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.

Graft-versus-host disease

Key Points

  • Graft-versus-host disease (GVHD) is initiated by mature CD4+ and/or CD8+ αβ T cells that accompany allogeneic haematopoietic stem-cell transplantation (SCT). Because of GVHD, all allogeneic haematopoietic SCT patients receive immunosuppressive therapies directed at T cells, including, in some patients, rigorous depletion of T cells from the allograft.

  • Alloimmune T-cell responses against multiple minor histocompatibility antigens (miHAs) show immunodominance. The presence of a specific immunodominant antigen can both predict GVHD occurrence and in part control the clinical and histological phenotype of GVHD.

  • Recipient antigen-presenting cells (APCs) that survive the immunosuppressive therapies (chemotherapy and often radiotherapy) are essential for initiating GVHD resulting from MHC-mismatched transplantation. Dendritic cells and Langerhans cells alone have been shown to be sufficient to initiate GVHD in this setting.

  • Recipient APCs are necessary and sufficient for CD8+ T-cell-mediated GVHD induced in response to miHAs only. Nonetheless, donor-derived APCs are required for maximal GVHD, presumably owing to cross-presentation of recipient antigens.

  • Either recipient- or donor-derived APCs are sufficient for CD4+ T-cell-mediated GVHD across only miHAs.

  • T-cell priming in either the spleen or lymph nodes and Peyer's patches is sufficient to cause GVHD. Conversely, T-cell priming in Peyer's patches is not required for GVHD in models that use lethal irradiation.

  • Most activating or suppressing T-cell-co-stimulatory molecules have been shown to influence the phenotype of GVHD. Activating receptors would be logical targets for the treatment or prevention of GVHD.

  • In MHC-mismatched GVHD mediated by CD4+ T cells, direct cognate interactions with recipient tissues is not necessary and death is probably cytokine-mediated.

  • The CD95–CD95 ligand (CD95L), and perforin and granzyme pathways contribute to histological GVHD.

  • Donor or recipient naturally occurring CD4+CD25+ regulatory T cells can suppress GVHD, as can recipient natural killer T cells.

  • Effector memory T cells have a reduced capacity to induce GVHD but can transfer functional T-cell memory.

Abstract

Allogeneic haematopoietic stem-cell transplantation (SCT) is a curative therapy for haematological malignancies and inherited disorders of blood cells, such as sickle-cell anaemia. Mature αβ T cells that are contained in the allografts reconstitute T-cell immunity and can eradicate malignant cells in the recipient. Unfortunately, these T cells recognize the recipient as 'non-self' and employ a wide range of immune mechanisms to attack recipient tissues in a process known as graft-versus-host disease (GVHD). The full therapeutic potential of allogeneic haematopoietic SCT will not be realized until approaches to minimize GVHD, while maintaining the positive contributions of donor T cells, are developed. This Review focuses on research in mouse models pursued to achieve this goal.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Allogeneic peripheral-blood stem-cell transplantation.
Figure 2: Minor histocompatibility antigens (miHAs) and T-cell recognition in allogeneic stem-cell transplantation.
Figure 3: Antigen presentation in GVHD in MHC-matched allogeneic stem-cell transplantation.
Figure 4: Mechanisms of injury by tissue-infiltrating alloreactive T cells.

References

  1. 1

    Bleakley, M. & Riddell, S. R. Molecules and mechanisms of the graft-versus-leukaemia effect. Nature Rev. Cancer 4, 371–380 (2004).

    CAS  Article  Google Scholar 

  2. 2

    Korngold, B. & 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. 148, 1687–1698 (1978). This study presents a formal demonstration that mature donor T cells induce GVHD.

    CAS  Article  Google Scholar 

  3. 3

    Korngold, R. & Sprent, J. Features of T cells causing H-2-restricted lethal graft-vs.-host disease across minor histocompatibility barriers. J. Exp. Med. 155, 872–883 (1982).

    CAS  Article  Google Scholar 

  4. 4

    Korngold, R. & Sprent, J. Variable capacity of L3T4+ T cells to cause lethal graft-versus-host disease across minor histocompatibility barriers in mice. J. Exp. Med. 165, 1552–1564 (1987).

    CAS  Article  Google Scholar 

  5. 5

    Wysocki, C. A. et al. Differential roles for CCR5 expression on donor T cells during graft-versus-host disease based on pretransplant conditioning. J. Immunol. 173, 845–854 (2004).

    CAS  Article  Google Scholar 

  6. 6

    Hill, G. R. et al. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 90, 3204–3213 (1997).

    CAS  Google Scholar 

  7. 7

    Chakraverty, R. et al. An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues. J. Exp. Med. 203, 2021–2031 (2006). This study shows that local inflammation induced by a TLR7 agonist promotes localized GVHD.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Higman, M. A. & Vogelsang, G. B. Chronic graft versus host disease. Br. J. Haematol. 125, 435–454 (2004).

