Best Practice & Research Clinical Haematology
Volume 21, Issue 2 , Pages 101-117 , June 2008

GVHD pathophysiology: is acute different from chronic?

  • Tomomi Toubai (Postdoctoral Fellow, Department of Internal Medicine)
  • ,
  • Yaping Sun (Postdoctoral Fellow, Department of Internal Medicine)
  • ,
  • Pavan Reddy (Assistant Professor of Medicine)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +1 734 647 5954; Fax: +1 734 647 9271.

References 

  1. Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature. 2001;411:385–389
  2. Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic hematopoietic stem cell transplantation. Annual Review of Immunology. 2007;25:139–170
  3. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment. Blood. 1990;76:1464–1472
  4. Sullivan KM, Agura E, Anasetti C, et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Seminars in Hematology. 1991;28:250–259
  5. Sullivan KM, Mori M, Sanders J, et al. Late complications of allogeneic and autologous marrow transplantation. Bone Marrow Transplantation. 1992;10(Suppl. 1):127–134
  6. 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. Biology of Blood and Marrow Transplantation. 2005;11:945–956
  7. Vogelsang GB, Lee L, Bensen-Kennedy DM. Pathogenesis and treatment of graft-versus-host disease after bone marrow transplant. Annual Review of Medicine. 2003;54:29–52
  8. Sale GE, Shulman HM. The pathology of bone marrow transplantation. New York: Masson; 1984;
  9. Sale GE. Does graft-versus-host disease attack epithelial stem cells?. Molecular Medicine Today. 1996;114–119
  10. Vogelsang GB, Arai S. Mycophenolate mofetil for the prevention and treatment of graft-versus-host disease following stem cell transplantation: preliminary findings. Bone Marrow Transplantation. 2001;27:1255–1262
  11. Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. The New England Journal of Medicine. 2004;351:2265–2275
  12. Lee SJ. New approaches for preventing and treating chronic graft-versus-host disease. Blood. 2005;105:4200–4206
  13. Reddy P, Johnson K, Uberti JP, et al. Nephrotic syndrome associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplantation. 2006;38:351–357
  14. Shulman HM, Kleiner D, Lee SJ, et al. Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. Pathology Working Group Report. Biology of Blood and Marrow Transplantation. 2006;12:31–47
  15. Billingham RE. The biology of graft-versus-host reactions. Harvey Lectures. 1966;62:21–78
  16. Korngold R, Sprent J. Murine models for graft-versus-host disease. In:  Thomas ED,  Blume KG,  Forman SJ editor. Hematopoietic cell transplantation. 2nd ed. Boston: Blackwell Science, Inc.; 1999;p. 296–304
  17. Shlomchik WD. Graft-versus-host disease. Nature Reviews. Immunology. 2007;7:340–352
  18. Sun Y, Tawara I, Toubai T, et al. Pathophysiology of acute graft-versus-host disease: recent advances. Translational Research. 2007;150:197–214
  19. Riddell SR, Appelbaum FR. Graft-versus-host disease: a surge of developments. PLoS Medicine. 2007;4:e198
  20. Petersdorf EW, Malkki M. Genetics of risk factors for graft-versus-host disease. Seminars in Hematology. 2006;43:11–23
  21. Anasetti C, Amos D, Beatty PG, et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. The New England Journal of Medicine. 1989;320:197–204
  22. Petersdorf EW, Longton G, Anasetti C, et al. Donor-recipient disparities for HLA-C genes is a risk factor for graft failure following marrow transplantation from unrelated donors. Blood. 1995;86(Suppl. 1):291a
  23. Petersdorf EW, Longton GM, Anasetti C, et al. Association of HLA-C disparity with great failure after marrow transplantation from unrelated donors. Blood. 1997;89:1818–1823
  24. Flomenberg N, Baxter-Lowe LA, Confer D, et al. Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood. 2004;104:1923–1930
