International Journal of Hematology

, Volume 78, Issue 3, pp 181–187 | Cite as

The Pathophysiology of Acute Graft-versus-Host Disease

  • James L. M. Ferrara
  • Kenneth R. Cooke
  • Takanori Teshima
Progress in Hematology


The pathophysiology of acute graft-versus-host disease (GVHD) is a complex process that can be conceptualized in three phases. In the first phase, high-dose chemoradiotherapy causes damage to host tissues, including a self-limited burst of inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin 1. These cytokines activate host antigen-presenting cells (APCs). In the second phase, donor T-cells recognize alloantigens on host APCs. These activated T-cells then proliferate, differentiate into effector cells, and secrete cytokines, particularly interferon (IFN)-γ. In the third phase, target cells undergo apoptosis mediated by cellular effectors (eg, donor cytotoxic T-lymphocytes) and inflammatory cytokines such as TNF-α. TNF-α secretion is amplified by stimuli such as endotoxin that leaks across damaged gastrointestinal mucosa injured by the chemoradiotherapy in the first phase. TNF-α and IFN-γ cause further injury to gastrointestinal epithelium, causing more endo-toxin leakage and establishing a positive inflammatory feedback loop. These events are examined in detail in the following review.Int J Hematol. 2003;78:181-187. 2003 The Japanese Society of Hematology

Key words

Bone marrow transplantation Graft-versus-host disease Cytokines TNF-α IL-1β 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Xun CQ, Thompson JS, Jennings CD, Brown SA, Widmer MB. 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;83:2360–23677.PubMedGoogle Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 3.
    Hill GR, Crawford JM, Cooke KJ, Brinson YS, Pan L, Ferrara JLM. Total body irradiation and acute graft versus host disease. The role of gastrointestinal damage and inflammatory cytokines.Blood. 1997;90:3204–3213.PubMedGoogle Scholar
  4. 4.
    Fefer A, Sullivan K, Weiden P. Graft versus leukemia effect in man: the relapse rate of acute leukemia is lower after allogeneic than after syngeneic marrow transplantation. In: Truitt R, Gale R, Bortin M, eds.Cellular Immunotherapy of Cancer. New York: AR Liss; 1987:401–408.Google Scholar
  5. 5.
    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.PubMedGoogle Scholar
  6. 6.
    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.PubMedCrossRefGoogle Scholar
  7. 7.
    Teshima T, Ordemann R, Reddy P, et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium.Nat Med. 2002;8:575–581.PubMedCrossRefGoogle Scholar
  8. 8.
    Sprent J, Schaefer M, Gao EK, Korngold R. Role of T cell subsets in lethal graft-versus-host disease (GVHD) directed to class I versus class II H-2 differences, I: L3T4+ cells can either augment or retard GVHD elicited by Lyt-2+ cells in class I different hosts.J Exp Med. 1988;167:556–569.PubMedCrossRefGoogle Scholar
  9. 9.
    Goumy L, Ferran C, Merite S, Bach J-F, Chatenoud L. In vivo anti- CD3-driven cell activation.Transplantation. 1996;61:83–87.PubMedCrossRefGoogle Scholar
  10. 10.
    Doolittle DP, Davisson MT, Guidi JN, Green MC. Catalog of mutant genes and polymorphic loci. In: Lyon MF, Tastan S, Brown SDM, eds.Genetic Variants and Strains of the Laboratory Mouse. New York: Oxford University Press; 1996:17–854.Google Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    Goulmy E, Schipper R, Pool J, Blokland E, Falkenburg F. Mismatches of minor histocompatibility antigens between HLA- identical donors and recipients and the development of graft- versus-host disease after bone marrow transplantation.New Engl J Med. 1996;334:281–285.PubMedCrossRefGoogle Scholar
  13. 13.
    Nash A, Pepe MS, Storb R, et al. Acute graft-versus-host disease analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate.Blood. 1992;80:1838–18455.PubMedGoogle Scholar
  14. 14.
    Hansen JA, Gooley TA, Martin PJ, et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia.N Engl J Med. 1998;338:962–968.PubMedCrossRefGoogle Scholar
  15. 15.