    Article  Google Scholar 

  9. 9

    Aosai, F. et al. Different types of allospecific CTL clones identified by their ability to recognize peptide loading-defective target cells. Eur. J. Immunol. 21, 2767–2774 (1991). References 9–11 address the role of peptide in T-cell recognition of allogeneic MHC molecules.

    CAS  Article  Google Scholar 

  10. 10

    Man, S., Salter, R. D. & Engelhard, V. H. Role of endogenous peptide in human alloreactive cytotoxic T cell responses. Int. Immunol. 4, 367–375 (1992).

    CAS  Article  Google Scholar 

  11. 11

    Crumpacker, D. B., Alexander, J., Cresswell, P. & Engelhard, V. H. Role of endogenous peptides in murine allogenic cytotoxic T cell responses assessed using transfectants of the antigen-processing mutant 174xCEM. T2. J. Immunol. 148, 3004–3011 (1992).

    CAS  Google Scholar 

  12. 12

    den Haan, J. M. et al. Identification of a graft versus host disease-associated human minor histocompatibility antigen. Science 268, 1476–1480 (1995). This study provides the molecular identification of the first human miHA.

    CAS  Article  Google Scholar 

  13. 13

    Wang, W. et al. Human H-Y: a male-specific histocompatibility antigen derived from the SMCY protein. Science 269, 1588–1590 (1995). References 13–29 describe the identity of many of the known mouse and human miHAs.

    CAS  Article  Google Scholar 

  14. 14

    Meadows, L. et al. The HLA-A*0201-restricted H-Y antigen contains a posttranslationally modified cysteine that significantly affects T cell recognition. Immunity 6, 273–281 (1997).

    CAS  Article  Google Scholar 

  15. 15

    Brickner, A. G. et al. The immunogenicity of a new human minor histocompatibility antigen results from differential antigen processing. J. Exp. Med. 193, 195–206 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Mutis, T. et al. Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease. Nature Med. 5, 839–842 (1999).

    CAS  Article  Google Scholar 

  17. 17

    de Bueger, M., Bakker, A., Van Rood, J. J., Van der Woude, F. & Goulmy, E. Tissue distribution of human minor histocompatibility antigens. Ubiquitous versus restricted tissue distribution indicates heterogeneity among human cytotoxic T lymphocyte-defined non-MHC antigens. J. Immunol. 149, 1788–1794 (1992).

    CAS  Google Scholar 

  18. 18

    Perreault, C., Jutras, J., Roy, D. C., Filep, J. G. & Brochu, S. Identification of an immunodominant mouse minor histocompatibility antigen (MiHA). T cell response to a single dominant MiHA causes graft-versus-host disease. J. Clin. Invest. 98, 622–628 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Malarkannan, S. et al. Differences that matter: major cytotoxic T cell-stimulating minor histocompatibility antigens. Immunity 13, 333–344 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Yadav, R. et al. The H4b minor histocompatibility antigen is caused by a combination of genetically determined and posttranslational modifications. J. Immunol. 170, 5133–5142 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Luedtke, B. et al. A single nucleotide polymorphism in the Emp3 gene defines the H4 minor histocompatibility antigen. Immunogenetics 55, 284–295 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Warren, E. H. et al. The human UTY gene encodes a novel HLA-B8-restricted H-Y antigen. J. Immunol. 164, 2807–2814 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Brickner, A. G. et al. The PANE1 gene encodes a novel human minor histocompatibility antigen that is selectively expressed in B-lymphoid cells and B-CLL. Blood 107, 3779–3786 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Murata, M., Warren, E. H. & Riddell, S. R. A human minor histocompatibility antigen resulting from differential expression due to a gene deletion. J. Exp. Med. 197, 1279–1289 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Vogt, M. H. et al. The DBY gene codes for an HLA-DQ5-restricted human male-specific minor histocompatibility antigen involved in graft-versus-host disease. Blood 99, 3027–3032 (2002).

    CAS  Article  Google Scholar 

  26. 26

    Vogt, M. H., de Paus, R. A., Voogt, P. J., Willemze, R. & Falkenburg, J. H. DFFRY codes for a new human male-specific minor transplantation antigen involved in bone marrow graft rejection. Blood 95, 1100–1105 (2000).

    CAS  Google Scholar 

  27. 27

    Scott, D. M. et al. Identification of a mouse male-specific transplantation antigen, H-Y. Nature 376, 695–698 (1995).

    CAS  Article  Google Scholar 

  28. 28

    den Haan, J. M. et al. The minor histocompatibility antigen HA-1: a diallelic gene with a single amino acid polymorphism. Science 279, 1054–1057 (1998).

    CAS  Article  Google Scholar 

  29. 29

    Malarkannan, S. et al. The molecular and functional characterization of a dominant minor H antigen, H60. J. Immunol. 161, 3501–3509 (1998).

    CAS  Google Scholar 

  30. 30

    Wettstein, P. J. & Korngold, R. T cell subsets required for in vivo and in vitro responses to single and multiple minor histocompatibility antigens. Transplantation 54, 296–307 (1992).