  25. Kawase T, Morishima Y, Matsuo K, et al. High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism. Blood. 2007;110:2235–2241
  26. Morishima Y, Sasazuki T, Inoko H, et al. The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood. 2002;99:4200–4206
  27. Spencer A, Szydlo RM, Brookes PA, et al. Bone marrow transplantation for chronic myeloid leukemia with volunteer unrelated donors using ex vivo or in vivo T-cell depletion: major prognostic impact of HLA class I identity between donor and recipient. Blood. 1995;86:3590–3597
  28. Mutis T, Gillespie G, Schrama E, et al. Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease. Natural Medicine. 1999;5:839–842
  29. Tivol E, Komorowski R, Drobyski WR. Emergent autoimmunity in graft-versus-host disease. Blood. 2005;105:4885–4891
  30. Den Haan JM, Sherman NE, Blokland E, et al. Identification of a graft versus host disease-associated human minor histocompatibility antigen. Science. 1995;268:1476–1480
  31. de Bueger M, Bakker A, Van Rood JJ, et al. Tissue distribution of human minor histocompatibility antigens. Ubiquitous versus restricted tissue distribution indicates heterogeneity among human cytotoxic T lymphocyte-defined non-MHC antigens. Journal of Immunology (Baltimore, Md.: 1950). 1992;149:1788–1794
  32. de Bueger M, Goulmy E. Human minor histocompatibility antigens. Transplant Immunology. 1993;1:28–38
  33. Goulmy E, Schipper R, Pool J, et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. The New England Journal of Medicine. 1996;334:281–285
  34. Goulmy E. Minor histocompatibility antigens: from transplantation problems to therapy of cancer. Human Immunology. 2006;67:433–438
  35. Murata M, Warren EH, Riddell SR. A human minor histocompatibility antigen resulting from differential expression due to a gene deletion. The Journal of Experimental Medicine. 2003;197:1279–1289
  36. Malarkannan S, Shih PP, Eden PA, et al. The molecular and functional characterization of a dominant minor H antigen, H60. Journal of Immunology (Baltimore, Md.: 1950). 1998;161:3501–3509
  37. Bleakley M, Riddell SR. Molecules and mechanisms of the graft-versus-leukaemia effect. Nature Reviews. Cancer. 2004;4:371–380
  38. Kaplan DH, Anderson BE, McNiff JM, et al. Target antigens determine graft-versus-host disease phenotype. Journal of Immunology (Baltimore, Md.: 1950). 2004;173:5467–5475
  39. Choi EY, Christianson GJ, Yoshimura Y, et al. Real-time T-cell profiling identifies H60 as a major minor histocompatibility antigen in murine graft-versus-host disease. Blood. 2002;100:4259–4265
  40. Choi EY, Christianson GJ, Yoshimura Y, et al. Immunodominance of H60 is caused by an abnormally high precursor T cell pool directed against its unique minor histocompatibility antigen peptide. Immunity. 2002;17:593–603
  41. Fontaine P, Roy-Proulx G, Knafo L, et al. Adoptive transfer of minor histocompatibility antigen-specific T lymphocytes eradicates leukemia cells without causing graft-versus-host disease. Natural Medicine. 2001;7:789–794
  42. Dickinson AM, Wang XN, Sviland L, et al. In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens. Natural Medicine. 2002;8:410–414
  43. Hess AD, Horwitz L, Beschorner WE, et al. Development of graft-vs.-host disease-like syndrome in cyclosporine-treated rats after syngeneic bone marrow transplantation. I. Development of cytotoxic T lymphocytes with apparent polyclonal anti-Ia specificity, including autoreactivity. The Journal of Experimental Medicine. 1985;161:718–730
  44. Hess A, Thoburn C, Bright E, et al. Specificity of effector mechanisms in syngeneic graft-vs-host disease: recognition of the MHC class II invariant chain peptide (CLIP). Transplantation Proceedings. 1997;29:725–727
  45. Holländer GA, Widmer B, Burakoff SJ. Loss of normal thymic repertoire selection and persistence of autoreactive T cells in graft vs. host disease. Journal of Immunology (Baltimore, Md.: 1950). 1994;152:1609–1617
