ABSTRACT
We have investigated the contribution of individual phosphoinositide 3-kinase (PI3K) Class I isoforms to the regulation of neutrophil survival using (i) a panel of commercially available small molecule isoform-selective PI3K Class I inhibitors, (ii) novel inhibitors, which target single or multiple Class I isoforms (PI3Kα, PI3Kß, PI3Kδ, and PI3Kγ), and (iii) transgenic mice lacking functional PI3K isoforms (p110δ(KO)γ(KO) or p110γ(KO)). Our data suggest that there is considerable functional redundancy amongst Class I PI3Ks (both Class IA and Class IB) with regard to GM-CSF-mediated suppression of neutrophil apoptosis. Hence pharmacological inhibition of any 3 or more PI3K isoforms was required to block the GM-CSF survival response in human neutrophils, with inhibition of individual or any two isoforms having little or no effect. Likewise, isolated blood neutrophils derived from double knockout PI3K p110δ(KO)γ(KO) mice underwent normal time-dependent constitutive apoptosis and displayed identical GM-CSF mediated survival to wild type cells, but were sensitized to pharmacological inhibition of the remaining PI3K isoforms. Surprisingly, the pro-survival neutrophil phenotype observed in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) was resilient to inactivation of the PI3K pathway.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Neutrophils/cytology , Neutrophils/metabolism , Aged , Aged, 80 and over , Animals , Cell Survival/drug effects , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/genetics , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Neutrophils/drug effects , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary Disease, Chronic Obstructive/enzymology , Pulmonary Disease, Chronic Obstructive/metabolism , Signal Transduction/drug effectsABSTRACT
The role of immunoglobulin E (IgE) in allergic asthmatic disease is well established. Allergen-specific IgE binds to its cognate receptors, thus triggering a series of cellular events. These events include presentation of antigen by dendritic cells and the degranulation of mast cells and basophils to release numerous factors that play an integral part in potentiating the disease symptoms. Studies in the mouse indicate that a reduction in IgE levels could lead to significant attenuation of the allergic inflammatory response associated with diseases such as asthma, making IgE a target for the development of new therapeutic agents. Omalizumab (Xolair), a recombinant humanised monoclonal anti-IgE antibody that blocks the interaction of IgE with its receptors, is the first anti-IgE agent to undergo clinical development. Several clinical studies have been performed in adults and children with moderate-to-severe allergic asthma to evaluate the efficacy and safety of this agent, but which have also enabled an insight into the role of IgE in human disease. IgE plays a significant role in a number of allergic conditions including allergic rhinitis and allergies to various substances. Recent data suggests that local IgE production may occur in mucosal tissues and that locally significant concentrations of IgE, not reflected by serum IgE concentrations, indicate that it may play a role in non-atopic as well as atopic disease.
Subject(s)
Anti-Allergic Agents/therapeutic use , Anti-Asthmatic Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Asthma/drug therapy , Hypersensitivity/drug therapy , Immunoglobulin E/immunology , Animals , Antibodies, Anti-Idiotypic , Antibodies, Monoclonal, Humanized , Asthma/immunology , Clinical Trials as Topic/methods , Humans , Hypersensitivity/immunology , Omalizumab , Receptors, IgE/immunology , Research Design , Treatment OutcomeABSTRACT
The role of immunoglobulin E (IgE) in allergic asthmatic disease is well established. Allergen-specific IgE binds to its cognate receptors, thus triggering a series of cellular events. These events include presentation of antigen by dendritic cells and the degranulation of mast cells and basophils to release numerous factors that play an integral part in potentiating the disease symptoms. Studies in the mouse indicate that a reduction in IgE levels could lead to significant attenuation of the allergic inflammatory response associated with diseases such as asthma, making IgE a target for the development of new therapeutic agents. Omalizumab (Xolair, a recombinant humanized monoclonal anti-IgE antibody that blocks the interaction of IgE with its receptors, is the first anti-IgE agent to undergo clinical development. Several clinical studies have been performed in adults and children with moderate-to-severe allergic asthma to evaluate the efficacy and safety of this agent. Treatment with omalizumab was well tolerated and showed clinical benefit in terms of a reduction in the frequency and number of asthma exacerbation episodes and lower usage of corticosteroids and other medications to control disease, along with improved quality of life. Such findings indicate that omalizumab represents a promising new treatment option for allergic asthma.
