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  • Review Article
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Cytolytic pathways in haematopoietic stem-cell transplantation

Key Points

  • Recent developments in allogeneic haematopoietic stem-cell transplantation (HSCT) for cancer patients are changing the focus of HSCT from a rescue strategy for high-dose chemotherapy and/or radiation therapy to a platform for new immunotherapeutic strategies.

  • Donor T cells are crucial in graft-versus-host disease (GVHD), graft-versus-tumour (GVT) activity and engraftment after allogeneic HSCT.

  • Donor T cells mediate GVHD and GVT activity through several pathways, including direct cytotoxicity by means of Fas ligand and cytotoxic granules that contain perforin and granzymes, and cytokines, such as tumour-necrosis factor and interferon-γ.

  • Donor T cells make selective use of their effector pathways to mediate target-organ GVHD. For example, Fas ligand is essential for liver GVHD, whereas TNF is important for intestinal GVHD.

  • Most studies indicate a dominant role for perforin in GVT activity.

  • Studies in mouse models have shown that GVHD and GVT activity can be separated by the specific inhibition of the Fas ligand or perforin pathways. This indicates that therapeutic strategies that target the cytolytic pathways could provide new opportunities to enhance GVT effects and/or decrease GVHD that is mediated by donor T cells.

Abstract

The remarkable activity of donor T cells against malignant cells in the context of an allogeneic haematopoietic stem-cell transplantation (HSCT) is arguably, at present, the most potent clinical immunotherapy for cancer. However, alloreactive donor T cells are also important effector cells in the development of graft-versus-host disease (GVHD), which is a potentially lethal complication for recipients of an allogeneic HSCT. Therefore, the separation of the GVHD and graft-versus-tumour (GVT) activity of donor T cells has become a topic of great interest for many investigators. Recent studies have shown that donor T cells make differential use of their cytolytic pathways in mediating GVHD and GVT effects. Therefore, the selective blockade or enhancement of cytolytic pathways provides an intriguing therapeutic opportunity to separate the desired GVT effect from the potentially devastating GVHD.

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Figure 1: Antigen-specific activity of donor and host T cells is important in GVHD, GVT effects and engraftment.
Figure 2: Donor T cells use specific cytolytic pathways against host tissues and tumour cells after allogeneic HSCT.

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Acknowledgements

We apologize to all researchers whose publications have not been cited owing to space constraints. This work was supported by a National Institutes of Health program project grant (S.J.B.) and an award of the Wendy Will Case Cancer Fund (M.R.M.B.). M.R.M.B is the recipient of Scholar awards of the Cancer Research Fund of the Damon Runyan-Walter Foundation, and the V Foundation.

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Correspondence to Marcel R. M. van den Brink.

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DATABASES

LocusLink

CD52

Fas

FasL

granzyme

granzyme B

IFN-γ

IL-1

IL-2

IL-12

perforin

TNF

TNFR1

TRAIL

TWEAK

Medscape DrugInfo

Campath-1

cyclosporine

Etanercept

fludarabine

Infliximab

prednisone

Mouse Genome Informatics

gld mice

lpr mice

OMIM

rheumatoid arthritis

Sjogren syndrome

FURTHER INFORMATION

Marcel van den Brinks's lab

Glossary

CONDITIONING REGIMEN

The preparative treatment given to a patient before an allogeneic HSCT. This regimen can include chemotherapy, irradiation or specific immunosuppressive therapy and must accomplish two goals: tumour or disease cytoreduction/eradication and immunosuppression to overcome host rejection of the donor graft.

SCLERODERMA

The clinical features of this syndrome are due to autoreactive antibodies and T cells and can vary greatly, including dermal fibrosis of the skin, liver-function abnormalities, keratoconjunctivitis sicca (dry eyes), dry mouth (due to salivary-gland involvement) and obstructive lung disease.

DONOR LEUKOCYTE INFUSION

(DLI). The infusion of donor leukocytes into patients that have a recurrence of their malignancy after an allogeneic haematopoietic stem-cell transplanation. This adoptive cellular immunotherapy has been particularly successful in patients with chronic myeloid leukaemia, and results in durable, complete responses in most patients.

NON-MYELOABLATIVE ALLOGENEIC HSCT

An allogeneic haematopoietic stem-cell transplantation (HSCT) in a recipient who has received a conditioning regimen to achieve immunosuppression and prevent graft rejection without the complete ablation of host haematopoiesis. The recipient might develop (transient) mixed chimerism owing to haematopoietic recovery of the host and engraftment of donor haematopoietic stem cells.

IMMUNE-PRIVILEGED SITES

These are areas in the body with a decreased immune response to foreign antigens, including tissue grafts. The sites include the brain, eye, testis and uterus.

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van den Brink, M., Burakoff, S. Cytolytic pathways in haematopoietic stem-cell transplantation. Nat Rev Immunol 2, 273–281 (2002). https://doi.org/10.1038/nri775

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