    Goulmy E. Human minor histocompatibility antigens: new concepts for marrow transplantation and adoptive immunotherapy.Immunol Rev. 1997;157:125–140.PubMedCrossRefGoogle Scholar
  16. 16.
    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.Nat Med. 2002;8:410–414.PubMedCrossRefGoogle Scholar
  17. 17.
    Matzinger P. The danger model: a renewed sense of self.Science. 2002;296:301–305.PubMedCrossRefGoogle Scholar
  18. 18.
    Roncarolo MG, Levings MK, Traversari C. Differentiation of T regulatory cells by immature dendritic cells.J Exp Med. 2001; 193:F5–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Reinhardt RL, Khoruts A, Merica R, Zell T, Jenkins MK. Visualizing the generation of memory CD4 T cells in the whole body.Nature. 2001;410:101–105.PubMedCrossRefGoogle Scholar
  20. 20.
    Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells.Science. 2003;299:1033–1036.PubMedCrossRefGoogle Scholar
  21. 21.
    Ordemann R, Hutchinson R, Friedman J, et al. Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease.J Clin Invest. 2002;109:1249–12566.PubMedGoogle Scholar
  22. 22.
    Zhang Y, Shlomchik WD, Joe G, et al. APCs in the liver and spleen recruit activated allogeneic CD8+ T cells to elicit hepatic graft- versus-host disease.J Immunol. 2002;169:7111–7118.PubMedGoogle Scholar
  23. 23.
    Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants.Science. 2002;295:2097–2100.PubMedCrossRefGoogle Scholar
  24. 24.
    Ruggeri L, Capanni M, Martelli MF, Velardi A. Cellular therapy: exploiting NK cell alloreactivity in transplantation.Curr Opin Hematol. 2001;8:355–359.PubMedCrossRefGoogle Scholar
  25. 25.
    Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone, I: definition according to profiles of lymphokine activities and secreted proteins.J Immunol. 1986;136:2348–2357.PubMedGoogle Scholar
  26. 26.
    Rissoan M, Soumelis V, Kadowaki N, et al. Reciprocal control of T helper cell and dendritic cell differentiation.Science. 1999;5405:1183–11866.CrossRefGoogle Scholar
  27. 27.
    Reid SD, Penna G, Adorini L. The control of T cell responses by dendritic cell subsets.Curr Opin Immunol. 2000;12:114–121.PubMedCrossRefGoogle Scholar
  28. 28.
    Carvalho-Pinto CE, Garcia MI, Mellado M, et al. Autocrine production of IFN-gamma by macrophages controls their recruitment to kidney and the development of glomerulonephritis in MRL/lpr mice.J Immunol. 2002;169:1058–1067.PubMedGoogle Scholar
  29. 29.
    Lalor PF, Shields P, Grant A, Adams DH. Recruitment of lymphocytes to the human liver.Immunol Cell Biol. 2002;80:52–64.PubMedCrossRefGoogle Scholar
  30. 30.
    Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells.J Exp Med. 2000;192:1213–1222.PubMedCrossRefGoogle Scholar
  31. 31.
    Zeller JC, Panoskaltsis-Mortari A, Murphy WJ, et al. Induction of CD4+ T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-beta.J Immunol. 1999;163:3684–3691.PubMedGoogle Scholar
  32. 32.
    Boussiotis VA, Chen ZM, Zeller JC, et al. Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-beta-treated allore- active T cells that do not induce graft-versus-host disease.Blood. 2001;97:565–571.PubMedCrossRefGoogle Scholar
  33. 33.
    Rolink AG, Gleichmann E. Allosuppressor- and allohelper-T cells in acute and chronic graft-versus-host (GVH) disease, III: different Lyt subsets of donor T cells induce different pathological syndromes.J Exp Med. 1983;158:546–558.PubMedCrossRefGoogle Scholar
  34. 34.
    Hurtenbach U, Shearer GM. Analysis of murine T lymphocyte markers during the early phases of GvH-associated suppression of cytotoxic T lymphocyte responses.J Immunol. 1983;130:1561–1566.PubMedGoogle Scholar
  35. 35.