    CAS  Article  Google Scholar 

  31. 31

    Wettstein, P. J. & Bailey, D. W. Immunodominance in the immune response to 'multiple' histocompatibility antigens. Immunogenetics 16, 47–58 (1982). References 30 and 31 show immunodominance in T-cell responses to miHAs.

    CAS  Article  Google Scholar 

  32. 32

    Korngold, R. & Wettstein, P. J. Immunodominance in the graft-vs-host disease T cell response to minor histocompatibility antigens. J. Immunol. 145, 4079–4088 (1990).

    CAS  Google Scholar 

  33. 33

    Choi, E. Y. et al. Real-time T-cell profiling identifies H60 as a major minor histocompatibility antigen in murine graft-versus-host disease. Blood 100, 4259–4265 (2002). References 32 and 33 demonstrate immunodominance in GVHD.

    CAS  Article  Google Scholar 

  34. 34

    Choi, E. Y. et al. Immunodominance of H60 is caused by an abnormally high precursor T cell pool directed against its unique minor histocompatibility antigen peptide. Immunity 17, 593–603 (2002). This study establishes a mechanism for immunodominance.

    Article  Google Scholar 

  35. 35

    Fontaine, P. et al. Adoptive transfer of minor histocompatibility antigen-specific T lymphocytes eradicates leukemia cells without causing graft-versus-host disease. Nature Med. 7, 789–794 (2001). This paper shows that T cells that recognize a single miHA can mediate GVL without causing GVHD. References 35–38 show that GVHD is not easily inducible across a single miHA.

    CAS  Article  Google Scholar 

  36. 36

    Korngold, R., Leighton, C., Mobraaten, L. E. & Berger, M. A. Inter-strain graft-vs.-host disease T-cell responses to immunodominant minor histocompatibility antigens. Biol. Blood Marrow Transplant. 3, 57–64 (1997).

    CAS  Google Scholar 

  37. 37

    Blazar, B. R. et al. Lack of GVHD across classical, single minor histocompatibility (miH) locus barriers in mice. Transplantation 61, 619–624 (1996).

    CAS  Article  Google Scholar 

  38. 38

    Goulmy, E. 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. 334, 281–285 (1996).

    CAS  Article  Google Scholar 

  39. 39

    Maruya, E. et al. Evidence that CD31, CD49b, and CD62L are immunodominant minor histocompatibility antigens in HLA identical sibling bone marrow transplants. Blood 92, 2169–2176 (1998).

    CAS  Google Scholar 

  40. 40

    Tseng, L. H. et al. Correlation between disparity for the minor histocompatibility antigen HA-1 and the development of acute graft-versus-host disease after allogeneic marrow transplantation. Blood 94, 2911–2914 (1999).

    CAS  Google Scholar 

  41. 41

    Randolph, S. S., Gooley, T. A., Warren, E. H., Appelbaum, F. R. & Riddell, S. R. Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood 103, 347–352 (2004). References 38–41 establish that the identity of specific miHAs can predict for GVHD and/or GVL in human allogeneic haematopoietic SCT.

    CAS  Article  Google Scholar 

  42. 42

    Dickinson, A. M. et al. In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens. Nature Med. 8, 410–414 (2002).

    CAS  Article  Google Scholar 

  43. 43

    Kaplan, D. H. et al. Target antigens determine graft-versus-host disease phenotype. J. Immunol. 173, 5467–5475 (2004). This paper establishes that the identity of immunodominant antigens can dictate the phenotype of GVHD.

    CAS  Article  Google Scholar 

  44. 44

    Sprent, J., Schaefer, M., Lo, D. & Korngold, R. Properties of purified T cell subsets. II. In vivo responses to class I vs. class II H-2 differences. J. Exp. Med. 163, 998–1011 (1986).

    CAS  Article  Google Scholar 

  45. 45

    Sprent, J., Miller, J. F. & Mitchell, G. F. Antigen-induced selective recruitment of circulating lymphocytes. Cell Immunol. 2, 171–181 (1971).

    CAS  Article  Google Scholar 

  46. 46

    Ruggeri, L. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100 (2002). This study shows that alloreactive NK cells can mediate a potent GVL effect and can suppress GVHD by eliminating recipient APCs.

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Teshima, T. et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nature Med. 8, 575–581 (2002). This study shows that CD4+ T cells can mediate GVHD in MHC-mismatched transplants without contacting recipient non-haematopoietic tissues.

    CAS  Article  Google Scholar 

  48. 48

    Trombetta, E. S. & Mellman, I. Cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol. 23, 975–1028 (2005).

    CAS  Article  Google Scholar 

  49. 49

    Ackerman, A. L. & Cresswell, P. Cellular mechanisms governing cross-presentation of exogenous antigens. Nature Immunol. 5, 678–684 (2004).

    CAS  Article  Google Scholar 

  50. 50

    Shlomchik, W. D. et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 285, 412–415 (1999).

