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  • Review Article
  • Published:

Emerging immune targets for the therapy of allergic asthma

Nature Reviews Drug Discovery volume 1, pages 55–64 (2002)Cite this article

Key Points

  • Despite the existence of effective therapies, allergic asthma and related atopic syndromes have recently emerged as epidemic diseases and important public health concerns. A remarkable collaboration has since ensued between basic researchers, clinicians and the pharmaceutical industry in an effort to develop more effective therapeutic and preventative strategies.

  • Studies from human and rodent models provide evidence that allergic asthma has an immune basis, involving antibodies such as immunoglobulin E and its receptor, FcɛRI, and T-helper type 2 (TH2)-cell-derived cytokines such as interleukin-4 (IL-4), IL-5 and IL-13.

  • Therapeutic strategies now being developed focus on interrupting IgE and TH2 effector pathways. These include anti-IgE antibodies, molecules directly associated with TH2 cells (co-stimulatory molecules, homing molecules, tyrosine kinases, transcription factors and CD4) or secreted TH2 cytokines, chemokines and intermediates in their signalling pathways. Other molecules that might suppress IgE and TH2 function include Toll-like receptors (TLRs), IL-12 and other cytokines.

  • Several potential immune targets seem to have limited therapeutic potential in allergic asthma either because they are relatively ineffective or because their general importance in immunity and other functions precludes safe targeting. These molecules include IL-5, the more widely shared cytokine-receptor signalling moieties, many transcription factors, including nuclear factor-κB (NF-κB) and most of the signal transducer and activator of transcription (STAT) factors, and the Janus-associated kinase (JAK) family of tyrosine kinases.

  • Molecules with more potential as therapeutic targets include: IgE and its receptor, FcɛRI; molecules that control TH2 homing, such as putative TH2-specific homing integrins, chemokines and chemokine receptors; and intermediates in the signalling pathways that involve IL-4, IL-13, the α-subunit of the IL-4 receptor (IL-4Rα) and TLR9. Although likely to be effective, approaches that target these molecules could be plagued by rapid disease recurrence with cessation of therapy.

  • The most promising approaches might be those that selectively remove or inactivate TH2 cells through the targeting of cell surface molecules such as T1, chemokine (C-C) motif receptor 8 (CCR8) and CCR4. Alternatively, molecules that prevent TH2 activation could be targeted. For example: IL-2-inducible tyrosine kinase (ITK); the co-stimulatory molecules CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4); the transcription factor GATA-binding protein 3 (GATA3); or CD4.

  • In addition to these new molecules, new approaches to blocking them will be developed, including soluble receptors, immunotoxin antibodies and gene therapy.

Abstract

Recent discoveries on the molecular and cellular basis of asthma have markedly altered our understanding of this common respiratory disorder. These insights have come during an unexplained period of rising disease incidence and severity and are now being applied to develop improved therapies. This review explores the latest advances in our understanding of the pathogenesis of allergic asthma, and provides insight into the expanding collaborations between research scientists, clinicians and the pharmaceutical industry in the race to control the asthma epidemic.

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Figure 1: Asthma pathogenesis.
Figure 2: TH2 molecules with therapeutic potential in asthma.
Figure 3: TH2-independent molecules with potential as asthma therapeutic targets.
Figure 4: TH2 homing.

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Acknowledgements

I thank F. Kheradmand for assistance with the figures and F. Kheradmand, B. Dickey and D. Huston for careful review of the manuscript.

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  1. Departments of Medicine and Immunology and the Biology of Inflammation Center, Baylor College of Medicine, Houston, 77030, Texas, USA

    David B. Corry

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DATABASES

LocusLink

BCL6

CCR2

CCR4

CCR8

CD4

CD28

CRTH2

CTLA-4

cyclooxygenase

eotaxin

FcɛRI

GATA3

GM-CSF

I-309

IFN-γ

IL-2

IL-3

IL-4

IL-5

IL-6

IL-7

IL-9

IL-12

IL-13

IL-15

IL-4Rα

IL-5Rα

IL-9Rα

IL-2Rγ

ITK

JAK3

LT

MCP1

MDC

NF-κB

STAT6

T1

TARC

TLR9

TNF-α

OMIM

acute myelogenous leukemia

FURTHER INFORMATION

Encyclopedia of life sciences

Asthma

Global Initiative for Asthma

Glossary

ATOPY

The propensity to develop hypersensitivity reactions, such as asthma, which is strongly linked to T-helper type 2 cells and immunoglobulin E.

TH2 CELL

A terminally differentiated subclass of T-helper cells that secretes a restricted repertoire of cytokines, including IL-4, IL-5, IL-9 and IL-13.

CYTOKINE

Secreted products derived from many cells that regulate immune responses.

AIRWAY HYPER-RESPONSIVENESS

An abnormal physiological alteration of the airways in which exaggerated, reversible bronchoconstriction occurs in response to various provocative stimuli.

TYPE I HYPERSENSITIVITY

One of four types of immune mechanism in which immunoglobulin E has an essential pathogenic role. Cells activated by IgE to release inflammatory products contribute to allergic diseases such as asthma, allergic rhinitis and anaphylaxis.

MAST CELL

A type of leukocyte with large secretory granules containing histamine and various protein mediators.

EOSINOPHIL

An allergic effector cell strongly associated with allergic inflammation of many kinds. Secreted products of eosinophils might contribute to airway obstruction and other pathology in allergic asthma.

TYPE IV HYPERSENSITIVITY

An immune hypersensitivity syndrome in which T-cell products, especially cytokines, contribute directly to the manifestations of diseases such as asthma.

GOBLET CELL

A type of cell found in the epithelium of many organs, especially in the intestinal and respiratory tracts. They secrete mucus, a viscous fluid composed primarily of highly glycosylated proteins called mucins.

JAK

Abbreviation for Janus-associated kinase, a subclass of tyrosine kinase involved in signal transduction through cytokine receptors.

CO-STIMULATORY MOLECULE

A molecule that activates accessory signalling pathways that are essential for the activation of T cells.

HOMING

The process of travelling from one organ or tissue to another in response to discrete signals.

STAT

Abbreviation for signal transducer and activator of transcription. This family of transcription factors is crucial for activating the transcription of hormone- and cytokine-dependent genes.

MAJOR HISTOCOMPATIBILITY COMPLEX

A complex of genetic loci, occurring in higher vertebrates, encoding a family of cellular antigens that help the immune system to recognize self from non-self.

INNATE IMMUNE RECEPTORS

The receptors involved in mediating the crucial immune response during the early phase of host defence against infection by pathogens (such as bacteria and viruses), before the antigen-specific, adaptive immune response is induced.

IMMUNOTOXIN

Any toxic agent coupled to an immune molecule, often an antibody. Typically used to kill cells expressing antibody-specific molecules.

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Corry, D. Emerging immune targets for the therapy of allergic asthma. Nat Rev Drug Discov 1, 55–64 (2002). https://doi.org/10.1038/nrd702

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