    Autran B, Leblond V, Sadat-Sowti Bea. A soluble factor released by CD8+CD57+ lymphocytes from bone marrow transplanted patients inhibits cell-mediated cytolysis.Blood. 1991;77:2237–2241.PubMedGoogle Scholar
  36. 36.
    Tsoi MS, Storb R, Dobbs S, et al. Non-specific suppressor cells in patients with chronic graft-versus-host disease after marrow grafting.J Immunol. 1979;123:1970–1973.PubMedGoogle Scholar
  37. 37.
    Strober S. Natural suppressor (NS) cells, neonatal tolerance, and total lymphoid irradiation: exploring obscure relationships.Annu Rev Immunol. 1984;2:219–237.PubMedCrossRefGoogle Scholar
  38. 38.
    Lan F, Zeng D, Higuchi M, Huie P, Higgins JP, Strober S. Predominance of NK1.1+TCR alpha beta+ or DX5+TCR alpha beta+ T cells in mice conditioned with fractionated lymphoid irradiation protects against graft-versus-host disease: “natural suppressor” cells.J Immunol. 2001;167:2087–2096.PubMedGoogle Scholar
  39. 39.
    Zeng D, Lewis D, Dejbakhsh-Jones S, et al. Bone marrow NK1.1(-) and NK1.1(+) T cells reciprocally regulate acute graft versus host disease.J Exp Med. 1999;189:1073–1081.PubMedCrossRefGoogle Scholar
  40. 40.
    Eberl G, MacDonald HR. Rapid death and regeneration of NKT cells in anti-CD3epsilon- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis.Immunity. 1998;9:345–353.PubMedCrossRefGoogle Scholar
  41. 41.
    Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor- type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation.J Exp Med. 2002;196:389–399.PubMedCrossRefGoogle Scholar
  42. 42.
    Kagi D, Vignaux F, Ledermann B, et al. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity.Science. 1994; 265:528–530.PubMedCrossRefGoogle Scholar
  43. 43.
    Lowin B, Hahne M, Mattmann C, Tschopp J. Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways.Nature (London). 1994;370:650–620.CrossRefGoogle Scholar
  44. 44.
    Shresta S, Pham C, Thomas D, Braubert T, Ley T. How do cytotoxic lymphocytes kill their targets?Curr Opin Immunol. 1998;10:581–5877.PubMedCrossRefGoogle Scholar
  45. 45.
    Krammer PH. CD95’s deadly mission in the immune system.Nature. 2000;407:789–795.PubMedCrossRefGoogle Scholar
  46. 46.
    Chinnaiyan A, O’Rourke K, Yu G, et al. Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95.Science. 1996;274:990–992.PubMedCrossRefGoogle Scholar
  47. 47.
    Chicheportiche Y, Bourdon PR, Xu H, et al. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis.J Biol Chem. 1997;272:32401–32410.PubMedCrossRefGoogle Scholar
  48. 48.
    Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R. The receptor for the cytotoxic ligand TRAIL.Science. 1997;276:111–1133.PubMedCrossRefGoogle Scholar
  49. 49.
    Ueno Y, Ishii M, Yahagi K, et al. Fas-mediated cholangiopathy in the murine model of graft versus host disease.Hepatology. 2000;31:966–9744.PubMedCrossRefGoogle Scholar
  50. 50.
    Shustov A, Nguyen P, Finkelman F, Elkon KB, Via CS. Differential expression of Fas and Fas ligand in acute and chronic graft-versus- host disease: up-regulation of Fas and Fas ligand requires CD8+ T cell activation and IFN-gamma production.J Immunol. 1998;161:2848–28555.PubMedGoogle Scholar
  51. 51.
    Lee S, Chong SY, Lee JW, et al. Difference in the expression of Fas/ Fas-ligand and the lymphocyte subset reconstitution according to the occurrence of acute GVHD.Bone Marrow Transplant. 1997;20:883–8888.PubMedCrossRefGoogle Scholar
  52. 52.
