaldi M, Lanthaler AJ, Dugas M, Lohse P, Pescosta N, Straka C, Mitterer M (2003) T-cell receptor excision circles: a novel prognostic parameter for the outcome of transplantation in multiple myeloma patients. Br J Haematol 122:795–801. doi:10.1046/j.1365-2141.2003.04482.x

    PubMed  CAS  Google Scholar 

  73. Hazenberg MD, Borghans JA, de Boer RJ, Miedema F (2003) Thymic output: a bad TREC record. Nat Immunol 4:97–99. doi:10.1038/ni0203-97

    PubMed  CAS  Google Scholar 

  74. Ribeiro RM, Perelson AS (2007) Determining thymic output quantitatively: using models to interpret experimental T-cell receptor excision circle (TREC) data. Immunol Rev 216:21–34

    PubMed  CAS  Google Scholar 

  75. Hockett RD, Nunez G, Korsmeyer SJ (1989) Evolutionary comparison in murine and human delta T-cell receptor deleting elements. New Biol 1:266–274

    PubMed  CAS  Google Scholar 

  76. Verschuren MC, Wolvers-Tettero IL, Breit TM, Noordzij J, van Wering ER, van Dongen JJ (1997) Preferential rearrangements of the T cell receptor-delta-deleting elements in human T cells. J Immunol 158:1208–1216

    PubMed  CAS  Google Scholar 

  77. Poulin JF, Sylvestre M, Champagne P, Dion ML, Kettaf N, Dumont A, Lainesse M, Fontaine P, Roy DC, Perreault C, Sekaly RP, Cheynier R (2003) Evidence for adequate thymic function but impaired naive T-cell survival following allogeneic hematopoietic stem cell transplantation in the absence of chronic graft-versus-host disease. Blood 102:4600–4607. doi:10.1182/blood-2003-05-1428

    PubMed  CAS  Google Scholar 

  78. Jamieson BD, Douek DC, Killian S, Hultin LE, Scripture-Adams DD, Giorgi JV, Marelli D, Koup RA, Zack JA (1999) Generation of functional thymocytes in the human adult. Immunity 10:569–575. doi:10.1016/S1074-7613(00)80056-4

    PubMed  CAS  Google Scholar 

  79. Douek DC, Koup RA (2000) Evidence for thymic function in the elderly. Vaccine 18:1638–1641. doi:10.1016/S0264-410X(99)00499-5

    PubMed  CAS  Google Scholar 

  80. Ortman CL, Dittmar KA, Witte PL, Le PT (2002) Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments. Int Immunol 14:813–822. doi:10.1093/intimm/dxf042

    PubMed  CAS  Google Scholar 

  81. Hakim FT, Gress RE (2005) Reconstitution of the lymphocyte compartment after lymphocyte depletion: a key issue in clinical immunology. Eur J Immunol 35:3099–3102. doi:10.1002/eji.200535385

    PubMed  CAS  Google Scholar 

  82. Williams KM, Hakim FT, Gress RE (2007) T cell immune reconstitution following lymphodepletion. Semin Immunol 19:318–330. doi:10.1016/j.smim.2007.10.004

    PubMed  CAS  Google Scholar 

  83. Jameson SC (2005) T cell homeostasis: keeping useful T cells alive and live T cells useful. Semin Immunol 17:231–237. doi:10.1016/j.smim.2005.02.003

    PubMed  CAS  Google Scholar 

  84. Scollay R, Godfrey DI (1995) Thymic emigration: conveyor belts or lucky dips? Immunol Today 16:268–273. doi:10.1016/0167-5699(95)80179-0

    PubMed  CAS  Google Scholar 

  85. Gorski J, Yassai M, Zhu X, Kissela B, Kissella B [corrected to Kissela B, Keever C, Flomenberg N (1994) Circulating T cell repertoire complexity in normal individuals and bone marrow recipients analyzed by CDR3 size spectratyping. Correlation with immune status. J Immunol 152:5109–5119

    Google Scholar 

  86. Sato K, Ohtsuka K, Hasegawa K, Yamagiwa S, Watanabe H, Asakura H, Abo T (1995) Evidence for extrathymic generation of intermediate T cell receptor cells in the liver revealed in thymectomized, irradiated mice subjected to bone marrow transplantation. J Exp Med 182:759–767. doi:10.1084/jem.182.3.759

    PubMed  CAS  Google Scholar 

  87. Heitger A, Neu N, Kern H, Panzer-Grumayer ER, Greinix H, Nachbaur D, Niederwieser D, Fink FM (1997) Essential role of the thymus to reconstitute naive (CD45RA+) T-helper cells after human allogeneic bone marrow transplantation. Blood 90:850–857

    PubMed  CAS  Google Scholar 

  88. Heitger A, Greinix H, Mannhalter C, Mayerl D, Kern H, Eder J, Fink FM, Niederwieser D, Panzer-Grumayer ER (2000) Requirement of residual thymus to restore normal T-cell subsets after human allogeneic bone marrow transplantation. Transplantation 69:2366–273. doi:10.1097/00007890-200006150-00026

    PubMed  CAS  Google Scholar 

  89. Klein AK, Patel DD, Gooding ME, Sempowski GD, Chen BJ, Liu C, Kurtzberg J, Haynes BF, Chao NJ (2001) T-Cell recovery in adults and children following umbilical cord blood transplantation. Biol Blood Marrow Transplant 7:454–466. doi:10.1016/S1083-8791(01)80013-6

