International Journal of Hematology

, Volume 79, Issue 3, pp 209–215 | Cite as

The pathophysiology of chronic graft-versus-host disease

  • Emin KansuEmail author
Progress in hematology


Chronic graft-versus-host disease (GVHD) still remains the most significant complication after allogeneic hematopoietic stem cell transplantation. The disease usually appears after day 100 and is characterized by signs and symptoms similar to autoimmune diseases.The pathophysiology of chronic GVHD is poorly understood because of the lack of highly satisfactory animal models and basic studies in patients. It has not been clearly determined whether the disease is a distinct entity or a continuation of acute GVHD. In experimental and clinical studies of chronic GVHD, thymic atrophy, lymphocyte depletion, and autoantibody formation have been described. Conditioning regimens and acute GVHD may disrupt thymic function and dysregulate the negative selection process of potentially autoreactive T-lymphocytes. Disruption of thymic apoptosis and failure to eliminate the majority of self-reactive lymphocytes may lead to impairment of lymphocyte homeostasis and self tolerance. Expansion and effector functions of autoreactive T-cells will then promote autoreactive B-cell activation and production of autoantibodies with target-organ damage. Chronic GVHD requires continuous CD4+ T-cell help for B-cells and is known as T-helper 2 (Th2) disease. Murine models have demonstrated the roles of interleukin (IL)-12 and IL-18 in chronic GVHD. IL-12 may cause an increase in donor CD8+ cytotoxic T-cells leading to conversion of chronic GVHD to an acute form. In contrast, IL-18 prevents chronic GVHD by decreasing numbers of CD4+ (Th2) cells and host-reactive B-cell activation and reducing alloantigen-specific immune response. Mouse and human cellular genomics coupled with advances in cell biology in donorrecipient tolerance will improve our understanding of transplantation immunology and may offer new approaches to the challenge of ameliorating chronic GVHD.