    Wasem C, Frutschi C, Arnold D, et al. Accumulation and activation- induced release of preformed Fas (CD95) ligand during the pathogenesis of experimental graft-versus-host disease.J Immunol. 2001;167:2936–2941.PubMedGoogle Scholar
  53. 53.
    Liem LM, van Lopik T, van NieuwenhuijzeAEM, van HouwelingenHC, Aarden L, Goulmy E. Soluble fas levels in sera of bone marrow transplantation recipients are increased during acute graft-versus-host disease but not during infections.Blood. 1998;91:1464–14688.PubMedGoogle Scholar
  54. 54.
    Das H, Imoto S, Murayama T, et al. Levels of soluble FasL and FasL gene expression during the development of graft-versus-host disease in DLT-treated patients.Br J Haematol. 1999;104:795–800.PubMedCrossRefGoogle Scholar
  55. 55.
    Kanda Y, Tanaka Y, Shirakawa K, et al. Increased soluble Fasligand in sera of bone marrow transplant recipients with acute graft-versus-host disease.Bone Marrow Transplant. 1998;22:751–7544.PubMedCrossRefGoogle Scholar
  56. 56.
    Kayaba H, Hirokawa M,Watanabe A, et al. Serum markers of graft- versus-host disease after bone marrow transplantation.J Allergy Clin Immunol. 2000;106:S40–44.PubMedCrossRefGoogle Scholar
  57. 57.
    Baker MB, Altman NH, Podack ER, Levy RB. The role of cell- mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice.J Exp Med. 1996;183:2645–26566.PubMedCrossRefGoogle Scholar
  58. 58.
    Baker MB, Riley RL, Podack ER, Levy RB. GVHD-associated lymphoid hypoplasia and B cell dysfunction is dependent upon donor T cell-mediated Fas-ligand function, but not perforin function.Proc Natl Acad Sci USA. 1997;94:1366–1371.PubMedCrossRefGoogle Scholar
  59. 59.
    Via CS, Nguyen P, Shustov A, Drappa J, Elkon KB. A major role for the Fas pathway in acute graft-versus-host disease.J Immunol. 1996;157:5387–5393.PubMedGoogle Scholar
  60. 60.
    Kondo T, Suda T, Fukuyama H, Adachi M, Nagata S. Essential roles of the Fas ligand in the development of hepatitis.Nat Med. 1997;4:409–4133.CrossRefGoogle Scholar
  61. 61.
    van denBrinkM, Moore E, Horndasch E, et al. Fas-Deficientlpr Mice are more susceptible to graft-versus-hostdisease.J Immunol. 2000;164:469–480.Google Scholar
  62. 62.
    Hattori K, Hirano T, Miyajima H, et al. Differential effects of anti- Fas ligand and anti-tumor necrosis factor-α antibodies on acute graft-versus-host disease pathologies.Blood. 1998;91:4051–4055.PubMedGoogle Scholar
  63. 63.
    Stuber E, Buschenfeld A, von FreierA, Arendt T, Folsch UR. Intestinal crypt cell apoptosis in murine acute graft versus host disease is mediated by tumour necrosis factor alpha and not by the FasL-Fas interaction: effect of pentoxifylline on the development of mucosal atrophy.Gut. 1999;45:229–235.PubMedCrossRefGoogle Scholar
  64. 64.
    Braun YM, Lowin B, French L, Acha-Orbea H, Tschopp J. Cytotoxic T cells deficient in both functional Fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease.J Exp Med. 1996;183:657–661.PubMedCrossRefGoogle Scholar
  65. 65.
    Martin PJ, Akatsuka Y, Hahne M, Sale G. Involvement of donor T-cell cytotoxic effector mechanisms in preventing allogeneic marrow graft rejection.Blood. 1998;92:2177–2181.PubMedGoogle Scholar
  66. 66.
    Jiang Z, Podack E, Levy RB. Major histocompatibility complex- mismatched allogeneic bone marrow transplantation using perforin and/or Fas ligand double-defective CD4(+) donor T cells: involvement of cytotoxic function by donor lymphocytes prior to graft-versus-host disease pathogenesis.Blood. 2001;98:390–397.PubMedCrossRefGoogle Scholar
  67. 67.
