Seminars in Hematology
Volume 43, Issue 1 , Pages 3-10 , January 2006

Pathophysiology of Graft-Versus-Host Disease

  • James L.M. Ferrara

      Affiliations

    • Corresponding Author InformationAddress correspondence to James L.M. Ferrara, MD, Professor of Pediatrics and Medicine, University of Michigan Medical School, 1500 E Medical Center Dr, 6308 CCGC, Ann Arbor, MI 48109-0942.
  • ,
  • Pavan Reddy

References 

  1. Billingham RE . The biology of graft-versus-host reactions . Harvey Lecture . 1966;62:21–78
  2. Korngold R , Sprent J . T cell subsets in graft-vs.-host disease . In:  Burakoff SJ ,  Deeg HJ ,  Ferrara J , et al. editor. Graft-vs.-Host Disease (Immunology, Pathophysiology, and Treatment) . New York, NY: Dekker; 1990;p. 31–50
  3. Kernan NA , Collins NH , Juliano L , Cartagena T , Dupont B , O’Reilly RJ . Clonable T lymphocytes in T cell-depleted bone marrow transplants correlate with development of graft-v-host disease . Blood . 1986;68:770–773
  4. Zeng D , Lewis D , Dejbakhsh-Jones S, Lan F , Garcia-Ojeda M , Sibley R , 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
  5. Anderson KC . Transfusion-associated graft-versus-host disease . In:  Ferrara JLM ,  Deeg HJ ,  Burakoff SJ editor. Graft-vs.-Host Disease . New York, NY: Dekker; 1997;p. 587–605
  6. Krensky AM , Weiss A , Crabtree G, Davis MM, Parham P . T-lymphocyte-antigen interactions in transplant rejection . N Engl J Med . 1990;322:510–517
  7. Antin JH , Ferrara JLM . Cytokine dysregulation and acute graft-versus-host disease . Blood . 1992;80:2964–2968
  8. Wang H , Clouthier S , Galchev V , Misek DE , Duffner U , Min CK , et al.   Intact-protein based high-resolution three-dimensional quantitative analysis system for proteome profiling of biological fluids . Mol Cell Proteomics . 2005;4:618–625
  9. Shlomchik WD , Couzens MS , Tang CB , McNiff J , Robert ME , Liu J , et al.   Prevention of graft versus host disease by inactivation of host antigen-presenting cells . Science . 1999;285:412–415
  10. Korngold R , Sprent J . Negative selection of T cells causing lethal graft-versus-host disease across minor histocompatibility barriers. Role of the H-2 complex . J Exp Med . 1980;151:1114–1124
  11. Clift RA , Buckner CD , Appelbaum FR, Bearman SI , Petersen FB , Fisher LD , 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
  12. Hill GR , Crawford JM , Cooke KR , Brinson YS , Pan L , Ferrara JL . Total body irradiation and acute graft-versus-host disease (The role of gastrointestinal damage and inflammatory cytokines) . Blood . 1997;90:3204–3213
  13. Dey BR , Yang YG , Szot GL , Pearson DA , Sykes M . Interleukin-12 inhibits graft-versus-host disease through an Fas-mediated mechanism associated with alterations in donor T-cell activation and expansion . Blood . 1998;91:3315–3322
  14. Reddy P , Teshima T , Kukuruga M , Ordemann R , Liu C , Lowler K , et al.   Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis . J Exp Med . 2001;194:1433–1440
  15. Teshima T , Reddy P , Lowler KP , KuKuruga MA , Liu C , Cooke KR , et al.   Flt3 ligand therapy for recipients of allogeneic bone marrow transplants expands host CD8 alpha(+) dendritic cells and reduces experimental acute graft-versus-host disease . Blood . 2002;99:1825–1832
  16. Matzinger P . The danger model (A renewed sense of self) . Science . 2002;296:301–305
  17. Roncarolo MG , Levings MK , Traversari C . Differentiation of T regulatory cells by immature dendritic cells . J Exp Med . 2001;193:F5–F9
  18. 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
  19. Ordemann R , Hutchinson R , Friedman J , Burakoff SJ , Reddy P , Duffner U . Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease . J Clin Invest . 2002;109:1249–1256
  20. Ruggeri L , Capanni M , Urbani E , Perruccio K , Shlomchik WD , Tosti A , et al.   Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants . Science . 2002;295:2097–2100