    CAS  Article  Google Scholar 

  51. 51

    Matte, C. C. et al. Donor APCs are required for maximal GVHD but not for GVL. Nature Med. 10, 987–992 (2004). References 50 and 51 establish that radiation-resistant recipient APCs are necessary and sufficient for CD8+ T-cell-mediated GVHD induced in response to miHAs only; nonetheless, donor APCs are required for maximal GVHD.

    CAS  Article  Google Scholar 

  52. 52

    Anderson, B. E. et al. Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ. Blood 105, 2227–2234 (2005).

    CAS  Article  Google Scholar 

  53. 53

    Anderson, B. E. et al. Memory CD4+ T cells do not induce graft-versus-host disease. J. Clin. Invest. 112, 101–108 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Beilhack, A. et al. In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood 106, 1113–1122 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Chen, B. J., Cui, X., Sempowski, G. D., Liu, C. & Chao, N. J. Transfer of allogeneic CD62L-memory T cells without graft-versus-host disease. Blood 103, 1534–1541 (2004). References 53–55 establish that effector memory T cells have a reduced capacity to induce GVHD.

    CAS  Article  Google Scholar 

  56. 56

    Duffner, U. A. et al. Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease. J. Immunol. 172, 7393–7398 (2004).

    CAS  Article  Google Scholar 

  57. 57

    Merad, M. et al. Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease. Nature Med. 10, 510–517 (2004). This paper establishes that recipient Langerhans cells that survive conditioning are sufficient to induce GVHD. This has implications for GVHD induced by donor leukocyte infusions.

    CAS  Article  Google Scholar 

  58. 58

    Blazar, B. R. 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. 158, 29–39 (1997).

    CAS  Google Scholar 

  59. 59

    MacDonald, K. P. et al. Cytokine expanded myeloid precursors function as regulatory antigen-presenting cells and promote tolerance through IL-10-producing regulatory T cells. J. Immunol. 174, 1841–1850 (2005).

    CAS  Article  Google Scholar 

  60. 60

    Sato, K., Yamashita, N., Baba, M. & Matsuyama, T. Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse. Immunity 18, 367–379 (2003). References 60–65 are classic studies on the roles of CD4+ and CD8+ T cells in GVHD.

    CAS  Article  Google Scholar 

  61. 61

    Teshima, T. et al. Flt3 ligand therapy for recipients of allogeneic bone marrow transplants expands host CD8α+ dendritic cells and reduces experimental acute graft-versus-host disease. Blood 99, 1825–1832 (2002).

    CAS  Article  Google Scholar 

  62. 62

    Sprent, J., Schaefer, M., Gao, E. K. & 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. 167, 556–569 (1988).

    CAS  Article  Google Scholar 

  63. 63

    Vallera, D. A., Soderling, C. C. & Kersey, J. H. Bone marrow transplantation across major histocompatibility barriers in mice. III. Treatment of donor grafts with monoclonal antibodies directed against Lyt determinants. J. Immunol. 128, 871–875 (1982).

    CAS  Google Scholar 

  64. 64

    Hamilton, B. L. L3T4-positive T cells participate in the induction of graft-vs-host disease in response to minor histocompatibility antigens. J. Immunol. 139, 2511–2515 (1987).

    CAS  Google Scholar 

  65. 65

    Korngold, R. & Sprent, J. Surface markers of T cells causing lethal graft-vs-host disease to class I vs class II H-2 differences. J. Immunol. 135, 3004–3010 (1985).

    CAS  Google Scholar 

  66. 66

    Gallardo, D. et al. Low-dose donor CD8+ cells in the CD4-depleted graft prevent allogeneic marrow graft rejection and severe graft-versus-host disease for chronic myeloid leukemia patients in first chronic phase. Bone Marrow Transplant. 20, 945–952 (1997).

    CAS  Article  Google Scholar 

  67. 67

    Champlin, R. et al. Selective depletion of CD8+ T lymphocytes for prevention of graft-versus-host disease after allogeneic bone marrow transplantation. Blood 76, 418–423 (1990).

    CAS  Google Scholar 

  68. 68

    Allen, R. D., Staley, T. A. & Sidman, C. L. Differential cytokine expression in acute and chronic murine graft-versus-host-disease. Eur. J. Immunol. 23, 333–337 (1993).

    CAS  Article  Google Scholar 

  69. 69

    Troutt, A. B. & Kelso, A. Enumeration of lymphokine mRNA-containing cells in vivo in a murine graft-versus-host reaction using the PCR. Proc. Natl Acad. Sci. USA 89, 5276–5280 (1992).

    CAS  Article  Google Scholar 

  70. 70

    De Wit, D. et al. Preferential activation of Th2 cells in chronic graft-versus-host reaction. J. Immunol. 150, 361–366 (1993).

