Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

New perspectives on the biology of acute GVHD

Bone Marrow Transplantation volume 45, pages 1–11 (2010)Cite this article

Abstract

The use of allogeneic hematopoietic cell transplantation (HCT) has increased as new techniques have been developed for transplantation in patients who previously would not have been considered HCT candidates. However, its efficacy continued to be limited by the development of frequent and severe acute GVHD. The complex and intricate pathophysiology of acute GVHD is a consequence of interactions between the donor and host innate and adaptive immune responses. Multiple inflammatory molecules and cell types are implicated in the development of GVHD that can be categorized as: (1) triggers that initiate GVHD by therapy-induced tissue damage and the antigen disparities between host and graft tissue; (2) sensors that detect the triggers, that is, process and present alloantigens; (3) mediators such as T-cell subsets (naive, memory, regulatory, Th17 and natural killer T cells) and (4) the effectors and amplifiers that cause damage of the target organs. These multiple inflammatory molecules and cell types that are implicated in the development of GVHD have been described with models that use stepwise cascades. Herein, we provide a novel perspective on the immunobiology of acute GVHD and briefly discuss some of the outstanding questions and limitations of the model systems.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Billingham RE . The biology of graft-versus-host reactions. Harvey Lect 1966-67; 62: 21–78.

    PubMed  Google Scholar 

  2. Korngold R, Sprent J . Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T-cells from marrow. J Exp Med 1978; 148: 1687–1698.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. Reddy P, Maeda Y, Liu C, Krijanovski OI, Korngold R, Ferrara JL . A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses. Nat Med 2005; 11: 1244–1249.

    Article  CAS  PubMed  Google Scholar 

  5. Matte CC, Liu J, Cormier J, Anderson BE, Athanasiadis I, Jain D et al. Donor APCs are required for maximal GVHD but not for GVL. Nat Med 2004; 10: 987–992.

    Article  CAS  PubMed  Google Scholar 

  6. Petersdorf EW, Malkki M . Genetics of risk factors for graft-versus-host disease. Semin Hematol 2006; 43: 11–23.

    Article  CAS  PubMed  Google Scholar 

  7. Flomenberg N, Baxter-Lowe LA, Confer D, Fernandez-Vina M, Filipovich A, Horowitz M 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.

    Article  CAS  PubMed  Google Scholar 

  8. Den Haan JM, Sherman NE, Blokland E, Huczko E, Koning F, Drijfhout JW et al. Identification of a graft versus host disease-associated human minor histocompatibility antigen. Science 1995; 268: 1476–1480.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. Murata M, Warren EH, Riddell SR . A human minor histocompatibility antigen resulting from differential expression due to a gene deletion. J Exp Med 2003; 197: 1279–1289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kaplan DH, Anderson BE, McNiff JM, Jain D, Shlomchik MJ, Shlomchik WD . Target antigens determine graft-versus-host disease phenotype. J Immunol 2004; 173: 5467–5475.

    Article  CAS  PubMed  Google Scholar 

  12. Bleakley M, Riddell SR . Molecules and mechanisms of the graft-versus-leukaemia effect. Nat Rev Cancer 2004; 4: 371–380.

    Article  CAS  PubMed  Google Scholar 

  13. Choi EY, Christianson GJ, Yoshimura Y, Sproule TJ, Jung N, Joyce S 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.

    Article  PubMed  Google Scholar 

  14. Fontaine P, Roy-Proulx G, Knafo L, Baron C, Roy DC, Perreault C . Adoptive transfer of minor histocompatibility antigen-specific T lymphocytes eradicates leukemia cells without causing graft-versus-host disease. Nat Med 2001; 7: 789–794.

    Article  CAS  PubMed  Google Scholar 

  15. Medzhitov R . Recognition of microorganisms and activation of the immune response. Nature 2007; 449: 819–826.

    Article  CAS  PubMed  Google Scholar 

  16. Cooke KR, Hill GR, Crawford JM, Bungard D, Brinson YS, Delmonte J Jr et al. Tumor necrosis factor-alpha production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. J Clin Invest 1998; 102: 1882–1891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hill GR, Ferrara JL . 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. 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: 2360–2367.