    PubMed  CAS  Google Scholar 

  90. Chen X, Barfield R, Benaim E, Leung W, Knowles J, Lawrence D, Otto M, Shurtleff SA, Neale GA, Behm FG, Turner V, Handgretinger R (2005) Prediction of T-cell reconstitution by assessment of T-cell receptor excision circle before allogeneic hematopoietic stem cell transplantation in pediatric patients. Blood 105:886–893. doi:10.1182/blood-2004-04-1405

    PubMed  CAS  Google Scholar 

  91. Benz C, Martins VC, Radtke F, Bleul CC (2008) The stream of precursors that colonizes the thymus proceeds selectively through the early T lineage precursor stage of T cell development. J Exp Med 205:1187–1199. doi:10.1084/jem.20072168

    PubMed  CAS  Google Scholar 

  92. Weinberg K, Annett G, Kashyap A, Lenarsky C, Forman SJ, Parkman R (1995) The effect of thymic function on immunocompetence following bone marrow transplantation. Biol Blood Marrow Transplant 1:18–23

    PubMed  CAS  Google Scholar 

  93. Kook H, Goldman F, Padley D, Giller R, Rumelhart S, Holida M, Lee N, Peters C, Comito M, Huling D, Trigg M (1996) Reconstruction of the immune system after unrelated or partially matched T-cell-depleted bone marrow transplantation in children: immunophenotypic analysis and factors affecting the speed of recovery. Blood 88:1089–1097

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  95. Small TN, Papadopoulos EB, Boulad F, Black P, Castro-Malaspina H, Childs BH, Collins N, Gillio A, George D, Jakubowski A, Heller G, Fazzari M, Kernan N, MacKinnon S, Szabolcs P, Young JW, O'Reilly RJ (1999) Comparison of immune reconstitution after unrelated and related T-cell- depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions. Blood 93:467–480

    PubMed  CAS  Google Scholar 

  96. Douek DC (2002) The contribution of the thymus to immune reconstitution after hematopoietic stem-cell transplantation. Cytotherapy 4:425–426. doi:10.1080/146532402320776035

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  98. Storek J, Dawson MA, Storer B, Stevens-Ayers T, Maloney DG, Marr KA, Witherspoon RP, Bensinger W, Flowers ME, Martin P, Storb R, Appelbaum FR, Boeckh M (2001) Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 97:3380–339. doi:10.1182/blood.V97.11.3380

    PubMed  CAS  Google Scholar 

  99. Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, Campbell C, Memon S, Nagle JW, Hakim FT, Gress RE, McFarland HF, Burt RK, Martin R (2005) Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med 201:805–816. doi:10.1084/jem.20041679

    PubMed  CAS  Google Scholar 

  100. Fry TJ, Mackall CL (2005) Immune reconstitution following hematopoietic progenitor cell transplantation: challenges for the future. Bone Marrow Transplant 35(Suppl 1):S53–S57. doi:10.1038/sj.bmt.1704848

    PubMed  Google Scholar 

  101. Clave E, Rocha V, Talvensaari K, Busson M, Douay C, Appert ML, Rabian C, Carmagnat M, Garnier F, Filion A, Socie G, Gluckman E, Charron D, Toubert A (2005) Prognostic value of pretransplantation host thymic function in HLA-identical sibling hematopoietic stem cell transplantation. Blood 105:2608–2613. doi:10.1182/blood-2004-04-1667

    PubMed  CAS  Google Scholar 

  102. Pannetier C, Cochet M, Darche S, Casrouge A, Zöller M, Kourilsky P (1993) The sizes of the CDR3 hypervariable regions of the murine T-cell receptor beta chains vary as a function of the recombined germ-line segments. Proc Natl Acad Sci U S A 90:4319–4323. doi:10.1073/pnas.90.9.4319

    PubMed  CAS  Google Scholar 

  103. 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. doi:10.1111/j.1600-065X.1997.tb00974.x

    PubMed  CAS  Google Scholar 

  104. Mackall CL, Hakim FT, Gress RE (1997) T-cell regeneration: all repertoires are not created equal. Immunol Today 18:245–251. doi:10.1016/S0167-5699(97)81664-7

    PubMed  CAS  Google Scholar 

  105. Roux E, Helg C, Dumont-Girard F, Chapuis B, Jeannet M, Roosnek E (1996) Analysis of T-cell repopulation after allogeneic bone marrow transplantation: significant differences between recipients of T-cell depleted and unmanipulated grafts. Blood 87:3984–3992

    PubMed  CAS  Google Scholar 

  106. Talvensaari K, Clave E, Douay C, Rabian C, Garderet L, Busson M, Garnier F, Douek D, Gluckman E, Charron D, Toubert A (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 99:1458–1464. doi:10.1182/blood.V99.4.1458

    PubMed  CAS  Google Scholar 

  107. Hentschke P, Omazic B, Mattsson J, Näsman-Björk I, Lundkvist I, Gigliotti D, Barkholt L, Ringdén O, Remberger M (2005) T-cell receptor Vbeta repertoire after myeloablative and reduced intensity conditioning allogeneic haematopoietic stem cell transplantation. Scand J Immunol 61:285–294. doi:10.1111/j.1365-3083.2005.01564.x

    PubMed  CAS  Google Scholar 

  108. 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 94:4358–4369

    PubMed  CAS  Google Scholar 

  109. Eyrich M, Croner T, Leiler C, Lang P, Bader P, Klingebiel T, Niethammer D, Schlegel PG (2002) Distinct contributions of CD4+ and CD8+ naive and memory T-cell subsets to overall T-cell-receptor repertoire complexity following transplantation of T-cell-depleted CD34-selected hematopoietic progenitor cells from unrelated donors. Blood 100:1915–1918. doi:10.1182/blood-2001-11-0005