    Laster SM, Wood JG, Gooding LR. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis.J Immunol. 1988;141:2629–2634.PubMedGoogle Scholar
  68. 68.
    Hill GR, Teshima T, Rebel VI, et al. The p55 TNF-alpha receptor plays a critical role in T cell alloreactivity.J Immunol. 2000;164:656–6633.PubMedGoogle Scholar
  69. 69.
    Brown GR, Lee E, Thiele DL. TNF-TNFR2 interactions are critical for the development of intestinal graft-versus-host disease in MHC class II-disparate (C57BL/6J→C57BL/6J × bm12)F1 mice.J Immunol. 2002;168:3065–3071.PubMedGoogle Scholar
  70. 70.
    Holler E, Kolb HJ, Moller A, et al. Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation.Blood. 1990;75:1011–1016.PubMedGoogle Scholar
  71. 71.
    Holler E, Kolb HJ, Hintermeier-Knabe R, et al. The role of tumor necrosis factor alpha in acute graft-versus-host disease and complications following allogeneic bone marrow transplantation.Transplant Proc. 1993;25:1234–1236.PubMedGoogle Scholar
  72. 72.
    Tanaka J, Imamura M, Kasai M, et al. Cytokine gene expression in peripheral blood mononuclear cells during graft-versus-host disease after allogeneic bone marrow transplantation.Br J Haematol. 1993;85:558–565.PubMedCrossRefGoogle Scholar
  73. 73.
    Tanaka J, Imamura M, Kasai M, et al. Rapid analysis of tumor necrosis factor-alpha mRNA expression during venooclusive disease of the liver after allogeneic bone marrow transplantation.Transplantation. 1993;55:430–432.PubMedGoogle Scholar
  74. 74.
    Herve P, Flesch M, Tiberghien P, et al. Phase I-II trial of a monoclonal anti-tumor necrosis factor alpha antibody for the treatment of refractory severe acute graft-versus-host disease.Blood. 1992;81:1993–19999.Google Scholar
  75. 75.
    Abhyankar S, Gilliland DG, Ferrara JLM. Interleukin 1 is a critical effector molecule during cytokine dysregulation in graft-versus- host disease to minor histocompatibility antigens.Transplantation. 1993;56:1518–1523.PubMedCrossRefGoogle Scholar
  76. 76.
    Eisenberg SP, Evans RJ, Arend WP, et al. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist.Nature. 1990;343:341.PubMedCrossRefGoogle Scholar
  77. 77.
    Hannum CH, Wilcox CJ, Arend WP, et al. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor.Nature. 1990; 343:336–340.PubMedCrossRefGoogle Scholar
  78. 78.
    Antin JH, Weisdorf D, Neuberg D, et al. Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation.Blood. 2002;100:3479–3482.PubMedCrossRefGoogle Scholar
  79. 79.
    Falzarano G, Krenger W, Snyder KM, Delmonte J, Karandikar M, Ferrara JLM. Suppression of B cell proliferation to lipopolysac- charide is mediated through induction of the nitric oxide pathway by tumor necrosis factor-a in mice with acute graft-versus-host disease.Blood. 1996;87:2853–2860.PubMedGoogle Scholar
  80. 80.
    Krenger W, Falzarano G, Delmonte J, Snyder KM, Byon JCH, Ferrara JLM. Interferon-γ suppresses T-cell proliferation to mitogen via the nitric oxide pathway during experimental acute graft- versus-host disease.Blood. 1996;88:1113–1121.PubMedGoogle Scholar
  81. 81.
    Nestel FP, Greene RN, Kichian K, Ponka P, Lapp WS. Activation of macrophage cytostatic effector mechanisms during acute graft- versus-host disease: release of intracellular iron and nitric oxide- mediated cytostasis.Blood. 2000;96:1836–1843.PubMedGoogle Scholar
  82. 82.
    Weiss G, Schwaighofer H, Herold M. Nitric oxide formation as predictive parameter for acute graft-versus-host disease after human allogeneic bone marrow transplantation.Transplantation. 1995;60:1239–12444.PubMedGoogle Scholar
  83. 83.