    Article  CAS  PubMed  Google Scholar 

  20. Chen X, Das R, Komorowski R, Beres A, Hessner MJ, Mihara M et al. Blockade of interleukin-6 signaling augments regulatory T cell reconstitution and attenuates the severity of graft versus host disease. Blood 2009; 114: 891–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Taylor PA, Ehrhardt MJ, Lees CJ, Panoskaltsis-Mortari A, Krieg AM, Sharpe AH et al. TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection. Blood 2008; 112: 3508–3516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chakraverty R, Flutter B, Fallah-Arani F, Eom HS, Means T, Andreola G et al. The host environment regulates the function of CD8+ graft-versus-host-reactive effector cells. J Immunol 2008; 181: 6820–6828.

    Article  CAS  PubMed  Google Scholar 

  23. Inohara N, Nunez G . NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 2003; 3: 371–382.

    Article  CAS  PubMed  Google Scholar 

  24. Holler E, Rogler G, Brenmoehl J, Hahn J, Herfarth H, Greinix H 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.

    Article  CAS  PubMed  Google Scholar 

  25. Holler E, Rogler G, Herfarth H, Brenmoehl J, Wild PJ, Hahn J et al. Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood 2004; 104: 889–894.

    Article  CAS  PubMed  Google Scholar 

  26. Chen GY, Tang J, Zheng P, Liu Y . CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 2009; 323: 1722–1725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Banchereau J, Steinman RM . Dendritic cells and the control of immunity. Nature 1998; 392: 245–252.

    Article  CAS  PubMed  Google Scholar 

  28. Merad M, Hoffmann P, Ranheim E, Slaymaker S, Manz MG, Lira SA et al. Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease. Nat Med 2004; 10: 510–517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shlomchik WD . Graft-versus-host disease. Nat Rev Immunol 2007; 7: 340–352.

    Article  CAS  PubMed  Google Scholar 

  30. Munz C . Enhancing immunity through autophagy. Annu Rev Immunol 2009; 27: 423–449.

    Article  CAS  PubMed  Google Scholar 

  31. Hadeiba H, Sato T, Habtezion A, Oderup C, Pan J, Butcher EC . CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nat Immunol 2008; 9: 1253–1260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Koyama M, Hashimoto D, Aoyama K, Matsuoka K, Karube K, Niiro H et al. Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells. Blood 2009; 113: 2088–2095.

    Article  CAS  PubMed  Google Scholar 

  33. Banovic T, Markey KA, Kuns RD, Olver SD, Raffelt NC, Don AL et al. Graft-versus-host disease prevents the maturation of plasmacytoid dendritic cells. J Immunol 2009; 182: 912–920.

    Article  CAS  PubMed  Google Scholar 

  34. Haniffa M, Ginhoux F, Wang XN, Bigley V, Abel M, Dimmick I et al. Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation. J Exp Med 2009; 206: 371–385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Appleman LJ, Boussiotis VA . T cell anergy and costimulation. Immunol Rev 2003; 192: 161–180.

    Article  CAS  PubMed  Google Scholar 

  36. Sharpe AH, Freeman GJ . The B7-CD28 superfamily. Nat Rev Immunol 2002; 2: 116–126.

    Article  CAS  PubMed  Google Scholar 

  37. Li XC, Rothstein DM, Sayegh MH . Costimulatory pathways in transplantation: challenges and new developments. Immunol Rev 2009; 229: 271–293.

    Article  CAS  PubMed  Google Scholar 

  38. Blazar BR, Kwon BS, Panoskaltsis-Mortari A, Kwak KB, Peschon JJ, Taylor PA . Ligation of 4-1BB (CDw137) regulates graft-versus-host disease, graft-versus-leukemia, and graft rejection in allogeneic bone marrow transplant recipients. J Immunol 2001; 166: 3174–3183.

    Article  CAS  PubMed  Google Scholar 

  39. Blazar BR, Levy RB, Mak TW, Panoskaltsis-Mortari A, Muta H, Jones M et al. CD30/CD30 ligand (CD153) interaction regulates CD4+ T cell-mediated graft-versus-host disease. J Immunol 2004; 173: 2933–2941.