    CAS  Google Scholar 

  71. 71

    Murphy, W. J. et al. Differential effects of the absence of interferon-γ and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice. J. Clin. Invest. 102, 1742–1748 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Yang, Y. G., Dey, B. R., Sergio, J. J., Pearson, D. A. & Sykes, M. Donor-derived interferon γ is required for inhibition of acute graft-versus-host disease by interleukin 12. J. Clin. Invest. 102, 2126–2135 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Reddy, P. et al. Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis. J. Exp. Med. 194, 1433–1440 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Dalton, D. K., Haynes, L., Chu, C. Q., Swain, S. L. & Wittmer, S. Interferon γ eliminates responding CD4 T cells during mycobacterial infection by inducing apoptosis of activated CD4 T cells. J. Exp. Med. 192, 117–122 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Refaeli, Y., Van Parijs, L., Alexander, S. I. & Abbas, A. K. Interferon γ is required for activation-induced death of T lymphocytes. J. Exp. Med. 196, 999–1005 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Liu, J. et al. Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease. Blood 98, 3367–3375 (2001).

    CAS  Article  Google Scholar 

  78. 78

    Shlomchik, W. D., Matte, C., Liu, J. L., Jain, D. & McNiff, J. CD8+ but not CD4+ T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens but CD4+ and CD8+ T cells both require direct leukemic contact for GVL. Blood 106 (ASH Annual Meeting Abstracts), Abstract 580 (2005).

    Google Scholar 

  79. 79

    Jones, S. C., Murphy, G. F., Friedman, T. M. & Korngold, R. Importance of minor histocompatibility antigen expression by nonhematopoietic tissues in a CD4+ T cell-mediated graft-versus-host disease model. J. Clin. Invest. 112, 1880–1886 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Blazar, B. R., Taylor, P. A. & Vallera, D. A. CD4+ and CD8+ T cells each can utilize a perforin-dependent pathway to mediate lethal graft-versus-host disease in major histocompatibility complex disparate recipients. Transplantation 64, 571–576 (1997).

    CAS  Article  Google Scholar 

  81. 81

    Jiang, Z., Podack, E. & Levy, R. B. 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 98, 390–397 (2001).

    CAS  Article  Google Scholar 

  82. 82

    Schmaltz, C. et al. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood 97, 2886–2895 (2001).

    CAS  Article  Google Scholar 

  83. 83

    Tsukada, N., Kobata, T., Aizawa, Y., Yagita, H. & Okumura, K. Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation. Blood 93, 2738–2747 (1999).

    CAS  Google Scholar 

  84. 84

    Martin, P. J., Akatsuka, Y., Hahne, M. & Sale, G. Involvement of donor T-cell cytotoxic effector mechanisms in preventing allogeneic marrow graft rejection. Blood 92, 2177–2181 (1998).

    CAS  Google Scholar 

  85. 85

    Baker, M. B., Altman, N. H., Podack, E. R. & Levy, R. B. The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. J. Exp. Med. 183, 2645–2656 (1996).

    CAS  Article  Google Scholar 

  86. 86

    Marks, L., Altman, N. H., Podack, E. R. & Levy, R. B. Donor T cells lacking Fas ligand and perforin retain the capacity to induce severe GvHD in minor histocompatibility antigen mismatched bone-marrow transplantation recipients. Transplantation 77, 804–812 (2004). References 85 and 86 describe the roles of perforin and CD95L in GVHD induced in response to miHAs only.

    Article  Google Scholar 

  87. 87

    van Den Brink, M. R. et al. Fas-deficient lpr mice are more susceptible to graft-versus-host disease. J. Immunol. 164, 469–480 (2000).

    CAS  Article  Google Scholar 

  88. 88

    Piguet, P. F., Grau, G. E., Allet, B. & Vassalli, P. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease. J. Exp. Med. 166, 1280–1289 (1987).

    CAS  Article  Google Scholar 

  89. 89

    Murphy, G. F., Sueki, H., Teuscher, C., Whitaker, D. & Korngold, R. Role of mast cells in early epithelial target cell injury in experimental acute graft-versus-host disease. J. Invest. Dermatol. 102, 451–461 (1994).

    CAS  Article  Google Scholar 

  90. 90

    Speiser, D. E. et al. TNF receptor p55 controls early acute graft-versus-host disease. J. Immunol. 158, 5185–5190 (1997).

    CAS  Google Scholar 

  91. 91

    Hattori, K. et al. Differential effects of anti-Fas ligand and anti-tumor necrosis factor α antibodies on acute graft-versus-host disease pathologies. Blood 91, 4051–4055 (1998).

    CAS  Google Scholar 

  92. 92

    Korngold, R., Marini, J. C., de Baca, M. E., Murphy, G. F. & Giles-Komar, J. Role of tumor necrosis factor-α in graft-versus-host disease and graft-versus-leukemia responses. Biol. Blood Marrow Transplant. 9, 292–303 (2003).

    CAS  Article  Google Scholar 

  93. 93

    Hill, G. R. et al. The p55 TNF-α receptor plays a critical role in T cell alloreactivity. J. Immunol. 164, 656–663 (2000).