  46. Teshima T, Reddy P, Liu C, et al. Impaired thymic negative selection causes autoimmune graft-versus-host disease. Blood. 2003;102:429–435
  47. Parkman R. Is chronic graft versus host disease an autoimmune disease?. Current Opinion in Immunology. 1993;5:800–803
  48. Sakoda Y, Hashimoto D, Asakura S, et al. Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease. Blood. 2007;109:1756–1764
  49. Randolph SS, Gooley TA, Warren EH, et al. Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood. 2004;103:347–352
  50. Miklos DB, Kim HT, Miller KH, et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood. 2005;105:2973–2978
  51. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097–2100
  52. Hsu KC, Gooley T, Malkki M, et al. KIR ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy. Biology of Blood and Marrow Transplantation. 2006;12:828–836
  53. Farag SS, Fehniger TA, Ruggeri L, et al. Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect. Blood. 2002;100:1935–1947
  54. Farag SS, Bacigalupo A, Eapen M, et al. The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. Biology of Blood and Marrow Transplantation. 2006;12:876–884
  55. Miller JS, Cooley S, Parham P, et al. Missing KIR-ligands are associated with less relapse and increased graft versus host disease (GVHD) following unrelated donor allogeneic HCT. Blood. 2007;109:5058–5061
  56. Cavet J, Middleton PG, Segall M, et al. Recipient tumor necrosis factor-alpha and interleukin-10 gene polymorphisms associate with early mortality and acute graft-versus-host disease severity in HLA-matched sibling bone marrow transplants. Blood. 1999;94:3941–3946
  57. Lin MT, Storer B, Martin PJ, et al. Relation of an interleukin-10 promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation. The New England Journal of Medicine. 2003;349:2201–2210
  58. Dickinson AM, Charron D. Non-HLA immunogenetics in hematopoietic stem cell transplantation. Current Opinion in Immunology. 2005;17:517–525
  59. Holler E, Rogler G, Brenmoehl J, et al. Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination. Blood. 2006;107:4189–4193
  60. Ritchie D, Seconi J, Wood C, et al. Prospective monitoring of tumor necrosis factor alpha and interferon gamma to predict the onset of acute and chronic graft-versus-host disease after allogeneic stem cell transplantation. Biology of Blood and Marrow Transplantation. 2005;11:706–712
  61. Xun CQ, Thompson JS, Jennings CD, et al. Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice. Blood. 1994;83:2360–2367
  62. Hill G, Ferrara J. 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. 2000;95:2754–2759
  63. Hill GR, Crawford JM, Cooke KR, et al. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood. 1997;90:3204–3213
  64. Gale RP, Bortin MM, van Bekkum DW, et al. Risk factors for acute graft-versus-host disease. British Journal of Haematology. 1987;67:397–406
  65. Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood. 1990;76:1867–1871
  66. Paris F, Fuks Z, Kang A, et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science. 2001;293:293–297
  67. Matzinger P. The danger model: a renewed sense of self. Science. 2002;296:301–305
  68. Shlomchik WD, Couzens MS, Tang CB, et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science. 1999;285:412–415
  69. Cooke K, Hill G, Crawford J, et al. Tumor necrosis factor-a production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft versus host disease. The Journal of Clinical Investigation. 1998;102:1882–1891
  70. Teshima T, Ordemann R, Reddy P, et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Natural Medicine. 2002;8:575–581
  71. Jones SC, Murphy GF, Friedman TM, et al. Importance of minor histocompatibility antigen expression by nonhematopoietic tissues in a CD4+ T cell-mediated graft-versus-host disease model. The Journal of Clinical Investigation. 2003;112:1880–1886