    Article  CAS  PubMed  Google Scholar 

  40. Blazar BR, Sharpe AH, Chen AI, Panoskaltsis-Mortari A, Lees C, Akiba H 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.

    Article  CAS  PubMed  Google Scholar 

  41. Blazar BR, Taylor PA, Linsley PS, Vallera DA . 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.

    Article  CAS  PubMed  Google Scholar 

  42. Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Buhlman J, Xu J, Flavell RA 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. J Immunol 1997; 158: 29–39.

    CAS  PubMed  Google Scholar 

  43. Hubbard VM, Eng JM, Ramirez-Montagut T, Tjoe KH, Muriglan SJ, Kochman AA et al. Absence of inducible costimulator on alloreactive T cells reduces graft versus host disease and induces Th2 deviation. Blood 2005; 106: 3285–3292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Blazar BR, Carreno BM, Panoskaltsis-Mortari A, Carter L, Iwai Y, Yagita H et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol 2003; 171: 1272–1277.

    Article  CAS  PubMed  Google Scholar 

  45. Morris ES, MacDonald KP, Kuns RD, Morris HM, Banovic T, Don AL et al. Induction of natural killer T cell-dependent alloreactivity by administration of granulocyte colony-stimulating factor after bone marrow transplantation. Nat Med 2009; 15: 436–441.

    Article  CAS  PubMed  Google Scholar 

  46. Ringden O, Labopin M, Gorin NC, Le Blanc K, Rocha V, Gluckman E et al. Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2004; 22: 416–423.

    Article  CAS  PubMed  Google Scholar 

  47. Reddy P, Maeda Y, Hotary K, Liu C, Reznikov LL, Dinarello CA et al. Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc Natl Acad Sci USA 2004; 101: 3921–3926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Reddy P, Sun Y, Toubai T, Duran-Struuck R, Clouthier SG, Weisiger E et al. Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J Clin Invest 2008; 118: 2562–2573.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Sun Y, Chin YE, Weisiger E, Malter C, Tawara I, Toubai T et al. Cutting edge: negative regulation of dendritic cells through acetylation of the nonhistone protein STAT-3. J Immunol 2009; 182: 5899–5903.

    Article  CAS  PubMed  Google Scholar 

  50. Wilson J, Cullup H, Lourie R, Sheng Y, Palkova A, Radford KJ et al. Antibody to the dendritic cell surface activation antigen CD83 prevents acute graft-versus-host disease. J Exp Med 2009; 206: 387–398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Maeda Y, Reddy P, Lowler KP, Liu C, Bishop DK, Ferrara JL . Critical role of host gammadelta T cells in experimental acute graft-versus-host disease. Blood 2005; 106: 749–755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Asai O, Longo DL, Tian Z, Hornung RL, Taub DD, Ruscetti FW . Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation. J Clin Invest 1998; 101: 1835–1842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Baker J, Verneris MR, Ito M, Shizuru JA, Negrin RS . Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood 2001; 97: 2923–2931.

    Article  CAS  PubMed  Google Scholar 

  54. Nishimura R, Baker J, Beilhack A, Zeiser R, Olson JA, Sega EI et al. In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood 2008; 112: 2563–2574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pillai AB, George TI, Dutt S, Strober S . Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4+CD25+Foxp3+ T regulatory cells that protects against graft-versus-host disease. Blood 2009; 113: 4458–4467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pillai AB, George TI, Dutt S, Teo P, Strober S . Host NKT cells can prevent graft-versus-host disease and permit graft antitumor activity after bone marrow transplantation. J Immunol 2007; 178: 6242–6251.

    Article  CAS  PubMed  Google Scholar 

  57. Morris ES, MacDonald KP, Rowe V, Banovic T, Kuns RD, Don AL et al. NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. J Clin Invest 2005; 115: 3093–3103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kuns RD, Morris ES, Macdonald KP, Markey KA, Morris HM, Raffelt NC et al. Invariant natural killer T cell-natural killer cell interactions dictate transplantation outcome after alpha-galactosylceramide administration. Blood 2009; 113: 5999–6010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rowe V, Banovic T, MacDonald KP, Kuns R, Don AL, Morris ES et al. Host B cells produce IL-10 following TBI and attenuate acute GVHD after allogeneic bone marrow transplantation. Blood 2006; 108: 2485–2492.

