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  • Review Article
  • Published:

Tolerogenic dendritic cells and the quest for transplant tolerance

Nature Reviews Immunology volume 7, pages 610–621 (2007)Cite this article

Key Points

  • Tolerogenic dendritic cells (DCs) of various subsets have been described in rodents and humans. They offer potential as therapeutic tools to ameliorate or prevent transplant rejection or graft-versus-host disease (GVHD), or to treat autoimmune disorders.

  • Tolerogenic DCs include immature, maturation-resistant or alternatively activated DCs that express surface MHC class I and class II molecules, have a low co-stimulatory to inhibitory signal ratio and have an impaired ability to synthesize T helper 1 (TH1)-cell-driving cytokines (such as interleukin-12p70). Various anti-inflammatory and immunosuppressive agents potentiate or confer tolerogenicity on DCs (in vitro or in vivo).

  • Growth-factor-induced DC expansion (mobilization) in donor or host tissues has resulted in variable transplant outcomes leading to tolerance or exacerbation of rejection, depending on the model.

  • Donor- or host-derived DCs, adoptively transferred to allograft recipients or targeted in situ (allopeptides, apoptotic cells or exosomes) can potentiate long-term transplant survival in normal hosts; this effect is potentiated by conventional and experimental immunosuppressive agents, including the co-stimulation blocking molecules.

  • Mechanisms by which DCs mediate their tolerogenic properties include T-cell deletion or anergy, polarization of TH2-cell responses and expansion or induction of regulatory T cells (with the ability to suppress T cells that recognize alloantigen through the direct or indirect pathways).

  • DC function may be modified in situ by local microenvironmental factors (for example, in the liver) such that they acquire tolerogenic properties.

  • There is a pressing need to ascertain whether the ability of rodent DCs to promote transplant tolerance can be extrapolated from rodents to non-human primates, which is likely to provide a better index of their potential for clinical application. Proof-of-principle studies show that autologous immature DCs can promote T-cell tolerance to model antigens in humans.

Abstract

In recent years, there has been a shift from the perception of dendritic cells (DCs) solely as inducers of immune reactivity to the view that these cells are crucial regulators of immunity, which includes their ability to induce and maintain tolerance. Advances in our understanding of the phenotypical and functional plasticity of DCs, and in our ability to manipulate their development and maturation in vitro and in vivo, has provided a basis for the therapeutic harnessing of their inherent tolerogenicity. In this Review, we integrate the available information on the role of DCs in the induction of tolerance, with a focus on transplantation.

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Figure 1: Roles of CD8− (myeloid) and CD8α+ DCs of mouse secondary lymphoid organs in T-cell immunity and peripheral tolerance.
Figure 2: Role of IDO+CD19+ DCs and plasmacytoid DCs in T-cell immunity and peripheral tolerance.
Figure 3: Generation of tolerogenic DCs in vitro.
Figure 4: DC-based methods of transplant tolerance.

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Acknowledgements

Owing to space limitations, many important studies could not be included, and we apologize for any such oversight. The work in our laboratories was supported in part by grants from the National Institutes of Health and the 2006 American Society of Transplantation Basic Science Career Development Award to A.E.M. We thank the members of our laboratories and colleagues in the field for their helpful suggestions and M. Freeman for administrative support.

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Authors and Affiliations

  1. Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. morelli@imap.pitt.edu,

    Adrian E. Morelli & Angus W. Thomson

  2. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, 15213, Pennsylvania, USA

    Adrian E. Morelli & Angus W. Thomson

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Supplementary information

Supplementary information S1 (table)

Promotion of indefinite allograft survival by donor DC administration (PDF 177 kb)

Supplementary information S2 (table)

Promotion of indefinite allograft survival by bone–marrow–derived recipient DC administration (PDF 138 kb)

Related links

Related links

FURTHER INFORMATION

T. E. Starzl transplantation institute homepage

Glossary

Conventional DC

A dendritic cell (DC) that already displays the morphology and function of a DC under steady-state conditions.

Precursor DC

(Pre-DC). An immediate predecessor of a dendritic cell (DC) that, in the steady state, does not have the appearance or function of a DC (for example, circulating monocytes are pre-DCs of myeloid DCs and pre-plasmacytoid DCs (pre-pDCs) are pre-DCs of pDCs). Pre-DCs acquire the morphology and T-cell stimulatory ability of DCs with little or no cell division in the presence of microbial or inflammatory stimuli.