  72. Reddy P, Maeda Y, Liu C, et al. A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses. Natural Medicine. 2005;11:1244–1249
  73. Arpinati M, Green CL, Heimfeld S, et al. Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. Blood. 2000;95:2484–2490
  74. Auffermann-Gretzinger S, Lossos IS, Vayntrub TA, et al. Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients. Blood. 2002;99:1442–1448
  75. MacDonald KP, Rowe V, Clouston AD, et al. Cytokine expanded myeloid precursors function as regulatory antigen-presenting cells and promote tolerance through IL-10-producing regulatory T cells. Journal of Immunology (Baltimore, Md.: 1950). 2005;174:1841–1850
  76. Morris ES, MacDonald KP, Hill GR. Stem cell mobilization with G-CSF analogs: a rational approach to separate GVHD and GVL?. Blood. 2006;107:3430–3435
  77. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–252
  78. Duffner UA, Maeda Y, Cooke KR, et al. Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease. Journal of Immunology (Baltimore, Md.: 1950). 2004;172:7393–7398
  79. Sato K, Yamashita N, Baba M, et al. Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse. Immunity. 2003;18:367–379
  80. Maeda Y, Reddy P, Lowler KP, et al. Critical role of host gammadelta T cells in experimental acute graft-versus-host disease. Blood. 2005;106:749–755
  81. Chorny A, Gonzalez-Rey E, Fernandez-Martin A, et al. Vasoactive intestinal peptide induces regulatory dendritic cells that prevent acute graft-versus-host disease while maintaining the graft-versus-tumor response. Blood. 2006;107:3787–3794
  82. Macdonald KP, Kuns RD, Rowe V, et al. Effector and regulatory T cell function is differentially regulated by RelB within antigen presenting cells during GVHD. Blood. 2007;109:5049–5057
  83. Paraiso KH, Ghansah T, Costello A, et al. Induced SHIP deficiency expands myeloid regulatory cells and abrogates graft-versus-host disease. Journal of Immunology (Baltimore, Md.: 1950). 2007;178:2893–2900
  84. Merad M, Hoffmann P, Ranheim E, et al. Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease. Natural Medicine. 2004;10:510–517
  85. Rowe V, Banovic T, MacDonald KP, et al. Host B cells produce IL-10 following TBI and attenuate acute GVHD after allogeneic bone marrow transplantation. Blood. 2006;108:2485–2492
  86. Cutler C, Giri S, Jeyapalan S, et al. Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis. Journal of Clinical Oncology. 2001;19:3685–3691
  87. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. Journal of Clinical Oncology. 2005;23:5074–5087
  88. Anderson BE, McNiff JM, Jain D, et al. Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ. Blood. 2005;105:2227–2234
  89. Ratanatharathorn V, Ayash L, Reynolds C, et al. Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody. Biology of Blood and Marrow Transplantation. 2003;9:505–511
  90. Cutler C, Miklos D, Kim HT, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood. 2006;108:756–762
  91. Hauri-Hohl MM, Keller MP, Gill J, et al. Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation. Blood. 2007;109:4080–4088
  92. Hsu KC, Dupont B. Natural killer cell receptors: regulating innate immune responses to hematologic malignancy. Seminars in Hematology. 2005;42:91–103
  93. Anderson BE, McNiff J, Matte C, et al. Recipient CD4+ T cells that survive irradiation regulate chronic graft-vs.-host disease. Blood. 2004;104:1565–1573
  94. Godder KT, Henslee-Downey PJ, Mehta J, et al. Long term disease-free survival in acute leukemia patients recovering with increased gammadelta T cells after partially mismatched related donor bone marrow transplantation. Bone Marrow Transplantation. 2007;39:751–757
  95. Morris ES, MacDonald KP, Rowe V, et al. NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. The Journal of Clinical Investigation. 2005;115:3093–3103