    Article  CAS  PubMed  Google Scholar 

  60. Michonneau D, Peffault de Latour R, Porcher R, Robin M, Benbunan M, Rocha V et al. Influence of bone marrow graft B lymphocyte subsets on outcome after HLA-identical sibling transplants. Br J Haematol 2009; 145: 107–114.

    Article  CAS  PubMed  Google Scholar 

  61. Beilhack A, Schulz S, Baker J, Beilhack GF, Nishimura R, Baker EM et al. Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs. Blood 2008; 111: 2919–2928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Anderson BE, Taylor PA, McNiff JM, Jain D, Demetris AJ, Panoskaltsis-Mortari A et al. Effects of donor T-cell trafficking and priming site on graft-versus-host disease induction by naive and memory phenotype CD4 T cells. Blood 2008; 111: 5242–5251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wu CJ, Ritz J . Induction of tumor immunity following allogeneic stem cell transplantation. Adv Immunol 2006; 90: 133–173.

    Article  CAS  PubMed  Google Scholar 

  64. Spierings E, Drabbels J, Hendriks M, Pool J, Spruyt-Gerritse M, Claas F et al. A uniform genomic minor histocompatibility antigen typing methodology and database designed to facilitate clinical applications. PLoS ONE 2006; 1: e42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Friedman TM, Goldgirsh K, Berger SA, Zilberberg J, Filicko-O’Hara J, Flomenberg N et al. Overlap between in vitro donor antihost and in vivo posttransplantation TCR Vbeta use: a new paradigm for designer allogeneic blood and marrow transplantation. Blood 2008; 112: 3517–3525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Anderson BE, McNiff J, Yan J, Doyle H, Mamula M, Shlomchik MJ et al. Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest 2003; 112: 101–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chen BJ, Cui X, Sempowski GD, Liu C, Chao NJ . Transfer of allogeneic CD62L− memory T cells without graft-versus-host disease. Blood 2004; 103: 1534–1541.

    Article  CAS  PubMed  Google Scholar 

  68. Ermann J, Hoffmann P, Edinger M, Dutt S, Blankenberg FG, Higgins JP et al. Only the CD62 L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 2005; 105: 2220–2226.

    Article  CAS  PubMed  Google Scholar 

  69. Taylor PA, Panoskaltsis-Mortari A, Swedin JM, Lucas PJ, Gress RE, Levine BL 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.

    Article  CAS  PubMed  Google Scholar 

  70. Zheng H, Matte-Martone C, Li H, Anderson BE, Venketesan S, Sheng Tan H et al. Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood 2008; 111: 2476–2484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Miller JS, Weisdorf DJ, Burns LJ, Slungaard A, Wagner JE, Verneris MR et al. Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood 2007; 110: 2761–2763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG . Alloreactive memory T cells are responsible for the persistence of graft-versus-host disease. J Immunol 2005; 174: 3051–3058.

    Article  CAS  PubMed  Google Scholar 

  73. Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG . Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat Med 2005; 11: 1299.

    Article  CAS  PubMed  Google Scholar 

  74. Dutt S, Tseng D, Ermann J, George TI, Liu YP, Davis CR et al. Naive and memory T cells induce different types of graft-versus-host disease. J Immunol 2007; 179: 6547–6554.

    Article  CAS  PubMed  Google Scholar 

  75. Blazar BR, Taylor PA . Regulatory T cells. Biol Blood Marrow Transpl 2005; 11 (2 Suppl 2): 46–49.

    Article  Google Scholar 

  76. Cohen JL, Boyer O . The role of CD4+CD25hi regulatory T cells in the physiopathogeny of graft-versus-host disease. Curr Opin Immunol 2006; 18: 580–585.

    Article  CAS  PubMed  Google Scholar 

  77. Roncarolo MG . The role of interleukin-10 in transplantation and GVHD. In: Ferrara JLM, Deeg HJ, Burakoff SJ (eds). Graft-vs-Host Disease, 2nd edn. Marcel Dekker: New York, 1997. pp 693–715.

    Google Scholar 

  78. Young KJ, DuTemple B, Phillips MJ, Zhang L . Inhibition of graft-versus-host disease by double-negative regulatory T cells. J Immunol 2003; 171: 134–141.