  21. Ruggeri L , Capanni M , Martelli MF, Velardi A . Cellular therapy (Exploiting NK cell alloreactivity in transplantation) . Curr Opin Hematol . 2001;8:355–359
  22. 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
  23. Goulmy E , Schipper R , Pool J , Blokland E , Falkenburg JH , Vossen 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 . N Engl J Med . 1996;334:281–285
  24. Doolittle DP , Davisson MT , Guidi JN , Green MC . Catalog of mutant genes and polymorphic loci . In:  Lyon MF ,  Rastan S ,  Brown SDM editor. Genetic Variants and Strains of the Laboratory Mouse . (ed 3). Oxford, UK: Oxford University Press; 1996;p. 12–403
  25. Hansen JA , Gooley TA , Martin PJ , Appelbaum F , Chauncey TR , Clift RA , et al.   Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia . N Engl J Med . 1998;338:962–968
  26. 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
  27. Ferrara JLM , Cooke KR , Pan L , Krenger W . The immunopathophysiology of acute graft-versus-host disease . Stem Cells . 1996;14:473–489
  28. Herve P , Wijdenes J , Bergerat JP , Bordigoni P , Milpied N , Cahn JY , et al.   Treatment of corticosteroid-resistant acute graft-versus-host disease by in vivo administration of anti-interleukin-2 receptor monoclonal antibody (B-B10) . Blood . 1990;75:1017–1023
  29. Belanger C , Esperou-Bourdeau H , Bordigoni P , Jouet JP , Souillet G , Milpied N , et al.   Use of an anti-interleukin-2 receptor monoclonal antibody for GVHD prophylaxis in unrelated donor BMT . Bone Marrow Transplant . 1993;11:293–297
  30. Kumaki S , Minegishi M , Fujie H , Sasahara Y , Ohashi Y , Tsuchiya S , et al.   Prolonged secretion of IL-15 in patients with severe forms of acute graft-versus-host disease after allogeneic bone marrow transplantation in children . Int J Hematol . 1998;67:307–312
  31. Dufour JH , Dziejman M , Liu MT , Leung JH , Lane TE , Luster AD . IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking . J Immunol . 2002;168:3195–3204
  32. Mohan K , Ding Z , Hanly J , Issekutz TB . IFN-gamma-inducible T cell alpha chemoattractant is a potent stimulator of normal human blood T lymphocyte transendothelial migration (Differential regulation by IFN-gamma and TNF-alpha) . J Immunol . 2002;168:6420–6428
  33. Mowat A . Antibodies to IFN-gamma prevent immunological mediated intestinal damage in murine graft-versus-host reactions . Immunology . 1989;68:18–24
  34. Dickinson AM , Sviland L , Dunn J , Carey P , Proctor SJ . Demonstration of direct involvement of cytokines in graft-versus-host reactions using an in vitro skin explant model . Bone Marrow Transplant . 1991;7:209–216
  35. Klimpel GR , Annable CR , Cleveland MG , Jerrells TR , Patterson JC . Immunosuppression and lymphoid hypoplasia associated with chronic graft-versus-host disease is dependent upon IFN-g production . J Immunol . 1990;144:84–93
  36. Krenger W , Falzarano G , Delmonte J , Snyder KM , Byon JC , Ferrara JL . Interferon-g suppresses T-cell proliferation to mitogen via the nitric oxide pathway during experimental acute graft-versus-host disease . Blood . 1996;88:1113–1121
  37. 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;175:405–413
  38. Haskill S , Martin G , Van Le L , Morris J , Peace A , Bigler CF . cDNA cloning of an intracellular form of the human interleukin-1 receptor antagonist associated with epithelium . Proc Natl Acad Sci USA . 1991;88:3681–3685
  39. 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
  40. Kagi D , Vignaux F , Ledermann B , Burki K , Depraetere V , Nagata S , et al.   Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity . Science . 1994;265:528–530
  41. Lowin B , Hahne M , Mattmann C , Tschopp J . Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways . Nature . 1994;370:650–652