    PubMed  CAS  Google Scholar 

  110. Dey BR, Spitzer TR (2006) Current status of haploidentical stem cell transplantation. Br J Haematol 135:423–437. doi:10.1111/j.1365-2141.2006.06300.x

    PubMed  Google Scholar 

  111. Koh LP, Chao NJ (2008) Nonmyeloablative allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors: a review. Blood Cells Mol Dis 40:20–24. doi:10.1016/j.bcmd.2007.06.017

    PubMed  Google Scholar 

  112. Aversa F (2008) Haploidentical haematopoietic stem cell transplantation for acute leukaemia in adults: experience in Europe and the United States. Bone Marrow Transplant 41:473–481. doi:10.1038/sj.bmt.1705966

    PubMed  CAS  Google Scholar 

  113. Laufer TM, DeKoning J, Markowitz JS, Lo D, Glimcher LH (1996) Unopposed positive selection and autoreactivity in mice expressing class II MHC only on thymic cortex. Nature 383:81–85. doi:10.1038/383081a0

    PubMed  CAS  Google Scholar 

  114. Laufer TM, Fan L, Glimcher LH (1999) Self-reactive T cells selected on thymic cortical epithelium are polyclonal and are pathogenic in vivo. J Immunol 162:5078–5084

    PubMed  CAS  Google Scholar 

  115. Tivol E, Komorowski R, Drobyski WR (2005) Emergent autoimmunity in graft-versus-host disease. Blood 105:4885–4891. doi:10.1182/blood-2004-12-4980

    PubMed  CAS  Google Scholar 

  116. Teshima T, Reddy P, Liu C, Williams DA, KCooke KR, Ferrara JLM (2003) Impaired thymic negative selection causes autoimmune graft-versus-host disease. Blood 102:429–435. doi:10.1182/blood-2003-01-0266

    PubMed  CAS  Google Scholar 

  117. Sakoda Y, Hashimoto D, Asakura S, Takeuchi K, Harada M, Tanimoto M, Teshima T (2007) Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease. Blood 109:1756–1764. doi:10.1182/blood-2006-08-042853

    PubMed  CAS  Google Scholar 

  118. Knobloch C, Friedrich W (1991) T cell receptor diversity in severe combined immunodeficiency following HLA-haploidentical bone marrow transplantation. Bone Marrow Transplant 8:383–387

    PubMed  CAS  Google Scholar 

  119. Haddad E, Landais P, Friedrich W, Gerritsen B, Cavazzana-Calvo M, Morgan G, Bertrand Y, Fasth A, Porta F, Cant A, Espanol T, Müller S, Veys P, Vossen J, Fischer A (1998) Long-term immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: a European retrospective study of 116 patients. Blood 91:3646–3653

    PubMed  CAS  Google Scholar 

  120. Sarzotti M, Patel DD, Li X, Ozaki DA, Cao S, Langdon S, Parrott RE, Coyne K, Buckley RH (2003) T cell repertoire development in humans with SCID after nonablative allogeneic marrow transplantation. J Immunol 170:2711–2718

    PubMed  CAS  Google Scholar 

  121. Woodard P, Cunningham JM, Benaim E, Chen X, Hale G, Horwitz E, Houston J, Kasow K, Leung W, Wang W, Yusuf U, Handgretinger R (2004) Effective donor lymphohematopoietic reconstitution after haploidentical CD34+ -selected hematopoietic stem cell transplantation in children with refractory severe aplastic anemia. Bone Marrow Transplant 33:411–418. doi:10.1038/sj.bmt.1704358

    PubMed  CAS  Google Scholar 

  122. Chen X, Hale GA, Barfield R, Benaim E, Leung WH, Knowles J, Horwitz EM, Woodard P, Kasow K, Yusuf U, Behm FG, Hayden RT, Shurtleff SA, Turner V, Srivastava DK, Handgretinger R (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 135:524–532. doi:10.1111/j.1365-2141.2006.06330.x

    PubMed  Google Scholar 

  123. Friedrich W, Hönig M, Müller SM (2007) Long-term follow-up in patients with severe combined immunodeficiency treated by bone marrow transplantation. Immunol Res 38:165–173. doi:10.1007/s12026-007-0030-2

    PubMed  Google Scholar 

  124. Fu YW, Wu de P, Cen JN, Feng YF, Chang WR, Zhu ZL, Qiu QC, Zhu P (2007) Patterns of T-cell reconstitution by assessment of T-cell receptor excision circle and T-cell receptor clonal repertoire after allogeneic hematopoietic stem cell transplantation in leukemia patients-a study in Chinese patients. Eur J Haematol 79:138–145. doi:10.1111/j.1600-0609.2007.00885.x

    PubMed  CAS  Google Scholar 

  125. Touraine JL, Plotnicky H, Roncarolo MG, Bacchetta R, Gebuhrer L (2007) Immunological lessons learnt from patients transplanted with fully mismatched stem cells. Immunol Res 38:201–209. doi:10.1007/s12026-007-0002-6

    PubMed  CAS  Google Scholar 

  126. Verfuerth S, Peggs K, Vyas P, Barnett L, O'Reilly RJ, Mackinnon S (2000) Longitudinal monitoring of immune reconstitution by CDR3 size spectratyping after T-cell-depleted allogeneic bone marrow transplant and the effect of donor lymphocyte infusions on T-cell repertoire. Blood 95:3990–3995