    Article  CAS  PubMed  Google Scholar 

  79. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zheng Y, Rudensky AY . Foxp3 in control of the regulatory T cell lineage. Nat Immunol 2007; 8: 457–462.

    Article  CAS  PubMed  Google Scholar 

  81. Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL . CD4(+)CD25(+) immunoregulatory T cells: new therapeutics for graft-versus-host disease. J Exp Med 2002; 196: 401–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003; 9: 1144–1150.

    Article  CAS  PubMed  Google Scholar 

  83. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jones SC, Murphy GF, Korngold R . Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD425 T cells to allow an effective graft-versus-leukemia response. Biol Blood Marrow Transpl 2003; 9: 243–256.

    Article  Google Scholar 

  85. Taylor PA, Lees CJ, Blazar BR . The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 2002; 99: 3493–3499.

    Article  CAS  PubMed  Google Scholar 

  86. Coghill JM, Carlson MJ, Moran TP, Serody JS . The biology and therapeutic potential of natural regulatory T-cells in the bone marrow transplant setting. Leuk Lymphoma 2008; 49: 1860–1869.

    Article  CAS  PubMed  Google Scholar 

  87. Nguyen VH, Shashidhar S, Chang DS, Ho L, Kambham N, Bachmann M et al. The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation. Blood 2008; 111: 945–953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G . Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 2001; 193: 1303–1310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH . Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 2001; 193: 1285–1294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hoffmann P, Boeld TJ, Eder R, Albrecht J, Doser K, Piseshka B et al. Isolation of CD4+CD25+ regulatory T cells for clinical trials. Biol Blood Marrow Transpl 2006; 12: 267–274.

    Article  CAS  Google Scholar 

  91. Zorn E, Mohseni M, Kim H, Porcheray F, Lynch A, Bellucci R et al. Combined CD4+ donor lymphocyte infusion and low-dose recombinant IL-2 expand FOXP3+ regulatory T cells following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2009; 15: 382–388.

    Article  PubMed  PubMed Central  Google Scholar 

  92. MacDonald KP, Rowe V, Clouston AD, Welply JK, Kuns RD, Ferrara JL et al. Cytokine expanded myeloid precursors function as regulatory antigen-presenting cells and promote tolerance through IL-10-producing regulatory T cells. J Immunol 2005; 174: 1841–1850.

    Article  CAS  PubMed  Google Scholar 

  93. Ferrara JL, Krenger W . Graft-versus-host disease: the influence of type 1 and type 2 T cell cytokines. Transf Med Rev 1998; 12: 1–17.

    Article  CAS  Google Scholar 

  94. Ferrara JLM . The cytokine storm of acute graft-versus host disease. Haematol Rev 1994; 8: 27.

    Google Scholar 

  95. Reddy P . Pathophysiology of acute graft-versus-host disease. Hematol Oncol 2003; 21: 149–161.

    Article  PubMed  Google Scholar 

  96. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 1998; 92: 2303–2314.

    CAS  PubMed  Google Scholar 

  97. Liu EH, Siegel RM, Harlan DM, O’Shea JJ . T cell-directed therapies: lessons learned and future prospects. Nat Immunol 2007; 8: 25–30.

    Article  CAS  PubMed  Google Scholar 

  98. Zeiser R, Nguyen VH, Beilhack A, Buess M, Schulz S, Baker J et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006; 108: 390–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhang H, Chua KS, Guimond M, Kapoor V, Brown MV, Fleisher TA et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med 2005; 11: 1238–1243.

    Article  CAS  PubMed  Google Scholar 

  100. Liston A, Rudensky AY . Thymic development and peripheral homeostasis of regulatory T cells. Curr Opin Immunol 2007; 19: 176–185.

    Article  CAS  PubMed  Google Scholar 

  101. Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 2007; 445: 771–775.

    Article  CAS  PubMed  Google Scholar 

  102. Yang YG, Dey BR, Sergio JJ, Pearson DA, Sykes M . Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12. J Clin Invest 1998; 102: 2126–2135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Yang YG, Qi J, Wang MG, Sykes M . Donor-derived interferon gamma separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells. Blood 2002; 99: 4207–4215.