  42. Krammer PH . CD95’s deadly mission in the immune system . Nature . 2000;407:789–795
  43. Aggarwal BB . Signalling pathways of the TNF superfamily (A double-edged sword) . Nat Rev Immunol . 2003;3:745–756
  44. Kondo T , Suda T , Fukuyama H , Adachi M , Nagata S . Essential roles of the Fas ligand in the development of hepatitis . Nat Med . 1997;4:409–413
  45. Teshima T , Ordemann R , Reddy P , Gagin S , Liu C , Cooke KR , et al.   Acute graft-versus-host disease does not require alloantigen expression on host epithelium . Nat Med . 2002;8:575–581
  46. Piguet PF , Grau GE , Allet B , Vassalli P . 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
  47. Herve P , Flesch M , Tiberghien P, Wijdenes J , Racadot E , Bordigoni 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;79:3362–3368
  48. Hattori K , Hirano T , Miyajima H , Yamakawa N , Tateno M , Oshimi K , et al.   Differential effects of anti-Fas ligand and anti-tumor necrosis factor-alpha antibodies on acute graft-versus-host disease pathologies . Blood . 1998;91:4051–4055
  49. Cooke KR , Hill GR , Gerbitz A , Kobzik L , Martin TR , Crawford JM , et al.   Tumor necrosis factor-alpha neutralization reduces lung injury after experimental allogeneic bone marrow transplantation . Transplantation . 2000;70:272–279
  50. Pan G , O’Rourke K , Chinnaiyan AM , Gentz R , Ebner R , Ni J , et al.   The receptor for the cytotoxic ligand TRAIL . Science . 1997;276:111–113
  51. Cooke KR , Hill G , Crawford JM, Bungard D , Brinson YS , Delmonte J , et al.   Tumor necrosis factor-a production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft versus host disease . J Clin Invest . 1998;102:1882–1891
  52. 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
  53. Fegan C , Poynton CH , Whittaker JA . The gut mucosal barrier in bone marrow transplantation . Bone Marrow Transplant . 1990;5:373–377
  54. Storb R , Prentice RL , Buckner CD, Clift RA , Appelbaum F , Deeg J , 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
  55. Beelen DW , Elmaagacli A , Muller KD , Hirche H , Schaefer UW . 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;93:3267–3275
  56. Moser B , Loetscher P . Lymphocyte traffic control by chemokines . Nat Immunol . 2001;2:123–128
  57. Sallusto F , Lenig D , Forster R , Lipp M , Lanzaveccia A . Two subsets of memory T lymphocytes with distinct homing potentials and effector functions . Nature . 1999;401:708–712
  58. Murai M , Yoneyama H , Harada A , Yi Z , Vestergaard C , Guo B , et al.   Active participation of CCR5(+)CD8(+) T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease . J Clin Invest . 1999;104:49–57
  59. Panoskaltsis-Mortari A , Strieter RM , Hermanson JR , Fegeding KV , Murphy WJ , Farrell CL , et al.   Induction of monocyte- and T-cell-attracting chemokines in the lung during the generation of idiopathic pneumonia syndrome following allogeneic murine bone marrow transplantation . Blood . 2000;96:834–839
  60. Schnare M , Barton GM , Holt AC , Takeda K , Akira S , Medzhitov R . Toll-like receptors control activation of adaptive immune responses . Nat Immunol . 2001;2:947–950
  61. Aversa F , Tabilio A , Velardi A , Cunningham I , Terenzi A , Falzette F , et al.   Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype . N Engl J Med . 1998;339:1186–1193
  62. Martin P , Schoch G , Fisher L , Byers V , Anasetti C , Appelbaum FR , et al.   A retrospective analysis of therapy for acute graft-versus-host diesase (Initial Treatment) . Blood . 1990;76:1464–1472
  63. Cragg L , Blazar BR , Defor T , Kolatker N , Miller W , Kersey J , et al.   A randomized trial comparing prednisone with antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute graft-versus-host disease . Biol Blood Marrow Transplant . 2000;6:441–447
  64. Antin JH , Weisdorf D , Neuberg D , Nixklow R , Clouthier S , Lee SJ , 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
