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  • Review Article
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Strategies to enhance T-cell reconstitution in immunocompromised patients

Nature Reviews Immunology volume 4, pages 856–867 (2004)Cite this article

Key Points

  • T-cell deficiency that results from ageing, infections (such as HIV), immunosuppressive therapies (especially in patients with cancer and recipients of transplants) and bone-marrow transplantation causes significant morbidity and mortality from infections.

  • Strategies to enhance T-cell recovery in recipients of an allogeneic haematopoietic stem-cell transplant, who suffer from a severe and prolonged T-cell deficiency after transplantation, have been studied in preclinical and clinical trials.

  • These strategies are, in most cases, also applicable to other patients with T-cell deficiencies.

  • Strategies include the following: adoptive transfer of lymphoid precursors; enhancing thymopoiesis with thymic grafts or grafting of thymic epithelial cells; generating thymic precursors or T cells using ex vivo culture systems; stimulating production of T cells using hormones and growth factors, including sex-steroid inhibition and/or administration of growth hormone and insulin-like growth factor 1 or keratinocyte growth factor; and stimulating production of T cells using cytokines and co-stimulation, including interleukin-2 (IL-2), IL-7, IL-12 and IL-15, superagonistic CD28-specific antibodies and oncostatin M.

Abstract

Immune deficiency, together with its associated risks such as infections, is becoming an increasingly important clinical problem owing to the ageing of the general population and the increasing number of patients with HIV/AIDS, malignancies (especially those treated with intensive chemotherapy or radiotherapy) or transplants (of either solid organs or haematopoietic stem cells). Of all immune cells, T cells are the most often affected, leading to a prolonged deficiency of T cells, which has important clinical consequences. Accordingly, strategies to improve the recovery and function of T cells, as we discuss here, should have a direct impact on reducing the morbidity and mortality of many patients and should increase the efficacy of therapeutic and prophylactic vaccinations against microbial pathogens or tumours.

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Figure 1: Strategies to enhance T-cell reconstitution after allogeneic bone-marrow transplantation.
Figure 2: T-cell reconstitution after allogeneic haematopoietic stem-cell transplantation.
Figure 3: T-cell precursors in mice.

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Acknowledgements

This work was supported by grants to M.R.M.B. from the National Institutes of Health, United States. M.R.M.B. is also the recipient of a Damon Runyon Scholar Award from the Damon Runyon Cancer Research Foundation, United Kingdom. This work was also supported by grants to R.L.B. from the National Health and Medical Research Council, Australia. The authors thank G. Goldberg for her many valuable contributions to the manuscript.

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Authors and Affiliations

  1. Departments of Medicine and Immunology, Box 111-Kettering 406D, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Marcel R. M. van den Brink & Önder Alpdogan

  2. Department of Pathology and Immunology, Central and Eastern Clinical School, Monash University, Clayton, 3181, Victoria, Australia

    Richard L. Boyd

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Correspondence to Marcel R. M. van den Brink.

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Richard Boyd and Marcel van den Brink are both consultants for Norwood Immunology Pty Ltd, which is involved in the development of Leuprolide to enhance immune reconstitution.

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DATABASES

Entrez Gene

CD28

growth hormone

IGF1

IL-7

IL-12

IL-15

KGF

oncostatin M

Notch-1

FURTHER INFORMATION

Marcel van den Brink's laboratory

Richard Boyd's laboratory

Glossary

SEVERE COMBINED IMMUNODEFICIENCY

(SCID). Humans or mice with this rare genetic disorder lack functional T and B cells owing to a mutation in a gene that is involved in T-cell and/or B-cell development; consequently, they suffer from recurrent infections. Several forms of SCID have been described, including mutations in the common cytokine-receptor γ-chain of several interleukin receptors, Janus activated kinase 3 (JAK3) and adenosine deaminase.

ALLOGENEIC

Allogeneic tissues or cells are genetically different from the host and can elicit an immune response when transplanted, resulting in rejection or graft-versus-host disease.

GRAFT-VERSUS-HOST DISEASE

(GVHD). Tissue damage in a recipient of allogeneic transplanted tissue (usually bone marrow) that results from the activity of donor cytotoxic T cells that recognize the tissue of the recipient as foreign. GVHD varies markedly in severity, but it can be life threatening in severe cases and, in particular, affects the intestines, liver and skin.

CONGENIC

An animal strain that is genetically identical to another strain except for one or more allelic differences that do not result in an antigen that can elicit an immunological response when tissue is transferred or transplanted from one strain to another.

DIGEORGE SYNDROME

A syndrome characterized by cardiac malformations, facial anomalies and hypoplasia of the parathyroid gland and thymus. Most cases are the result of a deletion of the chromosomal region 22q11.2. Mice deficient in the homeobox A3 protein (HOXA3) develop a phenotype similar to patients with DiGeorge syndrome.

CENTRAL TOLERANCE

Lack of self-responsiveness that occurs as lymphoid cells develop. It is associated with the deletion of autoreactive clones. For T cells, this occurs in the thymus.

MIXED LYMPHOCYTE REACTION

A tissue-culture technique that is used for the in vitro testing of the proliferative response of T cells from one individual to lymphocytes from another individual.

NUDE MICE

Mice with a mutation in the forkhead box N1 gene (Foxn1), which results in hairlessness, defective formation of the thymus and a lack of mature T cells.

DOUBLE-NEGATIVE 1 (DN1) TO DN2 TRANSITION

Thymic precursors at the DN1 (CD3−CD4−CD8−CD25−CD44+) stage lose the ability to generate B cells, natural killer cells and dendritic cells after their transition to DN2 (CD3−CD4−CD8−CD25+CD44+) thymocytes.

ACTIVATION-INDUCED CELL DEATH

(AICD). The apoptotic cell death of activated lymphocytes. It ensures the rapid elimination of effector cells after their antigen-dependent clonal expansion. Defects in AICD result in lymphoproliferative diseases that are associated with autoimmune disorders.

EFFECTOR MEMORY CELLS

Memory T cells that home to peripheral tissues and plasma cells that home to the bone marrow and secrete antibodies. They are responsible for immediate protection.

CENTRAL MEMORY CELLS

Memory T and B cells that home to secondary lymphoid organs. These cells are heterogeneous and do not have the full range of functions that are characteristic of effector T cells or plasma cells. They are responsible for secondary or chronic responses to antigen and might be involved in long-term maintenance of effector memory cells.

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van den Brink, M., Alpdogan, Ö. & Boyd, R. Strategies to enhance T-cell reconstitution in immunocompromised patients. Nat Rev Immunol 4, 856–867 (2004). https://doi.org/10.1038/nri1484

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