    PubMed  CAS  Google Scholar 

  127. Hashimoto F, Sugiura K, Inoue K, Ikehara S (1997) Major histocompatibility complex restriction between hematopoietic stem cells and stromal cells in vivo. Blood 89:49–54

    PubMed  CAS  Google Scholar 

  128. Zinkernagel RM, Althage A (1999) On the role of thymic epithelium vs. bone marrow-derived cells in repertoire selection of T cells. Proc Natl Acad Sci U S A 96:8092–8097. doi:10.1073/pnas.96.14.8092

    PubMed  CAS  Google Scholar 

  129. Vukmanovic S (1992) Positive selection of T lymphocytes induced by intrathymic injection of a thymic epithelial cell line. Nature 359:729–732. doi:10.1038/359729a0

    PubMed  CAS  Google Scholar 

  130. Hugo P, Kappler JW, McCormack JE, Marrack P (1993) Fibroblasts can induce thymocyte positive selection in vivo. Proc Natl Acad Sci U S A 90:10335–10339. doi:10.1073/pnas.90.21.10335

    PubMed  CAS  Google Scholar 

  131. Pawlowski T, Elliott JD, Loh DY, Staerz UD (1993) Positive selection of T lymphocytes on fibroblasts. Nature 364:642–645. doi:10.1038/364642a0

    PubMed  CAS  Google Scholar 

  132. Choi EY, Jung KC, Park HJ, Chung DH, Song JS, Yang SD, Simpson E, Park SH (2005) Thymocyte-thymocyte interaction for efficient positive selection and maturation of CD4 T cells. Immunity 23:387–396. doi:10.1016/j.immuni.2005.09.005

    PubMed  CAS  Google Scholar 

  133. Martinic MM, Rülicke T, Althage A, Odermatt B, Höchli M, Lamarre A, Dumrese T, Speiser DE, Kyburz D, Hengartner H, Zinkernagel RM (2003) Efficient T cell repertoire selection in tetraparental chimeric mice independent of thymic epithelial MHC. Proc Natl Acad Sci U S A 100:1861–1866. doi:10.1073/pnas.252641399

    PubMed  CAS  Google Scholar 

  134. Markert ML, Boeck A, Hale LP, Kloster AL, McLaughlin TM, Batchvarova MN, Douek DC, Koup RA, Kostyu DD, Ward FE, Rice HE, Mahaffey SM, Schiff SE, Buckley RH, Haynes BF (1999) Transplantation of thymus tissue in complete DiGeorge syndrome. N Engl J Med 341:1180–1189. doi:10.1056/NEJM199910143411603

    PubMed  CAS  Google Scholar 

  135. Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, Chinn IK, Hale LP, Kepler TB, He M, Sarzotti M, Skinner MA, Rice HE, Hoehner JC (2007) Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood 109:4539–4547. doi:10.1182/blood-2006-10-048652

    PubMed  CAS  Google Scholar 

  136. Markert ML, Kostyu DD, Ward FE, McLaughlin TM, Watson TJ, Buckley RH, Schiff SE, Ungerleider RM, Gaynor JW, Oldham KT, Mahaffey SM, Ballow M, Driscoll DA, Hale LP, Haynes BF (1997) Successful formation of a chimeric human thymus allograft following transplantation of cultured postnatal human thymus. J Immunol 158:998–1005

    PubMed  CAS  Google Scholar 

  137. Blazar BR, Murphy WJ (2005) Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD). Philos Trans R Soc Lond B Biol Sci 360:1747–1767. doi:10.1098/rstb.2005.1701

    PubMed  CAS  Google Scholar 

  138. Deeg HJ, Antin JH (2006) The clinical spectrum of acute graft-versus-host disease. Semin Hematol 43:24–31. doi:10.1053/j.seminhematol.2005.09.003

    PubMed  Google Scholar 

  139. Ferrara JLM (2007) Novel strategies for the treatment and diagnosis of graft-versus-host disease. Best Pract Res Clin Haematol 20:91–97. doi:10.1016/j.beha.2006.11.004

    PubMed  Google Scholar 

  140. Weisdorf D (2007) GVHD the nuts and bolts. Hematology (Am Soc Hematol Educ Program) 2007:62–67. doi:10.1182/asheducation-2007.1.62

    Google Scholar 

  141. Bacigalupo A (2007) Management of acute graft-versus-host disease. Br J Haematol 137:87–98. doi:10.1111/j.1365-2141.2007.06533.x

    PubMed  CAS  Google Scholar 

  142. Morris ES, Hill GR (2007) Advances in the understanding of acute graft-versus-host disease. Br J Haematol 137:3–19

    PubMed  CAS  Google Scholar 

  143. Ferrara JLM (2006) GVHD: in vivo veritas. Blood 106:772–773. doi:10.1182/blood-2005-05-1925

    Google Scholar 

  144. Ochs L, Shu XO, Miller J, Enright H, Wagner J, Filipovich A, Miller W, Weisdorf D (1995) Late infections after allogeneic bone marrow transplantations: comparison of incidence in related and unrelated donor transplant recipients. Blood 86:3979–3986

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  146. Weinberg KI (2007) Protection from posttransplantation immune deficiency? Blood 109:3617–3618. doi:10.1182/blood-2007-02-073064

    CAS  Google Scholar 

  147. Gratwohl A, Baldomero H, Frauendorfer K, Urbano-Ispizua A, Niederwieser D (2007) Results of the EBMT activity survey 2005 on haematopoietic stem cell transplantation: focus on increasing use of unrelated donors. Bone Marrow Transplant 39:71–87. doi:10.1038/sj.bmt.1705555

