Abstract
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
Similar content being viewed by others
References
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.
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.
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.
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.
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.
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.
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.
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.
Goumy L, Ferran C, Merite S, Bach J-F, Chatenoud L. In vivo anti- CD3-driven cell activation.Transplantation. 1996;61:83–87.
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.
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.
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.
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.
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.
Goulmy E. Human minor histocompatibility antigens: new concepts for marrow transplantation and adoptive immunotherapy.Immunol Rev. 1997;157:125–140.
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.
Matzinger P. The danger model: a renewed sense of self.Science. 2002;296:301–305.
Roncarolo MG, Levings MK, Traversari C. Differentiation of T regulatory cells by immature dendritic cells.J Exp Med. 2001; 193:F5–9.
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.
Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells.Science. 2003;299:1033–1036.
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.
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.
Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants.Science. 2002;295:2097–2100.
Ruggeri L, Capanni M, Martelli MF, Velardi A. Cellular therapy: exploiting NK cell alloreactivity in transplantation.Curr Opin Hematol. 2001;8:355–359.
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.
Rissoan M, Soumelis V, Kadowaki N, et al. Reciprocal control of T helper cell and dendritic cell differentiation.Science. 1999;5405:1183–11866.
Reid SD, Penna G, Adorini L. The control of T cell responses by dendritic cell subsets.Curr Opin Immunol. 2000;12:114–121.
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.
Lalor PF, Shields P, Grant A, Adams DH. Recruitment of lymphocytes to the human liver.Immunol Cell Biol. 2002;80:52–64.
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.
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.
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.
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.
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.
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.
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.
Strober S. Natural suppressor (NS) cells, neonatal tolerance, and total lymphoid irradiation: exploring obscure relationships.Annu Rev Immunol. 1984;2:219–237.
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.
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.
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.
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.
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.
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.
Shresta S, Pham C, Thomas D, Braubert T, Ley T. How do cytotoxic lymphocytes kill their targets?Curr Opin Immunol. 1998;10:581–5877.
Krammer PH. CD95’s deadly mission in the immune system.Nature. 2000;407:789–795.
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.
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.
Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R. The receptor for the cytotoxic ligand TRAIL.Science. 1997;276:111–1133.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
van denBrinkM, Moore E, Horndasch E, et al. Fas-Deficientlpr Mice are more susceptible to graft-versus-hostdisease.J Immunol. 2000;164:469–480.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Hannum CH, Wilcox CJ, Arend WP, et al. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor.Nature. 1990; 343:336–340.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Morrison DC, Ryan JL. Endotoxins and disease mechanisms.Annu Rev Med. 1987;38:417–432.
Raetz C. Biochemistry of endotoxins.Annu Rev Biochem. 1990;59:129–1700.
Fegan C, Poynton CH, Whittaker JA. The gut mucosal barrier in bone marrow transplantation.Bone Marrow Transplant. 1990;5:373–3777.
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.
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.
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.
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.
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.
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.
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.
Bayston K, Baumgartner J, Clark P, Cohen J. Anti-endotoxin antibody for prevention of acute GVHD.Bone Marrow Transplant. 1991;8:426–427.
Christ W, Asano O, Robidoux A, et al. E5531, a pure endotoxin antagonist of high potency.Science. 1995;268:80–83.
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.
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.
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.
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.
Ulich TR, Whitcomb L, Tang W, et al. Keratinocyte growth factor ameliorates cyclophosphamide-induced ulcerative hemorrhagic cystitis.Cancer Res. 1997;57:472–475.
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.
Danilenko DM. Preclinical and early clinical development of keratinocyte growth factor, an epithelial-specific tissue growth factor.Toxicol Pathol. 1999;27:64–71.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Ferrara, J.L.M., Cooke, K.R. & Teshima, T. The Pathophysiology of Acute Graft-versus-Host Disease. Int J Hematol 78, 181–187 (2003). https://doi.org/10.1007/BF02983793
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF02983793