Review Article | Published:

Graft-versus-host disease

Nature Reviews Immunology volume 7, pages 340352 (2007) | Download Citation

Subjects

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.

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.

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References

  1. 1.

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

  2. 2.

    & 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.

  3. 3.

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

  4. 4.

    & 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).

  5. 5.

    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).

  6. 6.

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

  7. 7.

    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.

  8. 8.

    & Chronic graft versus host disease. Br. J. Haematol. 125, 435–454 (2004).

  9. 9.

    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.

  10. 10.

    , & Role of endogenous peptide in human alloreactive cytotoxic T cell responses. Int. Immunol. 4, 367–375 (1992).

  11. 11.

    , , & 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).

  12. 12.

    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.

  13. 13.

    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.

  14. 14.

    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).

  15. 15.

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

  16. 16.

    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).

  17. 17.

    , , , & 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).

  18. 18.

    , , , & 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).

  19. 19.

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

  20. 20.

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

  21. 21.

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

  22. 22.

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

  23. 23.

    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).

  24. 24.

    , & A human minor histocompatibility antigen resulting from differential expression due to a gene deletion. J. Exp. Med. 197, 1279–1289 (2003).

  25. 25.

    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).

  26. 26.

    , , , & DFFRY codes for a new human male-specific minor transplantation antigen involved in bone marrow graft rejection. Blood 95, 1100–1105 (2000).

  27. 27.

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

  28. 28.

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

  29. 29.

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

  30. 30.

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

  31. 31.

    & 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.

  32. 32.

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

  33. 33.

    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.

  34. 34.

    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.

  35. 35.

    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.

  36. 36.

    , , & Inter-strain graft-vs.-host disease T-cell responses to immunodominant minor histocompatibility antigens. Biol. Blood Marrow Transplant. 3, 57–64 (1997).

  37. 37.

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

  38. 38.

    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).

  39. 39.

    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).

  40. 40.

    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).

  41. 41.

    , , , & 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.

  42. 42.

    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).

  43. 43.

    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.

  44. 44.

    , , & 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).

  45. 45.

    , & Antigen-induced selective recruitment of circulating lymphocytes. Cell Immunol. 2, 171–181 (1971).

  46. 46.

    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.

  47. 47.

    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.

  48. 48.

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

  49. 49.

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

  50. 50.

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

  51. 51.

    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.

  52. 52.

    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).

  53. 53.

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

  54. 54.

    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).

  55. 55.

    , , , & 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.

  56. 56.

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

  57. 57.

    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.

  58. 58.

    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).

  59. 59.

    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).

  60. 60.

    , , & 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.

  61. 61.

    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).

  62. 62.

    , , & 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).

  63. 63.

    , & 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).

  64. 64.

    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).

  65. 65.

    & 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).

  66. 66.

    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).

  67. 67.

    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).

  68. 68.

    , & Differential cytokine expression in acute and chronic murine graft-versus-host-disease. Eur. J. Immunol. 23, 333–337 (1993).

  69. 69.

    & 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).

  70. 70.

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

  71. 71.

    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).

  72. 72.

    , , , & Donor-derived interferon γ is required for inhibition of acute graft-versus-host disease by interleukin 12. J. Clin. Invest. 102, 2126–2135 (1998).

  73. 73.

    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).

  74. 74.

    , , , & 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).

  75. 75.

    , , & Interferon γ is required for activation-induced death of T lymphocytes. J. Exp. Med. 196, 999–1005 (2002).

  76. 76.

    , , , & Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. J. Clin. Invest. 105, 1289–1298 (2000).

  77. 77.

    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).

  78. 78.

    , , , & 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).

  79. 79.

    , , & 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).

  80. 80.

    , & 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).

  81. 81.

    , & 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).

  82. 82.

    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).

  83. 83.

    , , , & 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).

  84. 84.

    , , & Involvement of donor T-cell cytotoxic effector mechanisms in preventing allogeneic marrow graft rejection. Blood 92, 2177–2181 (1998).

  85. 85.

    , , & 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).

  86. 86.

    , , & 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.

  87. 87.

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

  88. 88.

    , , & 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).

  89. 89.

    , , , & Role of mast cells in early epithelial target cell injury in experimental acute graft-versus-host disease. J. Invest. Dermatol. 102, 451–461 (1994).

  90. 90.

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

  91. 91.

    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).

  92. 92.

    , , , & Role of tumor necrosis factor-α in graft-versus-host disease and graft-versus-leukemia responses. Biol. Blood Marrow Transplant. 9, 292–303 (2003).

  93. 93.

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

  94. 94.

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

  95. 95.

    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).

  96. 96.

    , , & The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+T cells. Nature Immunol. 7, 475–481 (2006).

  97. 97.

    , , & 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).

  98. 98.

    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).

  99. 99.

    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).

  100. 100.

    , & 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.

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

  102. 102.

    , , , & 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.

    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.

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

  105. 105.

    , , & Leukocyte migration and graft-versus-host disease. Blood 105, 4191–4199 (2005). This is a comprehensive review on leukocyte migration in GVHD.

  106. 106.

    , & Graft-versus-host disease in the absence of the spleen after allogeneic bone marrow transplantation. Transplantation 73, 1679–1681 (2002).

  107. 107.

    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).

  108. 108.

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

  109. 109.

    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).

  110. 110.

    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).

  111. 111.

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

  112. 112.

    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).

  113. 113.

    , , , & Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101–105 (2001).

  114. 114.

    , & 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 TReg cells suppress GVHD.

  115. 115.

    , , , & 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).

  116. 116.

    , , , & CD4+CD25+ immunoregulatory T Cells: new therapeutics for graft- versus-host disease. J. Exp. Med. 196, 401–406 (2002).

  117. 117.

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

  118. 118.

    , & 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).

  119. 119.

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

  120. 120.

    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).

  121. 121.

    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).

  122. 122.

    , , , & 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).

  123. 123.

    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).

  124. 124.

    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).

  125. 125.

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

  126. 126.

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

  127. 127.

    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).

  128. 128.

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

  129. 129.

    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.

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

  131. 131.

    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).

  132. 132.

    , , , & 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).

  133. 133.

    , , , & Acute graft-versus-host disease without costimulation via CD28. Transplantation 63, 1042–1044 (1997).

  134. 134.

    , , & 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).

  135. 135.

    , , & 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).

  136. 136.

    , , , & 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).

  137. 137.

    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).

  138. 138.

    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).

  139. 139.

    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).

  140. 140.

    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).

  141. 141.

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

  142. 142.

    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).

  143. 143.

    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).

  144. 144.

    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).

  145. 145.

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

  146. 146.

    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).

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Acknowledgements

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

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  1. Yale University School of Medicine, sections of Medical Oncology and Immunobiology, PO BOX 208032, New Haven, Connecticut 06520, USA.  warren.shlomchik@yale.edu

    • Warren D. Shlomchik

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The author declares no competing financial interests.

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.

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DOI

https://doi.org/10.1038/nri2000

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