    PubMed  CAS  Google Scholar 

  148. Sale GE, Alavaikko M, Schaefers KM, Mahan CT (1992) Abnormal CD4:CD8 ratios and delayed germinal center reconstitution in lymph nodes of human graft recipients with graft-versus-host disease (GVHD): an immunohistological study. Exp Hematol 20:1017–1021

    PubMed  CAS  Google Scholar 

  149. Beschorner WE, Hutchins GM, Elfenbein GJ, Santos GW (1978) The thymus in patients with allogeneic bone marrow transplants. Am J Pathol 92:173–181

    PubMed  CAS  Google Scholar 

  150. Seddik M, Seemayer TA, Lapp WS (1980) T cell functional defect associated with thymic epithelial cell injury induced by a graft-versus-host reaction. Transplantation 29:61–66. doi:10.1097/00007890-198001000-00013

    PubMed  CAS  Google Scholar 

  151. Seemayer TA, Lapp WS, Bolande RP (1978) Thymic epithelial injury in graft-versus-host reactions following adrenalectomy. Am J Pathol 93:325–338

    PubMed  CAS  Google Scholar 

  152. Lapp WS, Ghayur T, Mendez M, Seddik M, Seemeyer TA (1985) The functional and histological basis for graft-versus-host-induced immunosuppression. Immunol Rev 88:107–133. doi:10.1111/j.1600-065X.1985.tb01155.x

    PubMed  CAS  Google Scholar 

  153. Ghayur T, Seemayer T, Lapp WS (1990) Histologic correlates of immune functional deficits in graft-vs-host disease. In: Burakoff SJ, Deeg HJ, Ferrara J, Atkinson K (eds) Graft-vs.-Host Disease: Immunology, Pathophysiology, and Treatment. Marcel Dekker, New York, pp 109–132

    Google Scholar 

  154. Seemayer TA, Bolande RP (1980) Thymic involution mimicking thymic dysplasia: a consequence of transfusion-induced graft versus host disease in a premature infant. Arch Pathol Lab Med 104:141–144

    PubMed  CAS  Google Scholar 

  155. Gartner JG (1991) Thymic involution with loss of Hassall's corpuscles mimicking thymic dysplasia in a child with transfusion-associated graft-versus-host disease. Pediatr Pathol 11:449–456. doi:10.3109/15513819109064780

    PubMed  CAS  Google Scholar 

  156. Przybylski GK, Kreuzer KA, Siegert W, Schmidt CA (2007) No recovery of T-cell receptor excision circles (TRECs) after non-myeloablative allogeneic hematopoietic stem cell transplantation is correlated with the onset of GVHD. J Appl Genet 48:397–404

    PubMed  Google Scholar 

  157. Krenger W, Schmidlin H, Cavadini G, Holländer GA (2004) On the relevance of TCR rearrangement circles as molecular markers for thymic output during experimental graft-versus-host disease. J Immunol 172:7359–7367

    PubMed  CAS  Google Scholar 

  158. Krenger W, Ferrara JL (1996) Graft-versus-host disease and the Th1/Th2 paradigm. Immunol Res 15:50–73. doi:10.1007/BF02918284

    PubMed  CAS  Google Scholar 

  159. Krenger W, Hill GR, Ferrara JL (1997) Cytokine cascades in acute graft-versus-host disease. Transplantation 64:553–558. doi:10.1097/00007890-199708270-00001

    PubMed  CAS  Google Scholar 

  160. Hill GR, Ferrara JL (2000) The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood 95:2754–2759

    PubMed  CAS  Google Scholar 

  161. Reddy P, Ferrara JL (2003) Immunobiology of acute graft-versus-host disease. Blood Rev 17:187–194. doi:10.1016/S0268-960X(03)00009-2

    PubMed  Google Scholar 

  162. Wysocki CA, Panoskaltsis-Mortari A, Blazar BR, Serody JS (2005) Leukocyte migration and graft-versus-host disease. Blood 105:4191–4199. doi:10.1182/blood-2004-12-4726

    PubMed  CAS  Google Scholar 

  163. Ferrara JL, Reddy P (2006) Pathophysiology of graft-versus-host disease. Semin Hematol 43:3–10. doi:10.1053/j.seminhematol.2005.09.001

    PubMed  CAS  Google Scholar 

  164. Shlomchik WD (2007) Graft-versus-host disease. Nat Rev Immunol 7:340–352. doi:10.1038/nri2000

    PubMed  CAS  Google Scholar 

  165. Riddell SR, Appelbaum FR (2007) Graft-versus-host disease: a surge of developments. PLoS Med 4:1174–1177. doi:10.1371/journal.pmed.0040198

    CAS  Google Scholar 

  166. Via CS, Sharrow SO, Shearer GM (1987) Role of cytotoxic T lymphocytes in the prevention of lupus-like disease occurring in a murine model of graft-versus-host disease. J Immunol 139:1840–1849

    PubMed  CAS  Google Scholar 

  167. Via CS, Finkelman FD (1993) Critical role of interleukin-2 in the development of acute graft-versus-host disease. Int Immunol 5:565–572. doi:10.1093/intimm/5.6.565

    PubMed  CAS  Google Scholar 

  168. Via CS, Rus V, Gately MK, Finkelman FD (1994) IL-12 stimulates the development of acute graft-versus-host disease in mice that would normally develop chronic, autoimmune graft-versus-host disease. J Immunol 153:4040