Key words

Late effects Chronic graft-versus-host disease Autoimmunity Stem cell transplantation Immune tolerance 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kansu E, Koç Y, Sullivan KM. Chronic graft-versus-host disease after allogeneic stem cell transplantation. Turk J Cancer. 2003;33:9–22.Google Scholar
  2. 2.
    Kansu E, Sullivan KM. Late effects of hematopoietic stem cell transplantation. Hematology. 2000;5:1–14.CrossRefGoogle Scholar
  3. 3.
    Kansu E, Sullivan KM. Late complications of hematopoietic stem cell transplantation. In: Ho AD, Hass R, Champlin RE, eds. Hematopoietic Stem Cell Transplantation. New York: Marcel Dekker; 2000:413–433.CrossRefGoogle Scholar
  4. 4.
    Flowers MED, Kansu E, Sullivan KM. Pathophysiology and treatment of graft-versus-host disease. Hematol Oncol Clin North Am. 1999;13:1091–1112.CrossRefPubMedGoogle Scholar
  5. 5.
    Lee SJ, Vogelsang G, Flowers MED. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9:215–233.CrossRefGoogle Scholar
  6. 6.
    Socie G, Louiseau P, Tamouza R, et al. Both genetic and clinical factors predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Transplantation. 2001;72:699–706.CrossRefGoogle Scholar
  7. 7.
    Aractingi S, Chosidow O. Cutaneous graft-versus-host disease. Arch Dermatol. 1998;134:602–612.CrossRefPubMedGoogle Scholar
  8. 8.
    Ferrara JLM, Cooke KR, Teshima T. The pathophysiology of acute graft-versus-host disease. Int J Hematol. 2003;78:181–187.CrossRefPubMedGoogle Scholar
  9. 9.
    Parham P, McQueen KL. Alloreactive killer cells: hindrance and help for haematopoietic transplants. Nature Rev Immunol. 2003;3:108–122.CrossRefGoogle Scholar
  10. 10.
    Beschorner WE, Tutschka PJ, Santos GW. Chronic graft-versushost disease in the rat radiation chimera, I: clinical features, hematology, histology and immunopathology in long-term chimeras. Transplantation. 1982;33:393–399.CrossRefPubMedGoogle Scholar
  11. 11.
    Tutschka P, Teasdall R, Beschorner WE, Santos GW. Chronic graftversus- host disease in the rat radiation chimera. Transplantation. 1982;34:289–294.CrossRefPubMedGoogle Scholar
  12. 12.
    Beschorner W, Tutschka PJ, Santos GW. Chronic graft-versus-host disease in the rat radiation chimera, III: immunology and immunopathology in rapidly induced models. Transplantation. 1983;35:224–230.CrossRefPubMedGoogle Scholar
  13. 13.
    Gleichmann E, Gleichmann H, Wilke W. Autoimmunization and lymphomagenesis in parent-to-F1 combinations differing at the major histocompatibility complex: model for spontaneous disease caused by altered self-antigens? Transplant Rev. 1976;31:156–224.PubMedGoogle Scholar
  14. 14.
    Via CS, Shearer GM. T-cell interactions in autoimmunity: insights from a murine model of graft-versus-host disease. Immunol Today. 1988;9:207–213.CrossRefPubMedGoogle Scholar
  15. 15.
    Gleichmann E, Pals ST, Rolink AG, Radaszkiewicz T, Gleichmann H. Graft-versus-host reactions: clues to the etiopathology of a spectrum of immunologic diseases. Immunol Today. 1984;5:324–332CrossRefGoogle Scholar
  16. 16.
    De Wit D, Van Mechelen M, Zanin C, et al. Preferential activation of Th2 cells in chronic graft-versus-host reaction. J Immunol. 1993;150:361–366.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Rus V, Svetic A, Nguyen P, Gause WC, Via CS. Kinetics of Th1 and Th2 cytokine production during the early course of acute and chronic murine graft-versus-host disease. Regulatory role of donor CD8+ T cells. J Immunol. 1995;155:2396–2406.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Shustov A, Nguyen P, Finkelman F, Elkon KB, Via CS. Differential expression of Fas and Fas ligand in acute and chronic graft-versushost disease: up-regulation of Fas and Fas ligand requires CD8+ T-cell activation and IFN-gamma production. J Immunol. 1998;161:2848–2855.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Slayback DL, Dobkins JA, Harper JM. Genetic factors influencing the development of chronic graft-versus-host disease in a murine model. Bone Marrow Transplant. 2000;26:931–938.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kamradt T, Mitchison NA. Tolerance and autoimmunity. N Engl J Med. 2001;344:655–664.CrossRefPubMedGoogle Scholar
  21. 21.
    Parkman R, Weinberg KI. Immune reconstitution following hematopoietic cell transplantation. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas’ Hematopoietic Cell Transplantation. 3rd ed. Oxford: Blackwell Publishing; 2004:853–861.Google Scholar
  22. 22.
    Weinberg K, Blazar BR, Wagner JE, et al. Factors affecting thymic function after allogeneic stem cell transplantation. Blood. 2001;97:1458–1466.CrossRefPubMedGoogle Scholar
  23. 23.
    Sullivan KM. Graft-versus-host disease. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas’ Hematopoietic Cell Transplantation. 3rd ed. Oxford: Blackwell Publishing; 2004:635–664.Google Scholar
  24. 24.
    Atkinson K, Incefy GS, Storb R, et al. Low serum thymic hormone levels in patients with chronic graft-versus-host disease. Blood. 1982;59:1073–1077.PubMedGoogle Scholar