  65. Storb R , Deeg HJ , Pepe M , Appelbaum F , Anasetti C , Beatty P , et al.   Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia (Long-term follow-up of a controlled trial) . Blood . 1989;73:1729–1734
  66. Allison AC , Eugui EM . Mycophenolate mofetil and its mechanisms of action . Immunopharmacology . 2000;47:85–118
  67. van Bekkum DW , Roodenburg J , Heidt PJ , van der Waaij D . Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora . J Natl Cancer Inst . 1974;52:401–404
  68. Holler E , Kolb HJ , Moller A , Kempeni J , Liesenfeld S , Pechumer H , et al.   Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation . Blood . 1990;75:1011–1016
  69. Huang XJ , Wan J , Lu DP . Serum TNF alpha levels in patients with acute graft-versus-host disease after bone marrow transplantation . Leukemia . 2001;15:1089–1091
  70. Holler E , Kolb HJ , Mittermueller J , Kaul M , Ledderose G , Duell T , et al.   Modulation of acute graft-versus-host disease after allogeneic bone marrow transplantation by tumor necrosis factor alpha (TNFalpha) release in the course of pretransplant conditioning (Role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNFalpha (MAK 195F)) . Blood . 1995;86:890–899
  71. Kobbe G , Schneider P , Rohr U , Fenk R , Neumann F , Aivado M , et al.   Treatment of severe steroid refractory acute graft-versus-host disease with infliximab, a chimeric human/mouse antiTNFalpha antibody . Bone Marrow Transplant . 2001;28:47–49
  72. Dinarello CA . Interleukin-1 and interleukin-1 antagonism . Blood . 1991;77:1627–1652
  73. 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
  74. Cullup H , Dickinson AM , Jackson GH , Taylor PR , Cavet J , Middleton PG . Donor interleukin 1 receptor antagonist genotype associated with acute graft-versus-host disease in human leucocyte antigen-matched sibling allogeneic transplants . Br J Haematol . 2001;113:807–813
  75. McCarthy PL , Abhyankar S , Neben S , Newman G , Sieff C , Thompson RC , et al.   Inhibition of interleukin-1 by an interleukin-1 receptor antagonist prevents graft-versus-host disease . Blood . 1991;78:1915–1918
  76. Hill GR , Cooke KR , Teshima T , Crawford JM , Keith JC , Brinson YS , et al.   Interleukin-11 promotes T cell polarization and prevents acute graft-versus-host disease after allogeneic bone marrow transplantation . J Clin Invest . 1998;102:115–123
  77. Antin JH , Lee SJ , Neuberg D , Alyea E , Soiffer RJ , Sonis S , et al.   A phase I/II double-blind, placebo-controlled study of recombinant human interleukin-11 for mucositis and acute GVHD prevention in allogeneic stem cell transplantation . Bone Marrow Transplant . 2002;29:373–377
  78. Symington FW , Symington BE , Liu PY , Viguet H , Santhanam U , Sehgal PB . The relationship of serum IL-6 levels to acute graft-versus-host disease and hepatorenal disease after human bone marrow transplantation . Transplantation . 1992;54:457–462
  79. Rabinowitz J , Petros WP , Stuart AR , Peters WP . Characterization of endogenous cytokine concentrations after high-dose chemotherapy with autologous bone marrow support . Blood . 1993;81:2452–2459
  80. Uguccioni M , Meliconi R , Nesci S , Lucarelli G , Ceska M , Gasbarrini G , et al.   Elevated interleukin-8 serum concentrations in beta-thalassemia and graft-versus-host disease . Blood . 1993;81:2252–2256

 Supported by National Institutes of Health Grants No. K08 AI052863-01 (P.R.) and PO1 CA 49542 (J.L.M.F.). P.R. is the recipient of the Alaina J. Enlow Scholar Award from Amy Strelzer Manasevit-National Marrow Donor Program and the New Investigator Award from American Society of Blood and Marrow Transplantation. J.L.M.F. is the recipient of the Doris Duke Distinguished Clinical Scientist Award.

PII: S0037-1963(05)00166-6

doi: 10.1053/j.seminhematol.2005.09.001

Seminars in Hematology
Volume 43, Issue 1 , Pages 3-10 , January 2006