    Langrehr JM, Murase N, Markus PM, et al. Nitric oxide production in host-versus-graft and graft-versus-host reactions in the rat.J Clin Invest. 1992;90:679–683.PubMedCrossRefGoogle Scholar
  84. 84.
    Piguet PF, Grau GE, Allet B, Vassalli PJ. Tumor necrosis factor/ cachectin is an effector of skin and gut lesions of the acute phase of graft-versus-host disease.J Exp Med. 1987;166:1280–1289.PubMedCrossRefGoogle Scholar
  85. 85.
    Cooke K, Hill G, Crawford J, et al. Tumor necrosis factor-α production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft versus host disease.J Clin Invest. 1998;102:1882–1891.PubMedCrossRefGoogle Scholar
  86. 86.
    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.PubMedGoogle Scholar
  87. 87.
    Nestel FP, Price KS, Seemayer TA, Lapp WS. Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease.J Exp Med. 1992;175:405–4133.PubMedCrossRefGoogle Scholar
  88. 88.
    Price KS, Nestel FP, Lapp WS. Progressive accumulation of bacterial lipopolysaccaride in vivo during murine acute graft-versus-host disease.Scan J Immunol. 1997;45:294–300.CrossRefGoogle Scholar
  89. 89.
    Morrison DC, Ryan JL. Endotoxins and disease mechanisms.Annu Rev Med. 1987;38:417–432.PubMedGoogle Scholar
  90. 90.
    Raetz C. Biochemistry of endotoxins.Annu Rev Biochem. 1990;59:129–1700.PubMedCrossRefGoogle Scholar
  91. 91.
    Fegan C, Poynton CH, Whittaker JA. The gut mucosal barrier in bone marrow transplantation.Bone Marrow Transplant. 1990;5:373–3777.PubMedGoogle Scholar
  92. 92.
    Jackson SK, Parton J, Barnes RA, Poynton CH, Fegan C. Effect of IgM-enriched intravenous immunoglobulin (Pentaglobulin) on endotoxaemia and anti-endotoxin antibodies in bone marrow transplantation.Eur J Clin Invest. 1993;23:540–545.PubMedCrossRefGoogle Scholar
  93. 93.
    van BekkumDW, Roodenburg J, Heidt PJ, van derWaaijD. Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora.J Nat Cancer Inst. 1974;52:401–404.PubMedGoogle Scholar
  94. 94.
    Storb R, Prentice RL, Buckner CD, et al. Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of a protective environment.N Engl J Med. 1983;308:302–307.PubMedGoogle Scholar
  95. 95.
    Moller J, Skirhoj P, Hoiby N, Peterson FB. Protection against graft versus host disease by gut sterilization?Exp Hematol. 1982;10(suppl 12):101–102.Google Scholar
  96. 96.
    Beelen DW, Haralambie E, Brandt H, et al. Evidence that sustained growth suppression of intestinal anaerobic bacteria reduces the risk of acute graft-versus-host disease after sibling marrow transplantation.Blood. 1992;80:2668–2676.PubMedGoogle Scholar
  97. 97.
    Beelen D, Elmaagacli A, Muller K, Hirche H, Schaefer U. Influence of intestinal bacterial decontamination using metronidazole and ciprofloxacin or ciprofloxacin alone on the development of acute graft-versus-host disease after marrow transplantation in patients with hematologic malignancies: final results and long-term follow- up of an open-label prospective randomized trial.Blood. 1999;93:3267–32755.PubMedGoogle Scholar
  98. 98.
    Cohen JL, Boyer O, Salomon B, Onclerq R, Charlotte F. Prevention of graft-versus-host disease in mice using a suicide gene expressed in T lymphocytes.Blood. 1997;89:4636–4645.PubMedGoogle Scholar
  99. 99.
    Bayston K, Baumgartner J, Clark P, Cohen J. Anti-endotoxin antibody for prevention of acute GVHD.Bone Marrow Transplant. 1991;8:426–427.PubMedGoogle Scholar
  100. 100.