  96. Lowsky R, Takahashi T, Liu YP, et al. Protective conditioning for acute graft-versus-host disease. The New England Journal of Medicine. 2005;353:1321–1331
  97. Shlomchik WD. Antigen presentation in graft-vs-host disease. Experimental Hematology. 2003;31:1187–1197
  98. Lechler R, Ng WF, Steinman RM. Dendritic cells in transplantation – friend or foe?. Immunity. 2001;14:357–368
  99. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature Reviews. Immunology. 2002;2:116–126
  100. Blazar BR, Taylor PA, Linsley PS, et al. In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. Blood. 1994;83:3815–3825
  101. Blazar BR, Taylor PA, Panoskaltsis-Mortari A, et al. Blockade of CD40 ligand-CD40 interaction impairs CD4+ T cell-mediated alloreactivity by inhibiting mature donor T cell expansion and function after bone marrow transplantation. Journal of Immunology (Baltimore, Md.: 1950). 1997;158:29–39
  102. Blazar BR, Taylor PA, Panoskaltis-Mortari A, et al. Co-blockade of the LFA1:ICAM and CD28/CTLA4:B7 pathways is a highly effective means of preventing acute lethal graft-versus host disease induced by fully major histocompatibility complex-disparate donor grafts. Blood. 1995;85:2607–2618
  103. Blazar BR, Kwon BS, Panoskaltsis-Mortari A, et al. Ligation of 4-1BB (CDw137) regulates graft-versus-host disease, graft-versus-leukemia, and graft rejection in allogeneic bone marrow transplant recipients. Journal of Immunology (Baltimore, Md.: 1950). 2001;166:3174–3183
  104. Blazar BR, Sharpe AH, Chen AI, et al. Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients. Blood. 2003;101:3741–3748
  105. Blazar BR, Carreno BM, Panoskaltsis-Mortari A, et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism. Journal of Immunology (Baltimore, Md.: 1950). 2003;171:1272–1277
  106. Kotani A, Hori T, Fujita T, et al. Involvement of OX40 ligand + mast cells in chronic GVHD after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplantation. 2007;39:373–375
  107. Kotani A, Ishikawa T, Matsumura Y, et al. Correlation of peripheral blood OX40+(CD134+) T cells with chronic graft-versus-host disease in patients who underwent allogeneic hematopoietic stem cell transplantation. Blood. 2001;98:3162–3164
  108. Csencsits KL, Bishop DK. Contrasting alloreactive CD4+ and CD8+ T cells: there's more to it than MHC restriction. American Journal of Transplantation. 2003;3:107–115
  109. Korngold R, Sprent J. Features of T cells causing H-2-restricted lethal graft-vs.-host disease across minor histocompatibility barriers. The Journal of Experimental Medicine. 1982;155:872–883
  110. Korngold R, Sprent J. Surface markers of T cells causing lethal graft-vs-host disease to class I vs class II H-2 differences. Journal of Immunology. 1985;135:3004–3010
  111. Korngold R, Sprent J. T cell subsets and graft-versus-host disease. Transplantation. 1987;44:335–339
  112. Wu CJ, Ritz J. Induction of tumor immunity following allogeneic stem cell transplantation. Advances in Immunology. 2006;90:133–173
  113. Ferrara J, Krenger W. Graft versus host disease: the influence of type 1 and type 2 T cell cytokines. Transfusion Medicine Reviews. 1998;12:1–17
  114. Reddy P. Pathophysiology of acute graft-versus-host disease. Hematological Oncology. 2003;21:149–161
  115. Zeiser R, Nguyen VH, Beilhack A, et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood. 2006;108:390–399
  116. Zhang H, Chua KS, Guimond M, et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Natural Medicine. 2005;11:1238–1243
  117. Liston A, Rudensky AY. Thymic development and peripheral homeostasis of regulatory T cells. Current Opinion in Immunology. 2007;19:176–185
  118. Gavin MA, Rasmussen JP, Fontenot JD, et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature. 2007;445:771–775
  119. Reddy P. Interleukin-18: recent advances. Current Opinion in Hematology. 2004;11:405–410