  25. 25.
    Hess A, Thoburn C, Chen W, Horwitz L. Autoreactive T-cell subsets in acute and chronic syngeneic graft-versus-host disease. Transpl Proc. 2001;33:1754–1756.CrossRefGoogle Scholar
  26. 26.
    Graze PR, Gale RP. Chronic graft-versus-host disease: a syndrome of disordered immunity Am J Med. 1979;66:611–620.CrossRefPubMedGoogle Scholar
  27. 27.
    Lister J, Messner H, Keysteon E, Miller R, Fritzler MJ. Autoantibody analysis of patients with graft-versus-host disease. J Clin Lab Immunol. 1987;24:19–23.PubMedGoogle Scholar
  28. 28.
    Kier P, Penner E, Bakos S, et al. Autoantibodies in chronic GVHD: high prevalance of antinucleolar antibodies. Bone Marrow Transplant. 1990;6:93–96.PubMedGoogle Scholar
  29. 29.
    Bell SA, Faust H, Mittermuller J, Kolb H-J, Meurer M. Specificity of antinuclear antibodies in scleroderma-like chronic graft-versushost disease: clinical correlation and histocompatibility locus antigen association. Br J Dermatol. 1996;134:848–854.CrossRefPubMedGoogle Scholar
  30. 30.
    Wesierska-Gadek J, Penner E, Hitchman E, Kier P, Sauermann G. Nucleolar proteins B23 and C23 as target antigens in chronic graftversus- host disease. Blood. 1992;79:1081–1086.PubMedGoogle Scholar
  31. 31.
    Rouquette-Gally AM, Boyeldieu D, Prost AC, Gluckman E. Autoimmunity after allogeneic bone marrow transplantation: a study of 53 long-term-surviving patients. Transplantation. 1988;46:238–240.CrossRefPubMedGoogle Scholar
  32. 32.
    Santamaria P. Cytokines and chemokines in autoimmune disease: an overview. In: Santamaria P, ed. Cytokines and Chemokines in Autoimmune Diseases. New York: Academic/Plenum Publishers; 2003:1–7.CrossRefGoogle Scholar
  33. 33.
    Letterio JJ, Roberts AB. Regulation of immune responses by TGFbeta. Annu Rev Immunol. 1998;16:137–161.CrossRefPubMedGoogle Scholar
  34. 34.
    Zhang Y, McCormick LM, Desai SR, Wu C, Gilliam AC. Murine sclerodermatous graft-versus-host disease, a model for human scleroderma: cutaneous cytokines, chemokines and immune cell activation. J Immunol. 2002;168:3088–3098.CrossRefPubMedGoogle Scholar
  35. 35.
    Athie-Morales V, Smits HH, Cantrell DA, Hilkens CMU. Sustained IL-12 signaling is required for Th1 development. J Immunol. 2004;172:61–69.CrossRefPubMedGoogle Scholar
  36. 36.
    Williamson E, Garside P, Bradley JA, Mowat AM.IL-12 is a central mediator of acute graft-versus-host disease in mice. J Immunol. 1996;157:689–699.PubMedGoogle Scholar
  37. 37.
    Via CS, Rus V, Gately MK, Finkelman FD. IL-12 stimulates the development of acute graft-versus-host disease in mice that normally would develop chronic, autoimmune graft-versus-host disease. J Immunol. 1994;153:4040–4047.PubMedGoogle Scholar
  38. 38.
    Lauwerys BR, Renauld J-C, Houssiau FA. Inhibition of in-vitro immunoglobulin production by IL-12 in murine chronic graftversus- host disease: synergism with IL-18. Eur J Immunol. 1998;28:2017–2024.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Okamura H, Tsutsui H, Komastu T, et al. Cloning of a new cytokine that induces IFN-gamma production by T-cells. Nature. 1995;378:88–91.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Dinarello CA. Interleukin-18. Methods. 1999;19:121–132.CrossRefPubMedGoogle Scholar
  41. 41.
    Akira S. The role of IL-18 in innate immunity. Curr Opin Immunol. 2000;12:59–63.CrossRefPubMedGoogle Scholar
  42. 42.
    Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol. 2001; 19:423–474.CrossRefPubMedGoogle Scholar
  43. 43.
    Reddy P, Tshima T, Hildebrandt G, et al. Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects. Blood. 2003; 101:2877–2885.CrossRefPubMedGoogle Scholar
  44. 44.
    Okamoto I, Kohno K, Tanimoto T, et al. IL-18 prevents the development of chronic graft-versus-host disease in mice. J Immunol. 2000;164:6067–6074.CrossRefPubMedGoogle Scholar
  45. 45.
    Reid SD, Penna G, Adorini L. The control of T-cell responses by dendritic cell subsets. Curr Opin Immunol. 2000;12:114–121.CrossRefPubMedGoogle Scholar
  46. 46.
    Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S. Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol. 2002;20:621–667.CrossRefPubMedGoogle Scholar
  47. 47.
    Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767–811.CrossRefPubMedGoogle Scholar
  48. 48.
    Steinman RM, Nussenzweig MC. Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci U S A. 2002;99:351–358.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Ferrara JL, Cooke KR, Pan L, Krenger W. The immunopathophysiology of acute graft-versus-host disease. Stem Cells. 1996;14: 473–489.CrossRefPubMedGoogle Scholar
  50. 50.
    Chan GW, Gorgun G, Miller KB, Foss FM. Persistence of host dendritic cells after transplantation is associated with graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9:170–176.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2004

Authors and Affiliations

  1. 1.Hematopoietic Stem Cell Transplantation Unit, Institute of OncologyHacettepe UniversityAnkaraTurkey

Personalised recommendations