    Christ W, Asano O, Robidoux A, et al. E5531, a pure endotoxin antagonist of high potency.Science. 1995;268:80–83.PubMedCrossRefGoogle Scholar
  101. 101.
    Housley R, Morris C, Boyle W, et al. Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract.J Clin Invest. 1994;94:1764–1777.PubMedCrossRefGoogle Scholar
  102. 102.
    Pierce G, Yanagihara D, Klopchin K, et al. Stimulation of all epithelial elements during skin regeneration by keratinocyte growth factor.J Exp Med. 1994;179:831–840.PubMedCrossRefGoogle Scholar
  103. 103.
    Panos R, Rubin J, Aaronson S, Mason R. Keratinocyte growth factor scatter factor are heparin-binding growth factors for alveolar type II cells in fibroblast-conditioned medium.J Clin Invest. 1993; 92:969–977.PubMedCrossRefGoogle Scholar
  104. 104.
    Farrell C, Bready J, Rex K, et al. Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality.Cancer Res. 1998;58:933–939.PubMedGoogle Scholar
  105. 105.
    Ulich TR, Whitcomb L, Tang W, et al. Keratinocyte growth factor ameliorates cyclophosphamide-induced ulcerative hemorrhagic cystitis.Cancer Res. 1997;57:472–475.PubMedGoogle Scholar
  106. 106.
    Yi ES, Williams ST, Lee H, et al. Keratinocyte growth factor ameliorates radiation- and bleomycin-induced lung injury and mortality.Am J Pathol. 1996;149:1963–1970.PubMedGoogle Scholar
  107. 107.
    Danilenko DM. Preclinical and early clinical development of keratinocyte growth factor, an epithelial-specific tissue growth factor.Toxicol Pathol. 1999;27:64–71.PubMedCrossRefGoogle Scholar
  108. 108.
    Frank S, Muna B, Werner S. The human homologue of a bovine- none-selenium glutathione peroxidase is a novel keratinocyte growth factor-regulated gene.Oncogene. 1997;14:915–921.PubMedCrossRefGoogle Scholar
  109. 109.
    Takeoka M, Ward WF, Pollack H, Kamp DW, Panos RJ. KGF facilitates repair of radiation-induced DNA damage in alveolar epithelial cells.Amer J Physiol. 1997;276:L1174-L1180.Google Scholar
  110. 110.
    Krijanovski OI, Hill GR, Cooke KR, et al. Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus- host disease.Blood. 1999;94:825–831.PubMedGoogle Scholar
  111. 111.
    Panoskaltsis-Mortari A, Lacey DL, Vallera DA, Blazer BR. Keratinocyte growth factor administered before conditioning ameliorates graft-versus-host disease after allogeneic bone marrow transplantation in mice.Blood. 1998;92:3960–3967.PubMedGoogle Scholar
  112. 112.
    Panoskaltsis-Mortari A, Taylor PA, Rubin JS, et al. Keratinocyte growth factor facilitates alloengraftment and ameliorates graft- versus-host disease in mice by a mechanism independent of repair of conditioning-induced tissue injury.Blood. 2000;96:4350–4356.PubMedGoogle Scholar
  113. 113.
    Panoskaltsis-Mortari A, Ingbar DH, Jung P, et al. KGF pretreatment decreases B7 and granzyme B expression and hastens repair in lungs of mice after allogeneic BMT.Am J Physiol Lung Cell Mol Physiol. 2000;278:L988-L999.PubMedGoogle Scholar
  114. 114.
    Ziegler TR, Panoskaltsus-Mortari A, Gu LH, et al. Regulation of glutathione redox status in lung and liver by conditioning regimens and keratinocyte growth factor in murine allogeneic bone marrow transplantation.Transplantation. 2001;72:1354–1362.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2003

Authors and Affiliations

  • James L. M. Ferrara
    • 1
  • Kenneth R. Cooke
    • 1
  • Takanori Teshima
    • 1
  1. 1.University of Michigan Cancer Center, Bone Marrow Transplant ProgramAnn ArborUSA

Personalised recommendations