  120. Sykes M, Harty MW, Szot GL, et al. Interleukin-2 inhibits graft-versus-host disease-promoting activity of CD4+ cells while preserving CD4- and CD8-mediated graft-versus-leukemia effects. Blood. 1994;83:2560–2569
  121. Sykes M, Szot GL, Nguyen PL, et al. Interleukin-12 inhibits murine graft-versus-host disease. Blood. 1995;86:2429–2438
  122. Reddy P, Teshima T, Kukuruga M, et al. Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis. The Journal of Experimental Medicine. 2001;194:1433–1440
  123. Nikolic B, Lee S, Bronson R, et al. Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. The Journal of Clinical Investigation. 2000;105:1289–1298
  124. Fowler DH, Kurasawa K, Smith R, et al. Donor CD4-enriched cells of Th2 cytokine phenotype regulate graft-versus-host disease without impairing allogeneic engraftment in sublethally irradiated mice. Blood. 1994;84:3540
  125. Krenger W, Snyder KM, Byon CH, et al. Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft-versus-host disease. Journal of Immunology (Baltimore, Md.: 1950). 1995;155:585–593
  126. Pan L, Delmonte J, Jalonen C, et al. Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T-lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood. 1995;86:4422–4429
  127. Hill GR, Cooke KR, Teshima T, et al. Interleukin-11 promotes T cell polarization and prevents acute graft-versus-host disease after allogeneic bone marrow transplantation. The Journal of Clinical Investigation. 1998;102:115–123
  128. Reddy P, Teshima T, Hildebrandt G, et al. Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects. Blood. 2003;101:2877–2885
  129. Foley JE, Jung U, Miera A, et al. Ex vivo rapamycin generates donor Th2 cells that potently inhibit graft-versus-host disease and graft-versus-tumor effects via an IL-4-dependent mechanism. Journal of Immunology (Baltimore, Md.: 1950). 2005;175:5732–5743
  130. Jung U, Foley JE, Erdmann AA, et al. Ex vivo rapamycin generates Th1/Tc1 or Th2/Tc2 effector T cells with enhanced in vivo function and differential sensitivity to post-transplant rapamycin therapy. Biology of Blood and Marrow Transplantation. 2006;12:905–918
  131. Fowler DH, Gress RE. Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: considerations for the allogeneic transplantation therapy of leukemia and lymphoma. Leukemia & Lymphoma. 2000;38:221–234
  132. Okamoto I, Kohno K, Tanimoto T, et al. IL-18 prevents the development of chronic graft-versus-host disease in mice. Journal of Immunology (Baltimore, Md.: 1950). 2000;164:6067–6074
  133. Zhang Y, McCormick LL, Desai SR, et al. Murine sclerodermatous graft-versus-host disease, a model for human scleroderma: cutaneous cytokines, chemokines, and immune cell activation. Journal of Immunology (Baltimore, Md.: 1950). 2002;168:3088–3098
  134. Blazar BR, Taylor PA, Smith S, et al. Interleukin-10 administration decreases survival in murine recipients of major histocompatibility complex disparate donor bone marrow grafts. Blood. 1995;85:842–851
  135. Banovic T, MacDonald KP, Morris ES, et al. TGF-beta in allogeneic stem cell transplantation: friend or foe?. Blood. 2005;106:2206–2214
  136. Blazar BR, Taylor PA. Regulatory T cells. Biology of Blood and Marrow Transplantation. 2005;11:46–49
  137. Edinger M, Hoffmann P, Ermann J, et al. CD4(+)CD25(+) regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Natural Medicine. 2003;9:1144–1150
  138. Nguyen VH, Zeiser R, Dasilva DL, et al. In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation. Blood. 2007;109:2649–2656
  139. Stanzani M, Martins SL, Saliba RM, et al. CD25 expression on donor CD4+ or CD8+ T cells is associated with an increased risk of graft-versus-host disease following HLA-identical stem cell transplantation in humans. Blood. 2003;
  140. Miura Y, Thoburn CJ, Bright EC, et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood. 2004;104:2187–2193
