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  • Review Article
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Dendritic cells: emerging pharmacological targets of immunosuppressive drugs

Nature Reviews Immunology volume 4, pages 24–35 (2004)Cite this article

Key Points

  • The development of pharmacological immunosuppression has revolutionized the treatment of autoimmune diseases and transplant recipients.

  • Traditionally, lymphocytes have been considered the main targets of immunosuppressive drugs.

  • Dendritic cells (DCs) represent a heterogeneous population of uniquely well-equipped antigen-presenting cells (APCs) that initiate and regulate immune responses.

  • Accumulating evidence indicates that many immunosuppressive and anti-inflammatory drugs target DCs in defined ways.

  • Corticosteroids and vitamin D receptor ligands are potent inhibitors of DC differentiation and maturation, whereas rapamycin targets antigen uptake and maturation of DCs. Chloroquine interferes with endosomal antigen processing and mycophenolate mofetil (MMF), as well as the anti-inflammatory drug acetylsalicylic acid (aspirin), have been shown to suppress DC maturation. The new cyclophilin-binding immunosuppressant sanglifehrin A blocks the production of bioactive interleukin-12 (IL-12), without affecting the phenotypic maturation of DCs.

  • Pharmacological programming of DCs provides a safe and predictable means of their manipulation and allows the generation of DCs of any desired phenotype or function.

  • The simple concept that immature DCs are tolerogenic and mature DCs immunogenic has been revised by several reports showing that phenotypically mature, IL-12low DCs can induce regulatory T-cell responses. These DCs have been designated partially mature or semi-mature DCs.

  • Putative tolerogenic immature DCs can be generated in the laboratory in the presence of drugs that inhibit DC maturation. Putative tolerogenic partially mature DCs can be generated by a combination of agents that suppress pro-inflammatory cytokine production (for example, IL-10) with substances that promote phenotypic maturation (for example, tumour-necrosis factor).

Abstract

Immunosuppressive drugs have revolutionized organ transplantation and improved the therapeutic management of autoimmune diseases. The development of immunosuppressive drugs and understanding of their action traditionally has been focused on lymphocytes, but recent evidence indicates that these agents interfere with immune responses at the earliest stage, targeting key functions of dendritic cells (DCs). Here, we review our present understanding of how classical and new immunosuppressive agents interfere with DC development and function. This knowledge might provide a rational basis for the selection of immunosuppressive drugs in different clinical settings and for the generation of tolerogenic DCs in the laboratory.

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Figure 1: Checkpoints of dendritic-cell immunology.
Figure 2: Immunosuppressive and anti-inflammatory drugs target dendritic cells.
Figure 3: Generation of immunoregulatory dendritic cells in the laboratory.

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Acknowledgements

This work was supported by grants from the German Foundation of Haemotherapy Research, the German Science Foundation and the National Institutes of Health.

Author information

Authors and Affiliations

  1. Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University Giessen, Langhansstr. 7, Giessen, D-35392, Germany

    Holger Hackstein

  2. Thomas E. Starzl Transplantation Institute and Department of Immunology, University of Pittsburgh, 200 Lothrop Street Biomedical Science Tower W1544, Pittsburgh, 15213, Pennsylvania, USA

    Angus W. Thomson

Authors
  1. Holger Hackstein
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Correspondence to Holger Hackstein.

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DATABASES

LocusLink

CCL2

CCL3

CCL5

CCL18

CCL19

CCL21

CCL22

CCR1

CCR2

CCR5

CCR7

CD1a

CD11c

CD14

CD34

CD40L

CD80

CD86

COX2

CTLA4

CXCR1

DC-SIGN

FKBP12

FLT3L

GM-CSF

IDO

IFN-α

IL-10

IL-12

MDR1

MRP1

MTOR

TGF-β

TLR7

TLR9

TNF

Further information

Homepage of the Thomas Starzl Transplantation Institute

Glossary

PRODRUG

A pharmacologically inactive compound that is converted into the active form through endogenous metabolism.

DC SUBSETS

Langerhans cells are located in the epidermis of the skin and epithelia, whereas interstitial dendritic cells (DCs) reside in the dermis of the skin and in most peripheral tissues. Plasmacytoid DCs are the main type I interferon (IFN-α/β/ω)-producing cells in the immune system and circulate as precursor cells in the blood or reside as immature cells in primary and secondary lymphoid tissues.

DC ANTIGEN UPTAKE

Macropinocytosis is a non-selective form of endocytosis that allows the internalization of large volumes of soluble antigens. Receptor-mediated endocytosis promotes the recognition and uptake of pathogen-associated antigens, such as immune complexes through the Fc receptor and mannosylated antigens through the mannose receptor. Phagocytosis refers to the receptor-mediated, actin-dependent uptake of larger particles, ranging from 0.5–0.6 μm. Dendritic cells (DCs) also express various C-type lectins, for example, DEC205, Langerin and DC-SIGN, functioning as endocytic receptors.

CORTICOSTEROIDS

A group of natural and synthetic hormones with potent anti-inflammatory and immunosuppressive effects and a wide range of other functions.

EICOSANOIDS

A family of highly active lipid mediators, such as prostaglandins, thromboxanes and leukotrienes that are derived from arachidonic acid and mediate a large number of biological activities, including inflammatory responses.

SPHINGOLIPID ANALOGUES

Sphingolipids are a group of complex lipids, derived from sphingosine, that are found in cell membranes and nervous tissue, and function in signal transduction and cell–cell communication. Sphingolipid analogues are synthetic derivatives of sphingolipids.

NON-CALCEMIC

An agent that has no or only minor effects on blood calcium levels.

PURINES

Organic bases, such as adenine and guanine that occur in nucleic acids (DNA and RNA).

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Hackstein, H., Thomson, A. Dendritic cells: emerging pharmacological targets of immunosuppressive drugs. Nat Rev Immunol 4, 24–35 (2004). https://doi.org/10.1038/nri1256

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