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Averting inflammation by targeting the cytokine environment

Nature Reviews Drug Discovery volume 9, pages 703–718 (2010)Cite this article

Subjects

Key Points

  • Cytokines are key instigators and regulators of immune responses and thus hold great potential as targets for new therapeutic strategies.

  • Cytokines released at the early stages of inflammation are at key rate-limiting steps of disease development and have been the focus of extensive research and development. However, there are still considerable numbers of individuals for whom cytokine therapy is ineffective and targeting upstream cytokines carries the risk of general immunosuppressive side effects.

  • The most established means of blocking cytokine activity are monoclonal antibodies, soluble receptors or receptor–Fc fusion molecules and cytokine antagonists. In general, only biologicals seem to be able to block cytokine–receptor interactions efficiently, as small molecules have proved inefficient because they are too small to interfere with the large surface interactions that are present at the cytokine–receptor interface.

  • An improved understanding of cytokine networks may lead to the development of highly specific therapeutics targeting disease pathways in individuals or in certain patient cohorts. Rather than blocking early pleiotropic cytokines, future success may lie in the combined neutralization of effector cytokines with narrower ranges of defined activity.

Abstract

Cytokines are key instigators and regulators of immune responses and therefore hold great potential as targets for new therapeutic strategies. However, the selection of which cytokines to target, and in particular the identification of which cytokines regulate the rate-limiting steps of disease pathways, is crucial to the success of such strategies. Moreover, balancing the need for ablating pathological inflammatory responses and simultaneously maintaining the ability to control infectious agents is a key consideration. Recent advances in our understanding of cytokine networks, as well as technical progress in blocking cytokines in vivo, are likely to be a source for new drugs that can control chronic inflammatory diseases.

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Figure 1: Pro-inflammatory and effector cytokines involved in TH1/TH17-type autoimmune inflammatory and TH2-type allergic diseases.
Figure 2: The IL-6–IL-6R complex.
Figure 3: IL-1 production, binding and signalling.
Figure 4: Cytokine-based drugs.

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Acknowledgements

Some of the work described in this Review article was supported by funds of the Swiss National Science Foundation 310030-124922 and 3100A0-100233/1 and ETH Zürich intramural funds ETH-35/04-3 and ETH-0-20400-07.

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  1. Molecular Biomedicine, Institute of Integrative Biology, ETH Zürich, Wagistrasse 27, 8952, Zürich, Switzerland

    Manfred Kopf & Benjamin J. Marsland

  2. Cytos Biotechnology, Wagistrasse 25, 8952, Schlieren, Switzerland

    Martin F. Bachmann

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Martin F. Bachmann is an employee of Cytos Biotechnology and may hold shares or share options in the company.

Glossary

Systemic lupus erythematosus

(SLE). SLE is a chronic autoimmune disease that can affect any tissue and is associated with the induction of various autoantibodies, such as anti-double-stranded DNA and antihistones.

Sjögren's syndrome

Sjögren's syndrome is a disease in which the glands that produce tears and saliva are destroyed by an inflammatory autoimmune response. Sjögren's syndrome can be associated with other autoimmune diseases such as rheumatoid arthritis.

Hashimoto thyroiditis

Hashimoto thyroiditis is an autoimmune disease in which the thyroid gland is destroyed. The disease is characterized by infiltrating T cells and antibodies against thyroid peroxidase and/or thyroglobulinin.

Coeliac disease

Coeliac disease is an autoimmune disorder of the small intestine that is caused by a reaction to gliadin, a prolamin (gluten protein) found in wheat. Although multiple mechanisms may be involved, genetic analysis has linked certain major histocompatibility complex II haplotypes and deficiency in immunoglobulin A with the disease.

Black box warning

The most serious safety warning required on a pharmaceutical label, indicative of a considerable risk of a serious or even life-threatening adverse drug reaction.

Chitosan

A linear polysaccharide that is the structural element in the exoskeleton of crustaceans.

Castleman's disease

A non-cancerous (benign) disorder of one or many lymph nodes characterized by non-clonal hyperproliferation of B cells as a result from hypersecretion of interleukin-6.

NALP3-containing inflammasome

The NALP3-containing inflammasome is a multiprotein complex that functions to activate caspase 1 leading to the cleavage of pro-interleukin-18 (IL-18) and pro-IL-1β into their active subunits. Most inflammatory diseases associated with IL-1 involve activation of the inflammasome complex.

Pulmonary alveolar proteinosis

This is a disease in which abnormal accumulation of surfactant occurs in the alveoli and consequently impairs gas exchange. The mechanisms underlying the disease still need to be discovered; however, autoantibodies against the cytokine granulocyte–macrophage colony-stimulating factor can cause the disease.

JAK–STAT pathway

(Janus kinase–signal transducers and activators of transcription pathway). JAK–STAT signalling is involved in the signalling from many cytokine receptors. On ligation of a receptor by its ligand, JAK phosphorylates tyrosine residues on the receptor, which allows STAT dimers to form and ultimately leads to the transcription of their target genes.

TReg cells

(Regulatory T cells). TReg cells are present in the periphery and in the thymus. They develop in the thymus and are defined by the expression of the forkhead family transcription factor FOXP3, which is required for their development and function. TReg cells in the periphery are thought to be potent suppressors of inflammation.

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Kopf, M., Bachmann, M. & Marsland, B. Averting inflammation by targeting the cytokine environment. Nat Rev Drug Discov 9, 703–718 (2010). https://doi.org/10.1038/nrd2805

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