Chronic inflammation in the lung has long been linked to the pathogenesis of asthma. Central to this airway inflammation is a T-cell response to allergens, with Th2 cytokines driving the differentiation, survival and function of the major inflammatory cells involved in the allergic cascade. PI3Kδ (phosphoinositide 3-kinase δ) is a lipid kinase, expressed predominantly in leucocytes, where it plays a critical role in immune receptor signalling. A selective PI3Kδ inhibitor is predicted to block T-cell activation in the lung, reducing the production of pro-inflammatory Th2 cytokines. PI3Kδ is also involved in B-cell and mast cell activation. Therefore the inhibition of PI3Kδ should dampen down the inflammatory cascade involved in the asthmatic response through a wide breadth of pharmacology. Current anti-inflammatory therapies, which are based on corticosteroids, are effective in controlling inflammation in mild asthmatics, but moderate/severe asthmatic patients remain poorly controlled, experiencing recurrent exacerbations. Corticosteroids have no effect on mast cell degranulation and do not act directly on B-cells, so, overall, a PI3Kδ inhibitor has the potential to deliver improvements in onset of action, efficacy and reduced exacerbations in moderate/severe asthmatics. Additionally, PI3Kδ inhibition is expected to block effects of Th17 cells, which are increasingly implicated in steroid-insensitive asthma.
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February 2012
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Conference Article|
January 19 2012
Targeting phosphoinositide 3-kinase δ for allergic asthma
Wendy C. Rowan;
Wendy C. Rowan
*Biological Reagents and Assay Development, Platform Technology and Science, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
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Janet L. Smith;
Janet L. Smith
†Allergic Inflammation Discovery Performance Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
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Karen Affleck;
Karen Affleck
†Allergic Inflammation Discovery Performance Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
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Augustin Amour
Augustin Amour
1
‡Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
1To whom correspondence should be addressed (email augustin.j.amour@gsk.com).
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Publisher: Portland Press Ltd
Received:
July 26 2011
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem Soc Trans (2012) 40 (1): 240–245.
Article history
Received:
July 26 2011
Citation
Wendy C. Rowan, Janet L. Smith, Karen Affleck, Augustin Amour; Targeting phosphoinositide 3-kinase δ for allergic asthma. Biochem Soc Trans 1 February 2012; 40 (1): 240–245. doi: https://doi.org/10.1042/BST20110665
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