  141. Zorn E, Kim HT, Lee SJ, et al. Reduced frequency of FOXP3+CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease. Blood. 2005;106:2903–2911
  142. Ziegler SF. FOXP3: of mice and men. Annual Review of Immunology. 2006;24:209–226
  143. Taylor PA, Panoskaltsis-Mortari A, Swedin JM, et al. l-Selectin(hi) but not the l-selectin(lo) CD4+ 25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. Blood. 2004;104:3804–3812
  144. Ermann J, Hoffmann P, Edinger M, et al. Only the CD62L+ subpopulation of CD4+ CD25+ regulatory T cells protects from lethal acute GVHD. Blood. 2005;105:2220–2226
  145. Zeiser R, Nguyen VH, Hou JZ, et al. Early CD30 signaling is critical for adoptively transferred CD4+ CD25+ regulatory T cells in prevention of acute graft-versus-host disease. Blood. 2007;109:2225–2233
  146. Rieger K, Loddenkemper C, Maul J, et al. Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD. Blood. 2006;107:1717–1723
  147. Meignin V, Peffault de Latour R, Zuber J, et al. Numbers of Foxp3-expressing CD4+CD25 high T cells do not correlate with the establishment of long-term tolerance after allogeneic stem cell transplantation. Experimental Hematology. 2005;33:894–900
  148. Anderson BE, McNiff J, Yan J, et al. Memory CD4+ T cells do not induce graft-versus-host disease. The Journal of Clinical Investigation. 2003;112:101–108
  149. Chen BJ, Cui X, Sempowski GD, et al. Transfer of allogeneic CD62L memory T cells without graft-versus-host disease. Blood. 2004;103:1534–1541
  150. Zhang Y, Joe G, Zhu J, et al. Dendritic cell-activated CD44hiCD8+ T cells are defective in mediating acute graft-versus-host disease but retain graft-versus-leukemia activity. Blood. 2004;103:3970–3978
  151. Maeda Y, Tawara I, Teshima T, et al. Lymphopenia-induced proliferation of donor T cells reduces their capacity for causing acute graft-versus-host disease. Experimental Hematology. 2007;35:274–286
  152. Wu Z, Bensinger SJ, Zhang J, et al. Homeostatic proliferation is a barrier to transplantation tolerance. Natural Medicine. 2004;10:87–92
  153. Dutt S, Tseng D, Ermann J, et al. Naive and memory T cells induce different types of graft-versus-host disease. Journal of Immunology (Baltimore, Md.: 1950). 2007;179:6547–6554
  154. Zhang Y, Joe G, Hexner E, et al. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Natural Medicine. 2005;11:1299–1305
  155. Yamashita K, Horowitz ME, Kwatemaa A, et al. Unique abnormalities of CD4 (+) and CD8 (+) central memory cells associated with chronic graft-versus-host disease improve after extracorporeal photopheresis. Biology of Blood and Marrow Transplantation. 2006;12:22–30
  156. Nikolic B, Khan A, Sykes M. Induction of tolerance by mixed chimerism with nonmyeloblative host conditioning: the importance of overcoming intrathymic alloresistance. Biology of Blood and Marrow Transplantation. 2001;7:144–153
  157. Zhang Y, Hexner E, Frank D, et al. CD4+ T cells generated de novo from donor hemopoietic stem cells mediate the evolution from acute to chronic graft-versus-host disease. Journal of Immunology (Baltimore, Md.: 1950). 2007;179:3305–3314
  158. Zhang C, Todorov I, Zhang Z, et al. Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations. Blood. 2006;107:2993–3001
  159. Cutler C, Antin JH. Chronic graft-versus-host disease. Current Opinion in Oncology. 2006;18:126–131
  160. She K, Gilman AL, Aslanian S, et al. Altered toll-like receptor 9 responses in circulating B cells at the onset of extensive chronic graft-versus-host disease. Biology of Blood and Marrow Transplantation. 2007;13:386–397
  161. Sarantopoulos S, Stevenson KE, Kim HT, et al. High Levels of B-cell activating factor in patients with active chronic graft-versus-host disease. Clinical Cancer Research. 2007;13:6107–6114

PII: S1521-6926(08)00006-6

doi: 10.1016/j.beha.2008.02.005

Best Practice & Research Clinical Haematology
Volume 21, Issue 2 , Pages 101-117 , June 2008