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  • Review Article
  • Published:

Emerging concepts in haematopoietic cell transplantation

Nature Reviews Immunology volume 12, pages 403–416 (2012)Cite this article

Subjects

Key Points

  • The use of alternative donors, including umbilical cord blood and haploidentical donors, has enabled more patients to undergo haematopoietic cell transplantation (HCT). Recent studies also provide potential solutions for problems associated with the use of alternative donors, such as low stem cell content, increased graft rejection and graft-versus-host-disease (GVHD), and slow immune reconstitution.

  • Reduced intensity conditioning allows more patients to be eligible for HCT. In addition to allowing engraftment, some conditioning regimens may have the ability to reduce the incidence of GVHD while preserving graft-versus-tumour (GVT) effects.

  • Multiple approaches have been proposed to enhance immune reconstitution following HCT. Some of these approaches are currently being evaluated in clinical trials.

  • Alloresponses can directly mediate antitumour effects or indirectly promote antitumour immunity by generating a pro-inflammatory environment. In addition, autologous HCT can be used as haematopoietic rescue for patients receiving intensive conditioning to enhance the efficacy of antitumour effects mediated by tumour-specific T cells.

  • Allogeneic HCT has been used to induce tolerance for allogeneic kidney grafts in patients. Induction of mixed chimerism by xenogeneic HCT achieves T cell, B cell and natural killer cell tolerance to xenografts.

  • Both autologous and allogeneic HCT have been used to treat severe autoimmune diseases. Efforts are needed to elucidate the mechanisms of efficacy of these treatments.

Abstract

Haematopoietic cell transplantation (HCT) is the most widely used form of cellular therapy. It is the only known cure for some haematological malignancies and has recently been used in additional clinical settings, such as allograft tolerance induction and treatment of autoimmune diseases. Recent advances have enabled HCT in a wider range of patients with improved outcomes. This Review summarizes the latest developments in this therapy, focusing on issues that will affect future advancement.

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Figure 1: Haploidentical and umbilical cord blood transplantation.
Figure 2: Enhancing immune reconstitution with cellular therapy following haematopoietic cell transplantation.
Figure 3: Transplantation as an immunotherapy.

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Acknowledgements

We thank B. Sprangers for helpful review of the manuscript and S. Washington for expert assistance. This work was supported by grants from the National Cancer Institute, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Research Foundation.

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    Hao Wei Li & Megan Sykes

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Glossary

Cytokine-mobilized peripheral blood

Refers to treatment with granulocyte colony-stimulating factor and/or a stromal cell-derived factor 1 inhibitor to mobilize haematopoietic stem and progenitor cells from the marrow to the circulation, where they can be collected by leukapheresis for use in transplantation.

Umbilical cord blood

(UCB). Blood that is collected from the umbilical cord after childbirth and is used as a source of haematopoietic stem cells to treat patients with haematological disorders. One unit of cord blood refers to blood harvested from one umbilical cord.

Allogeneic

Of, or relating to, the same species. Allogeneic transplants are transplants between individuals of the same species. Mismatched MHC or minor histocompatibility antigens exist between the donor and the host, and this can elicit an immune response, which results in either graft rejection or graft-versus-host disease.

Graft-versus-host disease

(GVHD). A pathological process mediated by host alloantigen-activated donor T cells attacking the normal tissues (mainly skin, gut and liver) of the host.

Non-myeloablative conditioning

Also known as reduced-intensity conditioning. A less-intensive conditioning protocol that allows the engraftment of donor cells without ablating the host's haematopoietic system. Haematopoietic recovery occurs without engraftment of infused haematopoietic cells.

Autologous

In autologous transplantation, the infused haematopoietic cells are from the patients themselves.

Haploidentical

A haploidentical donor is matched for half of the MHC alleles of the recipient (one HLA haplotype). The donor can be the patient's parents, siblings, children or other relatives. Because as many as half of the alleles are mismatched, specific treatment of the patient and processing of the haematopoietic stem-cell graft are required to avoid severe immunological consequences

Mesenchymal stem cells

(MSCs). Multipotent stem cells that can differentiate into various types of stromal cells.

Myeloablative conditioning

Refers to intensive measures used to prepare hosts for allogeneic haematopoietic cell transplantation. It can include high doses of total body irradiation and/or chemotherapy to destroy pre-existing malignant cells and host immune cells. These highly intensive measures ablate normal haematopoietic cells of the host, which require the infusion of haematopoietic cells to prevent haematopoietic failure.

Killer-cell immunoglobulin-like receptors

(KIRs). These receptors, encoded on human chromosome 19, are expressed by natural killer cell subsets and by a minor population of T cells. Inhibitory KIRs have locus and allele specificity for MHC class I molecules.

Cyclophosphamide

A DNA-alkylating agent that is used widely as an antitumour agent or an immunosuppressive agent. Cyclophosphamide has been shown to destroy certain subsets of lymphocytes preferentially, including B cells and regulatory cells.

Anti-thymocyte globulin

(ATG). Polyclonal antibodies against human T cells that are produced by immunizing rabbits or horses.

Photodynamic purging

Refers to the process of deleting cells by introducing light-sensitive chemicals into the target cells, followed by exposure of these cells to light so that the chemicals cause the death of the target cells.

Suicide gene

A gene whose product can induce cell death by apoptosis.

Ganciclovir

An antiviral medication used to treat or prevent cytomegalovirus infections.

Exhaustion

Impaired ability of effector T cells to carry out their functions, such as cytotoxicity and cytokine secretion, owing to chronic stimulation by antigens.

Haemoglobinopathies

Diseases caused by genetic defects that lead to one of the globin chains of the haemoglobin molecule developing an abnormal structure.

Xenotransplantation

Transplantation of tissue between foreign species.

Natural antibody

Antibodies that are detected in the sera of normal individuals without any previous sensitization to the antigen. They can bind pathogens and self-antigens, such as ABO blood-group antigens.

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Li, H., Sykes, M. Emerging concepts in haematopoietic cell transplantation. Nat Rev Immunol 12, 403–416 (2012). https://doi.org/10.1038/nri3226

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