    PubMed  CAS  Google Scholar 

  169. Garside P, Reid S, Steel M, Mowat AM (1994) Differential cytokine production associated with distinct phases of murine graft-versus-host reaction. Immunology 82:211–214

    PubMed  CAS  Google Scholar 

  170. Krenger W, Snyder KM, Byon JC, Falzarano G, Ferrara JL (1995) Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft-versus-host disease. J Immunol 155:585–593

    PubMed  CAS  Google Scholar 

  171. Krenger W, Falzarano G, Delmonte J, Snyder KM, Byon JC, Ferrara JL (1996) Interferon-gamma suppresses T-cell proliferation to mitogen via the nitric oxide pathway during experimental acute graft-versus-host disease. Blood 88:1113–1121

    PubMed  CAS  Google Scholar 

  172. Krenger W, Rossi S, Piali L, Holländer GA (2000) Thymic atrophy in murine acute graft-versus-host disease is effected by impaired cell cycle progression of host pro-T and pre-T cells. Blood 96:347–354

    PubMed  CAS  Google Scholar 

  173. Hauri-Hohl MM, Keller MP, Gill J, Hafen K, Pachlatko E, Boulay T, Peter A, Holländer GA, Krenger W (2007) Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation. Blood 109:4080–4088. doi:10.1182/blood-2006-07-034157

    PubMed  CAS  Google Scholar 

  174. Seemayer TA, Lapp WS, Bolande RP (1977) Thymic involution in murine graft-versus-host reaction. Epithelial injury mimicking human thymic dysplasia. Am J Pathol 88:119–133

    PubMed  CAS  Google Scholar 

  175. Fukuzawa M, Via CS, Shearer GM (1988) Defective thymic education of L3T4+ T helper cell function in graft-vs-host mice. J Immunol 141:430–439

    PubMed  CAS  Google Scholar 

  176. 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 133:39–46

    PubMed  CAS  Google Scholar 

  177. Fukushi N, Arase H, Wang B, Ogasawara K, Gotohda T, Good RA, Onoe K (1990) Thymus: a direct target tissue in graft-versus-host reaction after allogeneic bone marrow transplantation that results in abrogation of induction of self-tolerance. Proc Natl Acad Sci U S A 87:6301–6305. doi:10.1073/pnas.87.16.6301

    PubMed  CAS  Google Scholar 

  178. 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 178:805–814. doi:10.1084/jem.178.3.805

    PubMed  CAS  Google Scholar 

  179. Holländer GA, Widmer B, Burakoff SJ (1994) Loss of normal thymic repertoire selection and persistence of autoreactive T cells in graft vs. host disease. J Immunol 152:1609–1617

    PubMed  Google Scholar 

  180. Dulude G, Roy DC, Perreault C (1999) The effect of graft-versus-host disease on T cell production and homeostasis. J Exp Med 189:1329–1342. doi:10.1084/jem.189.8.1329

    PubMed  CAS  Google Scholar 

  181. Van den Brink MR, Moore E, Ferrara JL, Burakoff SJ (2000) Graft-versus-host-disease-associated thymic damage results in the appearance of T cell clones with anti-host reactivity. Transplantation 69:446–449. doi:10.1097/00007890-200002150-00026

    PubMed  Google Scholar 

  182. Morohashi T, Ogasawara K, Kitaichi N, Iwabuchi K, Onoé K (2000) Abrogation of negative selection by GVHR induced by minor histocompatibility antigens or H-2D antigen alone. Immunobiology 202:268–279

    PubMed  CAS  Google Scholar 

  183. Krenger W, Rossi S, Holländer GA (2000) Apoptosis of thymocytes during acute graft-versus-host disease is independent of glucocorticoids. Transplantation 69:2190–2193. doi:10.1097/00007890-200005270-00040

    PubMed  CAS  Google Scholar 

  184. Huiskamp R, van Ewijk W (1985) Repopulation of the mouse thymus after sublethal fission neutron irradiation. I. Sequential appearance of thymocyte subpopulations. J Immunol 134:2161–2219

    PubMed  CAS  Google Scholar 

  185. Huiskamp R, Davids JA, van Ewijk W (1988) The effect of graded doses of fission neutrons or X rays on the stromal compartment of the thymus in mice. Radiat Res 113:25–39. doi:10.2307/3577177

    PubMed  CAS  Google Scholar 

  186. Kumamoto T, Inaba M, Toki J, Adachi Y, Imamura H, Ikehara S (1995) Cytotoxic effects of irradiation and deoxyguanosine on fetal thymus. Immunobiology 192:365–381

    PubMed  CAS  Google Scholar 

  187. Gleichmann E, Pals ST, Rolink AG, Radaskiewicz T, Gleichmann H (1984) Graft-versus-host reactions: clues to the etiopathology of a spectrum of immunological diseases. Immunol Today 5:324. doi:10.1016/0167-5699(84)90126-9

    Google Scholar 

  188. Godfrey DI, Kennedy J, Suda T, Zlotnik A (1993) A developmental pathway involving four phenotypically and functionally distinct substes of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J Immunol 150:4244–4252

    PubMed  CAS  Google Scholar 

  189. Penit C, Lucas B, Vasseur F (1995) Cell expansion and growth arrest phases during the transition from precursor (CD4–8-) to immature (CD4+8+) thymocytes in normal and genetically modified mice. J Immunol 154:5103–5513

    PubMed  CAS  Google Scholar 

  190. Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284:555–556. doi:10.1038/284555a0

    PubMed  CAS  Google Scholar 

  191. Khairallah M, Spach C, Maitre F, Motta R (1988) Endocrine involvement in minor (non-H-2) graft versus host reaction in mice: dissociated effect on corticosterone and aldosterone plasma levels. Endocrinology 123:1949–1954