    CAS  Article  Google Scholar 

  94. 94

    Schmaltz, C. et al. T cells require TRAIL for optimal graft-versus-tumor activity. Nature Med. 8, 1433–1437 (2002).

    CAS  Article  Google Scholar 

  95. 95

    Zhang, Y. et al. Dendritic cell-activated CD44hiCD8+ T cells are defective in mediating acute graft-versus-host disease but retain graft-versus-leukemia activity. Blood 103, 3970–3978 (2004).

    CAS  Article  Google Scholar 

  96. 96

    Hamilton, S. E., Wolkers, M. C., Schoenberger, S. P. & Jameson, S. C. The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+T cells. Nature Immunol. 7, 475–481 (2006).

    CAS  Article  Google Scholar 

  97. 97

    Min, B., Foucras, G., Meier-Schellersheim, M. & Paul, W. E. Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire. Proc. Natl Acad. Sci. USA 101, 3874–3879 (2004).

    CAS  Article  Google Scholar 

  98. 98

    Dutt, S. et al. L-Selectin and β7 integrin on donor CD4 T cells are required for the early migration to host mesenteric lymph nodes and acute colitis of graft versus host disease. Blood 106, 4009–4015 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Beilhack, A. et al. Prevention of acute graft-versus-host disease despite compensatory function of lymphoid organs in vivo. Biol. Blood Marrow Transplant. 12 (Suppl. 1), 11 (2006).

    Article  Google Scholar 

  100. 100

    Anderson, B. E., Shlomchik, W. D. & Shlomchik, M. J. The influence of migration, alloreactive repertoire and memory subset on the differential ability of naive and memory T cells to induce GVHD. Blood 106 (ASH Annual Meeting Abstracts), Abstract 577 (2005).

  101. 101

    Arstila, T. P. et al. A direct estimate of the human αβT cell receptor diversity. Science 286, 958–961 (1999).

    CAS  Article  Google Scholar 

  102. 102

    Bleakley, M., Mollerup, A., Chaney, C., Brown, M. & Riddell, S. R. Human minor histocompatibility antigen-specific CD8+ T cells are found predominantly in the CD45RA+ CD62L+ naive T cell subset. Blood 106 (ASH Annual Meeting Abstracts), Abstract 578 (2005).

  103. 103

    Zheng, H. et al. CD8+ central memory T cells mediate graft-versus-host disease although retain graft-versus-leukemia effect. Blood 106 (ASH Annual Meeting Abstracts), Abstract 1312 (2005).

  104. 104

    Chen, B. J., Xiuyu, C. & Chao, N. J. Memory T cells (CD62L+ and CD62L) do not induce graft-vs.-host disease. Blood 102 (ASH Annual Meeting Abstracts), Abstract 665 (2003).

  105. 105

    Wysocki, C. A., Panoskaltsis-Mortari, A., Blazar, B. R. & Serody, J. S. Leukocyte migration and graft-versus-host disease. Blood 105, 4191–4199 (2005). This is a comprehensive review on leukocyte migration in GVHD.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Clouthier, S. G., Ferrara, J. L. & Teshima, T. Graft-versus-host disease in the absence of the spleen after allogeneic bone marrow transplantation. Transplantation 73, 1679–1681 (2002).

    Article  Google Scholar 

  107. 107

    Murai, M. et al. Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. Nature Immunol. 4, 154–160 (2003).

    CAS  Article  Google Scholar 

  108. 108

    Welniak, L. A. et al. An absence of CCR5 on donor cells results in acceleration of acute graft-vs-host disease. Exp. Hematol. 32, 318–324 (2004).

    CAS  Article  Google Scholar 

  109. 109

    Welniak, L. A. et al. Peyer patches are not required for acute graft-versus-host disease after myeloablative conditioning and murine allogeneic bone marrow transplantation. Blood 107, 410–412 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Mora, J. R. et al. Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues. J. Exp. Med. 201, 303–316 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Mora, J. R. et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424, 88–93 (2003).

    CAS  Article  Google Scholar 

  112. 112

    Petrovic, A. et al. LPAM (α4β7 integrin) is an important homing integrin on alloreactive T cells in the development of intestinal graft-versus-host disease. Blood 103, 1542–1547 (2004).

    CAS  Article  Google Scholar 

  113. 113

    Reinhardt, R. L., Khoruts, A., Merica, R., Zell, T. & Jenkins, M. K. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101–105 (2001).

    CAS  Article  Google Scholar 

  114. 114

    Taylor, P. A., Lees, C. J. & Blazar, B. R. The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99, 3493–3499 (2002). References 114–116 initially established that donor T Reg cells suppress GVHD.

    CAS  Article  PubMed  Google Scholar 

  115. 115

    Hoffmann, P., Ermann, J., Edinger, M., Fathman, C. G. & Strober, S. Donor-type CD4+CD25+ regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J. Exp. Med. 196, 389–399 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Cohen, J. L., Trenado, A., Vasey, D., Klatzmann, D. & Salomon, B. L. CD4+CD25+ immunoregulatory T Cells: new therapeutics for graft- versus-host disease. J. Exp. Med. 196, 401–406 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Anderson, B. E. et al. Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease. Blood 104, 1565–1573 (2004).