    Article  CAS  PubMed  Google Scholar 

  104. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Burman AC, Banovic TD, Kuns RD, Clouston AD, Stanley AC, Morris ES et al. IFN{gamma} differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract. Blood 2007; 110: 1064–1072.

    Article  CAS  PubMed  Google Scholar 

  106. Fowler DH, Kurasawa K, Smith R, Eckhaus MA, Gress RE . Donor CD4-enriched cells of Th2 cytokine phenotype regulate graft-versus-host disease without impairing allogeneic engraftment in sublethally irradiated mice. Blood 1994; 84: 3540–3549.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  108. Pan L, Delmonte J, Jalonen C, Ferrara J . 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.

    Article  CAS  PubMed  Google Scholar 

  109. Hill GR, Cooke KR, Teshima T, Crawford JM, Keith Jr 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Reddy P, Teshima T, Hildebrandt G, Williams DL, Liu C, Cooke KR 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.

    Article  CAS  PubMed  Google Scholar 

  111. Foley JE, Jung U, Miera A, Borenstein T, Mariotti J, Eckhaus M 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. J Immunol 2005; 175: 5732–5743.

    Article  CAS  PubMed  Google Scholar 

  112. Jung U, Foley JE, Erdmann AA, Toda Y, Borenstein T, Mariotti J 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. Biol Blood Marrow Transpl 2006; 12: 905–918.

    Article  CAS  Google Scholar 

  113. 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. Leuk Lymphoma 2000; 38: 221–234.

    Article  CAS  PubMed  Google Scholar 

  114. Tawara I, Maeda Y, Sun Y, Lowler KP, Liu C, Toubai T et al. Combined Th2 cytokine deficiency in donor T cells aggravates experimental acute graft-vs-host disease. Exp Hematol 2008; 36: 988–996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Nikolic B, Lee S, Bronson R, Grusby M, Sykes M . Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. J Clin Invest 2000; 105: 1289–1298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Yi T, Zhao D, Lin CL, Zhang C, Chen Y, Todorov I et al. Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease. Blood 2008; 112: 2101–2110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kappel LW, Goldberg GL, King CG, Suh DY, Smith OM, Ligh C et al. IL-17 contributes to CD4-mediated graft-versus-host disease. Blood 2009; 113: 945–952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Carlson MJ, West ML, Coghill JM, Panoskaltsis-Mortari A, Blazar BR, Serody JS . In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations. Blood 2009; 113: 1365–1374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Cyster JG . Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 2005; 23: 127–159.

    Article  CAS  PubMed  Google Scholar 

  120. Krenger W, Hollander GA . The immunopathology of thymic GVHD. Semin Immunopathol 2008; 30: 439–456.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  122. Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M et al. Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 2001; 97: 1458–1466.

    Article  CAS  PubMed  Google Scholar 

  123. Clave E, Busson M, Douay C, Peffault de Latour R, Berrou J, Rabian C et al. Acute graft-versus-host disease transiently impairs thymic output in young patients after allogeneic hematopoietic stem cell transplantation. Blood 2009; 113: 6477–6484.

    Article  CAS  PubMed  Google Scholar 

  124. Sackstein R . A revision of Billingham's tenets: the central role of lymphocyte migration in acute graft-versus-host disease. Biol Blood Marrow Transpl 2006; 12 (1 Suppl 1): 2–8.

    Article  Google Scholar 

  125. Wysocki CA, Panoskaltsis-Mortari A, Blazar BR, Serody JS . Leukocyte migration and graft-versus-host disease. Blood 2005; 105: 4191–4199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Duffner U, Lu B, Hildebrandt GC, Teshima T, Williams DL, Reddy P et al. Role of CXCR3-induced donor T-cell migration in acute GVHD. Exp Hematol 2003; 31: 897–902.

    Article  CAS  PubMed  Google Scholar 

  127. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Wysocki CA, Burkett SB, Panoskaltsis-Mortari A, Kirby SL, Luster AD, McKinnon K et al. Differential roles for CCR5 expression on donor T cells during graft-versus-host disease based on pretransplant conditioning. J Immunol 2004; 173: 845–854.