    Article  PubMed  CAS  Google Scholar 

  192. Kornbluth M, You-Ten E, Desbarats J, Gamache S, Xenocostas A, Lapp WS (1991) T cell subsets in the thymus of graft-versus-host immunosuppressed mice. Sensitivity of the L3T4+Lyt-2- subset to cortisone. Transplantation 51:262–267. doi:10.1097/00007890-199101000-00044

    PubMed  CAS  Google Scholar 

  193. You-Ten KE, Lapp WS (1996) The role of endogenous glucocorticoids on host T cell populations in the peripheral lymphoid organs of mice with graft-versus-host disease. Transplantation 61:76–83. doi:10.1097/00007890-199601150-00016

    PubMed  CAS  Google Scholar 

  194. Gao EK, Kosaka H, Surh CD, Sprent J (1991) T cell contact with Ia antigens on nonhemopoietic cells in vivo can lead to immunity rather than tolerance. J Exp Med 174:435–446. doi:10.1084/jem.174.2.435

    PubMed  CAS  Google Scholar 

  195. Kosaka H, Surh CD, Sprent J (1992) Stimulation of mature unprimed CD8+ T cells by semiprofessional antigen-presenting cells in vivo. J Exp Med 176:1291–1302. doi:10.1084/jem.176.5.1291

    PubMed  CAS  Google Scholar 

  196. Dakic A, Shao QX, D'Amico A, O'Keeffe M, Chen WF, Shortman K, Wu L (2004) Development of the dendritic cell system during mouse ontogeny. J Immunol 172:1018–1027

    PubMed  CAS  Google Scholar 

  197. Pimenta-Araujo R, Mascarell L, Huesca M, Cumano A, Bandeira A (2001) Embryonic thymic epithelium naturally devoid of APCs is acutely rejected in the absence of indirect recognition. J Immunol 167:5034–5041

    PubMed  CAS  Google Scholar 

  198. Yang SJ, Ahn S, Park CS, Holmes KL, Westrup J, Chang CH, Kim MG (2006) The quantitative assessment of MHC II on thymic epithelium: implications in cortical thymocyte development. Int Immunol 18:729–739. doi:10.1093/intimm/dxl010

    PubMed  CAS  Google Scholar 

  199. Michie SA, Kirkpatrick EA, Rouse RV (1988) Rare peripheral T cells migrate to and persist in normal mouse thymus. J Exp Med 168:1929–1934. doi:10.1084/jem.168.5.1929

    PubMed  CAS  Google Scholar 

  200. Agus D, Surh C, Sprent J (1991) Reentry of T cells to the adult thymus is restricted to activated T cells. J Exp Med 173:1039–1046. doi:10.1084/jem.173.5.1039

    PubMed  CAS  Google Scholar 

  201. Surh CD, Sprent J, Webb SR (1993) Exclusion of circulating T cells from the thymus does not apply in the neonatal period. J Exp Med 177:379–385. doi:10.1084/jem.177.2.379

    PubMed  CAS  Google Scholar 

  202. Westermann J, Smith T, Peters U, Tschernig T, Pabst R, Steinhoff G, Sparshott SM, Bell EB (1996) Both activated and nonactivated leukocytes from the periphery continuously enter the thymic medulla of adult rats: phenotypes, sources and magnitude of traffic. Eur J Immunol 26:1866–1874. doi:10.1002/eji.1830260830

    PubMed  CAS  Google Scholar 

  203. Daikeler T, Tyndall A (2007) Autoimmunity following haematopoietic stem-cell transplantation. Best Pract Res Clin Haematol 20:349–360. doi:10.1016/j.beha.2006.09.008

    PubMed  CAS  Google Scholar 

  204. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME (2005) 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 11:945–956. doi:10.1016/j.bbmt.2005.09.004

    PubMed  Google Scholar 

  205. Mackey JR, Desai S, Larratt L, Cwik V, Nabholtz JM (1997) Myasthenia gravis in association with allogeneic bone marrow transplantation: clinical observations, therapeutic implications and review of literature. Bone Marrow Transplant 19:939–942. doi:10.1038/sj.bmt.1700759

    PubMed  CAS  Google Scholar 

  206. Chu YW, Gress RE (2008) Murine models of chronic graft-versus-host disease: insights and unresolved issues. Biol Blood Marrow Transplant 14:365–378. doi:10.1016/j.bbmt.2007.12.002

    PubMed  CAS  Google Scholar 

  207. McCormick LL, Zhang Y, Tootell E, Gilliam AC (1999) Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human scleroderma. J Immunol 163:5693–5699

    PubMed  CAS  Google Scholar 

  208. Zhang C, Todorov I, Zhang Z, Liu Y, Kandeel F, Forman S, Strober S, Zeng D (2006) Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations. Blood 107:2993–3001. doi:10.1182/blood-2005-09-3623

    PubMed  CAS  Google Scholar 

  209. Anderson BE, McNiff JM, Matte C, Athanasiadis I, Shlomchik WD, Shlomchik MJ (2004) Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease. Blood 104:1565–1573. doi:10.1182/blood-2004-01-0328

    PubMed  CAS  Google Scholar 

  210. Zhang Y, Hexner E, Frank D, Emerson SG (2007) CD4+ T cells generated de novo from donor hemopoietic stem cells mediate the evolution from acute to chronic graft-versus-host disease. J Immunol 179:3305–3314