    CAS  Article  Google Scholar 

  118. 118

    Jones, S. C., Murphy, G. F. & 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 Transplant. 9, 243–256 (2003).

    Article  Google Scholar 

  119. 119

    Ermann, J. et al. Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 105, 2220–2226 (2005).

    CAS  Article  Google Scholar 

  120. 120

    Wysocki, C. A. et al. Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease. Blood 106, 3300–3307 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Zeiser, R. et al. Early CD30 signaling is critical for adoptively transferred CD4+CD25+ regulatory T cells in prevention of acute graft-versus-host disease. Blood 109, 2225–2233 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Lan, F., Zeng, D., Higuchi, M., Higgins, J. P. & Strober, S. Host conditioning with total lymphoid irradiation and antithymocyte globulin prevents graft-versus-host disease: the role of CD1-reactive natural killer T cells. Biol. Blood Marrow Transplant. 9, 355–363 (2003).

    Article  Google Scholar 

  123. 123

    Lan, F. et al. Predominance of NK1.1+TCR αβ+ or DX5+TCR αβ+ T cells in mice conditioned with fractionated lymphoid irradiation protects against graft-versus-host disease: 'natural suppressor' cells. J. Immunol. 167, 2087–2096 (2001).

    CAS  Article  Google Scholar 

  124. 124

    Zeng, D. et al. Bone marrow NK1.1 and NK1.1+ T cells reciprocally regulate acute graft versus host disease. J. Exp. Med. 189, 1073–1081 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Lowsky, R. et al. Protective conditioning for acute graft-versus-host disease. N. Engl. J. Med. 353, 1321–1331 (2005).

    CAS  Article  Google Scholar 

  126. 126

    Parkman, R. Clonal analysis of murine graft-vs-host disease. I. Phenotypic and functional analysis of T lymphocyte clones. J. Immunol. 136, 3543–3548 (1986).

    CAS  Google Scholar 

  127. 127

    Fukushi, N. et al. Thymus: a direct target tissue in graft-versus-host reaction after allogeneic bone marrow transplantation that results in abrogation of induction of self-tolerance. Proc. Natl Acad. Sci. USA 87, 6301–6305 (1990).

    CAS  Article  Google Scholar 

  128. 128

    Hollander, G. A., Widmer, B. & Burakoff, S. J. Loss of normal thymic repertoire selection and persistence of autoreactive T cells in graft vs host disease. J. Immunol. 152, 1609–1617 (1994).

    CAS  Google Scholar 

  129. 129

    Mullally, A. et al. Genome wide single nucleotide polymorphism typing for identification of putative minor histocompatibility antigens in graft versus host disease. Blood 108 (ASH Annual Meeting Abstracts), Abstract 447 (2006).

  130. 130

    Cutler, C. et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 108, 756–762 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Miklos, D. B. et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood 105, 2973–2978 (2005).

    CAS  Article  Google Scholar 

  132. 132

    Blazar, B. R., Taylor, P. A., Panoskaltsis-Mortari, A., Sharpe, A. H. & Vallera, D. A. Opposing roles of CD28:B7 and CTLA-4:B7 pathways in regulating in vivo alloresponses in murine recipients of MHC disparate T cells. J. Immunol. 162, 6368–6377 (1999).

    CAS  Google Scholar 

  133. 133

    Speiser, D. E., Bachmann, M. F., Shahinian, A., Mak, T. W. & Ohashi, P. S. Acute graft-versus-host disease without costimulation via CD28. Transplantation 63, 1042–1044 (1997).

    CAS  Article  Google Scholar 

  134. 134

    Blazar, B. R., Taylor, P. A., Linsley, P. S. & Vallera, D. A. 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 83, 3815–3825 (1994).

    CAS  Google Scholar 

  135. 135

    Blazar, B. R., Taylor, P. A., Gray, G. S. & Vallera, D. A. The role of T cell subsets in regulating the in vivo efficacy of CTLA4-Ig in preventing graft-versus-host disease in recipients of fully MHC or multiple minor histocompatibility-disparate donor inocula. Transplantation 58, 1422–1426 (1994).

    CAS  Google Scholar 

  136. 136

    Via, C. S., Rus, V., Nguyen, P., Linsley, P. & Gause, W. C. Differential effect of CTLA4Ig on murine graft-versus-host disease (GVHD) development: CTLA4Ig prevents both acute and chronic GVHD development but reverses only chronic GVHD. J. Immunol. 157, 4258–4267 (1996).

    CAS  Google Scholar 

  137. 137

    Blazar, B. R. et al. Infusion of anti-B7.1 (CD80) and anti-B7.2 (CD86) monoclonal antibodies inhibits murine graft-versus-host disease lethality in part via direct effects on CD4+ and CD8+ T cells. J. Immunol. 157, 3250–3259 (1996).

