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  • Review Article
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Alloreactive killer cells: hindrance and help for haematopoietic transplants

Nature Reviews Immunology volume 3, pages 108–122 (2003)Cite this article

Key Points

  • Success in the use of haematopoietic-cell transplantation (HCT) as a treatment for cancer has come from using allogeneic donors with the maximum possible HLA match. This reduces the severity of graft-versus-host disease (GVHD) caused by alloreactive, donor-derived T cells in the graft.

  • Some degree of T-cell alloreactivity is beneficial for engraftment and for curing the primary disease, as seen from the increased rates of graft rejection and tumour relapse that are observed with autologous transplants and T-cell-depleted allogeneic transplants. New modifications to protocols aim to preserve the benefit of an alloreactive T-cell response in facilitating engraftment and eliminating tumour cells, but to reduce the probability of causing GVHD.

  • For those patients for whom an appropriately HLA-matched donor cannot be found, an HLA-mismatched haploidentical transplant is becoming an increasingly viable option. Recent success with this approach has come from increasing the size of the graft, depleting it of T cells and conditioning the recipient to prevent graft rejection.

  • In recipients of haploidentical transplants, GVHD does not occur, but alloreactive natural killer (NK) cells with specificity for the HLA class I molecules of the recipient can be detected for a period of up to four months after transplantation. The predominant alloreactive NK cells are HLA-C specific, and their presence depends on the precise HLA-C mismatch between donor and recipient and is controlled by the inhibitory HLA-C-specific killer-cell immunoglobulin-like receptor (KIR) that is expressed by NK cells.

  • For patients who receive HCT for acute myelogenous leukaemia, the presence of an alloreactive NK-cell response is correlated with longer disease-free survival and with the capacity of the alloreactive NK cells to kill cells from the patient's tumour. By contrast, the presence of alloreactive NK cells confers no benefit to patients with acute lymphoid leukaemia (ALL), correlating with the failure of NK cells to kill ALL cells owing to their lack of expression of the adhesion molecule leukocyte function-associated antigen 1.

  • In addition to eliminating tumour cells from transplant recipients, alloreactive NK cells might also reduce the severity of GVHD by killing dendritic cells of the recipient that are necessary for presenting antigens to the alloreactive T cells that cause GVHD.

  • Retrospective analysis of 'conventional' transplants across HLA-C mismatches has been carried out to look for beneficial effects. So far, the results have shown that HLA-C incompatibility is a risk factor for graft rejection and GVHD.

  • In addition to HLA-C ligands, it is possible that KIR differences between donor and recipient can affect the specificity of alloreactive NK cells that are present after haploidentical transplantation. A large majority of transplants involve a KIR mismatch, and initial studies indicate that when donors have more genes encoding activating KIRs than do recipients, then the probability of GVHD is increased.

  • The protocols that are used in conventional HLA-matched HCT and in HLA-mismatched haploidentical HCT differ, and they seem to create a different immunological environment in the recipient after transplantation. Future research will need to explain the seemingly discordant effects of HLA-C differences and the role of alloreactive NK cells in the different types of transplant.

Abstract

Haematopoietic-cell transplantation is a treatment for leukaemia and lymphoma. To reduce the incidence of graft-versus-host disease (GVHD) caused by transplanted T cells, donors and recipients are HLA matched. For patients for whom a matched donor is not available, one option is transplantation from an HLA-mismatched relative who shares one HLA haplotype. This procedure is distinguished by the use of a stronger conditioning regimen for the patient and of a T-cell-depleted graft containing numerous stem cells. After transplantation, natural killer cells are prevalent, and they can include alloreactive cells that kill tumour cells and prevent GVHD. The alloreactions seem to be determined by the mismatched HLA class I ligands and their killer-cell immunoglobulin-like receptors.

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Figure 1: Haematopoietic-cell transplantation and graft-versus-host disease.
Figure 2: MHC class I receptors of human natural killer cells.
Figure 3: Patterns of NK-cell alloreactivity owing to differences in HLA-C type between transplant donor and recipient.
Figure 4: Alloreactive NK cells might prevent GVHD in allogeneic haematopoietic-cell transplantation by killing DCs in susceptible tissues.
Figure 5: Gene organization of the KIR locus.
Figure 6: Representive human KIR genotypes.

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Acknowledgements

We thank N. Yawata, M. Yawata and J. Shizuru for their help. Research in our laboratory was supported by grants from the National Institutes of Health and the Cancer Research Institute.

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Authors and Affiliations

  1. Departments of Structural Biology and Microbiology & Immunology, Stanford University, Stanford, 94305, California, USA

    Peter Parham & Karina L. McQueen

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  1. Peter Parham
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Correspondence to Peter Parham.

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DATABASES

Cancer.gov

ALL

AML

CML

LocusLink

CD94

G-CSF

HLA-A

HLA-B

HLA-C

HLA-E

HLA-DP

HLA-DQ

HLA-DR

IFN-γ

KIR2DL1

KIR2DL2

KIR2DL3

KIR2DL4

KIR2DL5

KIR2DS1

KIR2DS2

KIR2DS3

KIR2DS4

KIR2DS5

KIR3DL1

KIR3DL2

KIR3DL3

KIR3DS1

NKG2A

FURTHER INFORMATION

IMGT/HLA Database

Anthony Nolan Trust HLA class I and II sequence alignments

Glossary

MYELOABLATIVE CHEMOTHERAPY

The administration of high-dose chemotherapy, with or without total body irradiation, to patients before haematopoietic-cell transplantation (HCT) to eradicate the underlying disease and/or ablate the immune system of the patient. HCT is required after this conditioning regimen for recovery and complete chimerism on engraftment.

CYTOKINE STORM

The high-level secretion of cytokines and growth factors induced by the pre-transplant conditioning regimen, which damages dividing cells, that leads to downstream immune effects such as graft-versus-host disease.

NON-MYELOABLATIVE CONDITIONING

A mild regimen of low toxicity that involves the administration of myelotoxic or immunosuppressive, but not myeloablative, agents to patients before HCT. Conditioning does not eradicate host haematopoiesis and should allow prompt haematopoietic recovery (within 28 < days) without a transplant.

VETO CELLS

Cells in the CD34+ population that can specifically suppress cytotoxic T-cell precursors specific for antigens that are presented by the veto cells themselves, but not those that are specific for third-party antigens.

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Parham, P., McQueen, K. Alloreactive killer cells: hindrance and help for haematopoietic transplants. Nat Rev Immunol 3, 108–122 (2003). https://doi.org/10.1038/nri999

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