    PubMed  CAS  Google Scholar 

  211. Chen X (2007) Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. Blood 110:3804–3813. doi:10.1182/blood-2007-05-091074

    PubMed  CAS  Google Scholar 

  212. Goldberg G (2007) Clinical strategies to enhance T cell reconstitution. Semin Immunol 19:289–296. doi:10.1016/j.smim.2007.08.001

    PubMed  CAS  Google Scholar 

  213. Finch PW, Rubin JS (2004) Keratinocyte growth factor/fibroblast growth factor 7, a homeostatic factor with therapeutic potential for epithelial protection and repair. Adv Cancer Res :69–115. doi:10.1016/S0065-230X(04)91003-2

  214. Radtke ML, Kolesar JM (2005) Palifermin (Kepivance) for the treatment of oral mucositis in patients with hematologic malignancies requiring hematopoietic stem cell support. J Oncol Pharm Pract 11:121–125. doi:10.1191/1078155205jp159oa

    PubMed  CAS  Google Scholar 

  215. Siddiqui MA, Wellington K (2005) Palifermin: in myelotoxic therapy-induced oral mucositis. Drugs 65:2139–2146. doi:10.2165/00003495-200565150-00008

    PubMed  Google Scholar 

  216. Guo L, Degenstein L, Fuchs E (1996) Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev 10:165–175. doi:10.1101/gad.10.2.165

    PubMed  CAS  Google Scholar 

  217. Min D, Panoskaltsis-Mortari A, Kuro OM, Hollander GA, Blazar BR, Weinberg KI (2007) Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 109:2529–2537. doi:10.1182/blood-2006-08-043794

    PubMed  CAS  Google Scholar 

  218. Min D, Taylor PA, Panoskaltsis-Mortari A, Chung B, Danilenko DM, Farrell C, Lacey DL, Blazar BR, Weinberg KI (2002) 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 99:4592–4600. doi:10.1182/blood.V99.12.4592

    PubMed  CAS  Google Scholar 

  219. Seggewiss R, Loré K, Guenaga FJ, Pittaluga S, Mattapallil J, Chow CK, Koup RA, Camphausen K, Nason MC, Meier-Schellersheim M, Donahue RE, Blazar BR, Dunbar CE, Douek DC (2007) Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques. Blood 110:441–449. doi:10.1182/blood-2006-12-065623

    PubMed  CAS  Google Scholar 

  220. Blazar BR, Weisdorf DJ, DeFor TE, Goldman A, Braun T, Silver S, Ferrara JLM (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 108:3216–3222. doi:10.1182/blood-2006-04-017780

    PubMed  CAS  Google Scholar 

  221. Seggewiss R, Einsele H (2007) Hematopoietic growth factors including keratinocyte growth factor in allogeneic and autologous stem cell transplantation. Semin Hematol 44:203–211. doi:10.1053/j.seminhematol.2007.04.009

    PubMed  CAS  Google Scholar 

  222. Kelly RM, Highfill SL, Panoskaltsis-Mortari A, Taylor PA, Boyd RL, Holländer GA, Blazar BR (2008) 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 111:5734–5744. doi:10.1182/blood-2008-01-136531

    PubMed  CAS  Google Scholar 

  223. Heng TS, Goldberg GL, Gray DH, Sutherland JS, Chidgey AP, Boyd RL (2005) Effects of castration on thymocyte development in two different models of thymic involution. J Immunol 175:2982–2993

    PubMed  CAS  Google Scholar 

  224. Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS, Blazar BR, Millar JL, Malin MA, Chidgey AP, Boyd RL (2005) Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 175:2741–2753

    PubMed  CAS  Google Scholar 

  225. Olsen NJ, Olson G, Viselli SM, Gu X, Kovacs WJ (2001) Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology 142:1278–1283. doi:10.1210/en.142.3.1278

    PubMed  CAS  Google Scholar 

  226. Erickson M, Morkowski S, Lehar S, Gillard G, Beers C, Dooley J, Rubin JS, Rudensky A, Farr AG (2002) Regulation of thymic epithelium by keratinocyte growth factor. Blood 100:3269–278. doi:10.1182/blood-2002-04-1036

    PubMed  CAS  Google Scholar 

  227. Suniara RK, Jenkinson EJ, Owen JJ (2000) An essential role for thymic mesenchyme in early T cell development. J Exp Med 191:1051–1056. doi:10.1084/jem.191.6.1051

    PubMed  CAS  Google Scholar 

  228. Revest JM, Spencer-Dene B, Kerr K, De Moerlooze L, Rosewell I, Dickson C (2001) Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4. Dev Biol 231:47–62. doi:10.1006/dbio.2000.0144

    PubMed  CAS  Google Scholar 

  229. Brauchle M, Fässler R, Werner S (1995) Suppression of keratinocyte growth factor expression by glucocorticoids in vitro and during wound healing. J Invest Dermatol 105:579–584. doi:10.1111/1523-1747.ep12323521

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomedicine, University of Basel, Basel, 4005, Switzerland

    Werner Krenger & Georg A. Holländer

  2. Basel University Children’s Hospital (UKBB), Basel, 4005, Switzerland

    Werner Krenger & Georg A. Holländer

  3. Laboratory of Pediatric Immunology, Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland

    Werner Krenger & Georg A. Holländer

Authors
  1. Werner Krenger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Georg A. Holländer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Werner Krenger or Georg A. Holländer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krenger, W., Holländer, G.A. The immunopathology of thymic GVHD. Semin Immunopathol 30, 439–456 (2008). https://doi.org/10.1007/s00281-008-0131-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-008-0131-6

Keywords

Search

Navigation