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  • Review Article
  • Published:

Graft-versus-host disease

Nature Reviews Immunology volume 7, pages 340–352 (2007)Cite this article

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.

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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.

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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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    Warren D. Shlomchik

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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

(β2m). 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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Shlomchik, W. Graft-versus-host disease. Nat Rev Immunol 7, 340–352 (2007). https://doi.org/10.1038/nri2000

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