    Article  CAS  PubMed  Google Scholar 

  129. Wysocki CA, Jiang Q, Panoskaltsis-Mortari A, Taylor PA, McKinnon KP, Su L et al. Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease. Blood 2005; 106: 3300–3307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Waldman E, Lu SX, Hubbard VM, Kochman AA, Eng JM, Terwey TH et al. Absence of beta7 integrin results in less graft-versus-host disease because of decreased homing of alloreactive T cells to intestine. Blood 2006; 107: 1703–1711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Mapara MY, Leng C, Kim YM, Bronson R, Lokshin A, Luster A et al. Expression of chemokines in GVHD target organs is influenced by conditioning and genetic factors and amplified by GVHR. Biol Blood Marrow Transpl 2006; 12: 623–634.

    Article  CAS  Google Scholar 

  132. 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.

    Article  CAS  PubMed  Google Scholar 

  133. van den Brink MR, Burakoff SJ . Cytolytic pathways in haematopoietic stem-cell transplantation. Nat Rev Immunol 2002; 2: 273–281.

    Article  CAS  PubMed  Google Scholar 

  134. 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.

    Article  CAS  PubMed  Google Scholar 

  135. Brown GR, Lee EL, El-Hayek J, Kintner K, Luck C . IL-12-independent LIGHT signaling enhances MHC class II disparate CD4+ T cell alloproliferation, IFN-gamma responses, and intestinal graft-versus-host disease. J Immunol 2005; 174: 4688–4695.

    Article  CAS  PubMed  Google Scholar 

  136. Sato K, Nakaoka T, Yamashita N, Yagita H, Kawasaki H, Morimoto C et al. TRAIL-transduced dendritic cells protect mice from acute graft-versus-host disease and leukemia relapse. J Immunol 2005; 174: 4025–4033.

    Article  CAS  PubMed  Google Scholar 

  137. Schmaltz C, Alpdogan O, Kappel BJ, Muriglan SJ, Rotolo JA, Ongchin J et al. T cells require TRAIL for optimal graft-versus-tumor activity. Nat Med 2002; 8: 1433–1437.

    Article  CAS  PubMed  Google Scholar 

  138. Xu Y, Flies AS, Flies DB, Zhu G, Anand S, Flies SJ et al. Selective targeting of the LIGHT-HVEM co-stimulatory system for the treatment of graft-versus-host disease. Blood 2006; 109: 4097–4104.

    Article  PubMed  CAS  Google Scholar 

  139. Zimmerman Z, Shatry A, Deyev V, Podack E, Mammolenti M, Blazar BR et al. Effector cells derived from host CD8 memory T cells mediate rapid resistance against minor histocompatibility antigen-mismatched allogeneic marrow grafts without participation of perforin, Fas ligand, and the simultaneous inhibition of 3 tumor necrosis factor family effector pathways. Biol Blood Marrow Transpl 2005; 11: 576–586.

    Article  CAS  Google Scholar 

  140. 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.

    Article  CAS  PubMed  Google Scholar 

  141. Abhyankar S, Gilliland DG, Ferrara JL . Interleukin-1 is a critical effector molecule during cytokine dysregulation in graft versus host disease to minor histocompatibility antigens. Transplantation 1993; 56: 1518–1523.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  143. 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.

    Article  CAS  PubMed  Google Scholar 

  144. Antin JH, Ferrara JL . Cytokine dysregulation and acute graft-versus-host disease. Blood 1992; 80: 2964–2968.

    Article  CAS  PubMed  Google Scholar 

  145. Welniak LA, Blazar BR, Murphy WJ . Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 2007; 25: 139–170.

    Article  CAS  PubMed  Google Scholar 

  146. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Gen Res 2003; 13: 2498–2504.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by NIH AI-075284, and HL-090775 (to PR).

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

    S Paczesny & D Hanauer

  2. Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

    Y Sun & P Reddy

Authors
  1. S Paczesny
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Hanauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Reddy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paczesny, S., Hanauer, D., Sun, Y. et al. New perspectives on the biology of acute GVHD. Bone Marrow Transplant 45, 1–11 (2010). https://doi.org/10.1038/bmt.2009.328

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2009.328

Keywords

This article is cited by

Search

Advanced search

Quick links