Danger signal

An agent that, through the induction of pro-inflammatory mediators, initiates innate and adaptive immune responses. Exogenous danger signals (such as lipopolysaccharide) are derived from microbial pathogens. Endogenous danger signals (such as high-mobility group box 1 protein and heat shock proteins) are released by stressed or damaged cells.

Graft-versus-host disease

(GVHD). A disease that results from the immunological attack by donor allogeneic T cells that are transferred along with the allograft (such as bone marrow, liver or gut allografts) of target recipient organs or tissues (such as the skin or gut). GVHD occurs in graft recipients that are unable to eliminate the host-reactive donor T cells owing to immunosuppression, immunological immaturity or tolerance of the recipient.

T-cell anergy

A state of T-cell unresponsiveness to stimulation with antigen. It can be induced by stimulation with a large amount of specific antigen in the absence of the engagement of co-stimulatory molecules.

Alternatively activated DC

A dendritic cell (DC) that is activated after pretreatment with corticosteroids or anti-inflammatory cytokines, resulting in a stable, semi-mature DC that can induce T-cell hyporesponsiveness in vitro and prolong allograft survival or inhibit GVHD.

FOXP3+CD4+CD25+ TReg cell

A naturally occurring regulatory T (TReg) cell that arises in the thymus, but is also detected in the periphery, expresses high levels of the transcription factor FOXP3 in the nucleus and inhibits autologous T-cell proliferative responses by a contact-dependent mechanism.

RNA interference

A phenomenon in which the expression of a gene is inhibited when a double-stranded complementary RNA is introduced into the organism.

FMS-like tyrosine kinase 3 ligand

(FLT3L). An endogenous cytokine that stimulates the proliferation of stem and progenitor cells through binding to the FLT3 receptor (a type III receptor tyrosine kinase member of the PDGF family). FLT3L administration substantially increases the number of DCs in lymphoid and non-lymphoid tissues.

Chimerism

The presence of donor-derived cells (normally of haematopoietic origin) in the tissues of allograft recipients.

Chronic rejection

Late graft rejection that is associated with tissue injury, mediated by chronic inflammation, alloantibodies and vascular pathology, which is believed to be caused by T- and B-cell-mediated immunity.

'Two-signal' hypothesis

The concept that both the MHC–peptide complex (signal 1) and co-stimulatory signals delivered by B7 family molecules expressed by APCs (signal 2) are required for T-cell activation. The absence of signal 2 results in the induction of T-cell anergy or deletion.

T regulatory type 1 (TR1) cells

A subset of CD4+ regulatory T cells that secrete high levels of IL-10 and that downregulate TH1- and TH2-cell responses in vitro and in vivo by a contact-independent mechanism(s) mediated by the secretion of soluble IL-10 and TGFβ1.

Third-party transplant

A graft from a non-identical strain (usually MHC-mismatched) that is used to assess the specificity of unresponsiveness to donor alloantigen in vivo.

Graft-vesus-leukaemia (GVL) effect

The anti-tumour activity of donor T cells against residual leukaemic cells of the graft recipient following (allogeneic) bone marrow transplantation.

Linked suppression

A mechanism of inhibition of the T-cell alloresponse by which an 'A' recipient that is rendered tolerant to a 'B' graft, accepts grafts from a B × C donor, but rejects tissues from an A × C donor.

Delayed-type hypersensitivity

A cellular immune response to antigen that develops over 24–72 hours with the infiltration of T cells and monocytes, and is dependent on the production of TH1-cell-specific cytokines.

Exosome

A membrane nanovesicle (<100 nm) that is produced by different cell types and released into the extracellular space by fusion of multivesicular bodies with the plasma membrane.

Endotoxin tolerance or cross tolerance

A transient state of hyporesponsiveness of the host or of cultured macrophages and/or monocytes to LPS (endotoxin tolerance) or other TLR ligands (cross tolerance) following previous exposure to LPS.

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Morelli, A., Thomson, A. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol 7, 610–621 (2007). https://doi.org/10.1038/nri2132

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