    CAS  Google Scholar 

  138. 138

    Tamada, K. et al. LIGHT, a TNF-like molecule, costimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response. J. Immunol. 164, 4105–4110 (2000).

    CAS  Article  Google Scholar 

  139. 139

    Tamada, K. et al. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nature Med. 6, 283–289 (2000).

    CAS  Article  Google Scholar 

  140. 140

    Tamada, K. et al. Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease. J. Clin. Invest. 109, 549–557 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Hubbard, V. M. et al. Absence of inducible costimulator on alloreactive T cells reduces graft-versus-host disease and induces Th2 deviation. Blood 106, 3285–3292 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    Taylor, P. A. et al. Targeting of inducible costimulator (ICOS) expressed on alloreactive T cells down-regulates graft-versus-host disease (GVHD) and facilitates engraftment of allogeneic bone marrow (BM). Blood 105, 3372–3380 (2005).

    CAS  Article  Google Scholar 

  143. 143

    Tsukada, N. et al. Blockade of CD134 (OX40)–CD134L interaction ameliorates lethal acute graft-versus-host disease in a murine model of allogeneic bone marrow transplantation. Blood 95, 2434–2439 (2000).

    CAS  Google Scholar 

  144. 144

    Blazar, B. R. et al. Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients. Blood 101, 3741–3748 (2003).

    CAS  Article  Google Scholar 

  145. 145

    Blazar, B. R. et al. CD30/CD30 ligand (CD153) interaction regulates CD4+ T cell-mediated graft-versus-host disease. J. Immunol. 173, 2933–2941 (2004).

    CAS  Article  Google Scholar 

  146. 146

    Blazar, B. R. et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-γ-dependent mechanism. J. Immunol. 171, 1272–1277 (2003).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Work in my laboratory is supported by P01AI064343, R01HL083072, R01HL66279, R01CA96943 and from the Leukemia and Lymphoma Society.

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Warren D. Shlomchik's homepage

Glossary

Graft versus leukaemia

(GVL). An alloimmune attack against recipient haematopoietic neoplasms, which is mounted by donor immune cells in an allogeneic haematopoietic SCT. With the exception of T-cell-depleted haploidentical allogeneic SCTs, wherein GVL can be mediated by alloreactive natural killer cells, GVL is mediated by αβ T cells contained in the donor allograft.

Graft-versus-host disease

(GVHD). An immune response mounted against the recipient of an allograft by mature donor αβ T cells contained in the graft. Typically, it is seen in the context of allogeneic haematopoietic SCT, although it can also occur in immunodeficient patients when they receive blood transfusions.

Eosinophilic fasciitis

A condition in which there is skin thickening and tethering with oedema, along with thickening of the sub-epidermal fascia and infiltration with eosinophils.

Haematopoiesis

The commitment and differentiation processes that lead from a haematopoietic stem cell to the production of mature cells of all lineages.

Systemic sclerosis

A systemic disease marked by the formation of hyalinized and thickened collagenous fibrous tissue, with thickening and adhesion of skin to underlying tissues. Also known as scleroderma.

Epitope spreading

The de novo activation of autoreactive T cells by self-antigens that have been released after virus-specific T- or B-cell-mediated bystander damage.

Minor histocompatibility antigens

(miHAs). In the context of allogeneic haematopoietic stem-cell transplantation, miHAs are polymorphic peptides that are recognized by donor T cells. miHAs are derived from polymorphic alleles of genes in which the donor and recipient differ. Both GVHD and GVL are induced in response to these polymorphic antigens.

Cross-presentation

The process by which antigens that are expressed by one cell are processed and presented on MHC class I molecules of another cell.

Congenic

An animal strain that is genetically identical to another strain except for one or more allelic differences.

Immunodominant antigens

Those antigens, among a larger mix of potential antigens that are preferentially targeted by responding T cells. In the context of an allogeneic haematopoietic stem-cell transplant, these are the polymorphic peptides targeted by alloimmune T cells.

β2-microglobulin

2m). A single immunoglobulin-like domain that non-covalently associates with the main polypeptide chain of MHC class I molecules. In the absence of β2m, MHC class I molecules are unstable and are therefore found at very low levels at the cell surface.

Alymphoplasia

(aly). A mouse phenotype that is characterized by the absence of lymph nodes and Peyer's patches. It is caused by a spontaneous mutation in the gene that encodes nuclear-factor-κB-inducing kinase (NIK).

Total lymphoid irradiation

Selective external beam irradiation of lymphoid tissues given as a method of treating lymphoma or as immunosuppressive conditioning to allow engraftment of a donor haematopoietic allograft.

Treatment-refractory GVHD

Graft-versus-host disease (GVHD) that does not respond to initial therapy, which is typically corticosteroid based.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Shlomchik, W. Graft-versus-host disease. Nat Rev Immunol 7, 340–352 (2007). https://doi.org/10.1038/nri2000

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing