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  • Review Article
  • Published:

Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases

Nature Reviews Drug Discovery volume 6, pages 313–325 (2007)Cite this article

Key Points

  • Immunological activation of mast cells is an important trigger in the cascade of inflammatory events that lead to the manifestation of allergic diseases. Prostaglandin D2 (PGD2) is a cyclooxygenase product of arachidonic-acid metabolism that is produced by mast cells, dendritic cells and T helper 2 (TH2) lymphocytes.

  • Mast cells produce particularly high quantities of PGD2 in response to the crosslinking of cell-surface immunoglobulin E (IgE) and the PGD2 produced contributes to the characteristic pattern of vascular and cellular changes associated with both the early and late phases of the allergic response. These effects are achieved by the interaction of PGD2 with its two high-affinity receptors DP1 and CRTH2 (chemoattractant receptor-homologous molecule expressed on TH2 cells; also known as DP2).

  • The combined action of DP1 and CRTH2 have a fundamental role in the polarization of T cells to the TH2 phenotype and their subsequent recruitment and activation. Pharmacological studies with recently discovered antagonists combined with genetic analysis support the view that these receptors have a pivotal role in mediating aspects of allergic diseases that are resistant to current therapy.

  • Antagonism of CRTH2 is a particularly attractive therapeutic strategy as the ability of PGD2 to promote activation and recruitment of both TH2 lymphocytes and eosinophils is mediated by this receptor. Of particular interest is the recent finding that the ability of mast-cell supernatants to promote migration of TH2 lymphocytes is mediated by PGD2 acting on CRTH2, whereas PGD2 possesses the unique property of stimulating TH2-cytokine production in the absence of co-stimulation, again through an action on CRTH2.

  • This Review focuses on the emerging role that CRTH2 has in mediating aspects of allergic diseases and discusses the recent progress in the discovery and development of selective antagonists of this receptor.

Abstract

Immunological activation of mast cells is an important trigger in the cascade of inflammatory events leading to the manifestation of allergic diseases. Pharmacological studies using the recently discovered DP1 and CRTH2 antagonists combined with genetic analysis support the view that these receptors have a pivotal role in mediating aspects of allergic diseases that are resistant to current therapy. This Review focuses on the emerging roles that DP1 and CRTH2 (also known as DP2) have in acute and chronic aspects of allergic diseases and proposes that, rather than having opposing actions, these receptors have complementary roles in the initiation and maintenance of the allergy state. We also discuss recent progress in the discovery and development of selective antagonists of these receptors.

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Figure 1: Pathways of PGD2 metabolism.
Figure 2: Proposed scheme describing the role of mast-cell-derived PGD2 in the polarization and activation of TH2 lymphocytes, effects achieved through combined action on DP1 and CRTH2 receptors.
Figure 3: PGD2 and related prostanoids.
Figure 4: NSAIDs used as starting points for the design of selective CRTH2 antagonists.
Figure 5: Ramatroban analogues with CRTH2 antagonist activity.
Figure 6: Physicogenetically identified CRTH2 antagonists.
Figure 7: Indole-acetic-acid based compounds with CRTH2 antagonist activity.
Figure 8: Aryl acetic acid CRTH2 antagonists.
Figure 9: Non-acidic CRTH2 antagonists.

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Acknowledgements

The authors would like to thank M. Hunter and M. Payton for their comments on this manuscript and for their encouragement in conducting research referred to in this Review.

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Authors and Affiliations

  1. Oxagen Limited, 91 Milton Park, Abingdon, OX14 4RY, Oxfordshire, UK

    Roy Pettipher & Richard Armer

  2. National Heart and Lung Institute Clinical Studies Unit, Royal Brompton Hospital, Fulham Road, London, SW3 6HP, UK

    Trevor T. Hansel

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  1. Roy Pettipher
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Correspondence to Roy Pettipher.

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Competing interests

R.P. and R.A. are named as inventors on Oxagen patents related to use of CRTH2 antagonists. T.H. has received study grants from Johnson & Johnson, GlaxoSmithKline, Novartis, Oxagen and Millenium Pharmaceuticals in the period from 2005 to March 2007.

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Glossary

Prostaglandins

Acidic lipids derived from the metabolism of arachidonic acid by the action of cyclo-oxygenase enzymes and downstream synthase enzymes. Prostaglandins have a diverse range of activities and have a well recognized role in pain and inflammation. Prostaglandin D2 (PGD2) is the main prostanoid produced by mast cells and is the predominant prostaglandin found at sites of allergic inflammation.

Mast cell

A granular cell that bears Fc receptors for immunoglobulin E (IgE), which, when crosslinked by IgE and antigen, causes degranulation and release of mediators such as histamine, leukotrienes and PGD2.

Dendritic cells

These professional antigen-presenting cells are increasingly being recognized as having crucial immuno-regulatory functions. They are found in various tissues where they take up antigens, process them, migrate to the lymph nodes and present the antigens to T cells.

CRTH2

Chemoattractant receptor-homologous molecule expressed on T helper 2 (TH2) cells (CRTH2; also known as DP2) is a cell-surface receptor of the G-protein-coupled receptor family that binds prostaglandin D2 and mediates its effects on TH2 lymphocytes, eosinophils and basophils. CRTH2 was originally described as GPR44, an orphan receptor.

DP1

Another receptor for prostaglandin D2, encoded by the PTGDR gene, that mediates its effects on vascular tissue and might be involved in the polarization of T helper 2 cells.

TP

High affinity receptor for thromboxane A2 that mediates platelet activation, vasoconstriction and bronchoconstriction. The PGD2 metabolite 9α11BPGF2 also binds this receptor.

Lymphocytes

White blood cells of lymphoid origin that function as part of the immune system.

Eosinophil

A blood granulocyte that has a physiological role in the destruction of parasites. Eosinophils are strongly implicated in allergic inflammation, and are able to release an array of tissue-destructive mediators.

TH2 cytokines

Proteins that include interleukin-4 (IL4), IL5 and IL13, which are produced by activated T helper 2 (TH2) lymphocytes that have a central role in a number of key features of allergic disease, including immunoglobulin E production, eosinophilia, mucus production and airway hyperresponsivenesss.

Chemotaxis

The movement of cells in response to a chemical gradient that is provided by chemotactic agents such as interleukin-8 (IL8) and leukotriene B4, which attract neutrophils.

Cystatin

A family of cysteine protease inhibitors.

Charcot–Leydon crystal protein

A cell constituent that is unique to eosinophils and basophils, which possesses lysophospholipase activity.

Langerhans cell

Professional antigen-presenting dendritic cells that are localized in the skin epidermis.

IC50

The half maximal inhibitory concentration. Represents the concentration of an inhibitor that is required for 50% inhibition of a biological or molecular process. pIC50 referes to the negative logarithm of this value.

Site-directed mutagenesis

An in vitro technique that introduces mutations (base-pair changes) at a specific site in the DNA sequence, giving rise to amino-acid charges.

pA2

pA2 refers to the negative logarithm of the concentration of antagonist that gives a concentration ratio of 2 when agonist concentration–response curves, conducted in the presence of the antagoinst, are plotted using Schild analysis. It is a measure of the activity of an antagonist.

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Pettipher, R., Hansel, T. & Armer, R. Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov 6, 313–325 (2007). https://doi.org/10.1038/nrd2266

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