Walsh, Garry M.

Frontiers in Pharmacology

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Aberdeen University Research

OPINION ARTICLEpublished: 22         November 2012doi: 10.3389/fphar.2012.00197Antagonism of cytokine-induced eosinophil accumulationin asthmaGarry M. Walsh*School of Medicine and Dentistry, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK*Correspondence: g.m.walsh@abdn.ac.ukEdited by:Amr El-Shazly, Liege University Hospital, BelgiumReviewed by:Amr El-Shazly, Liege University Hospital, BelgiumAsthma is a chronic inflammatory con-dition of the airways characterized byreversible airway obstruction, airwayhyperresponsiveness (AHR) to normallyharmless stimuli and airway inflamma-tion. Eosinophilic asthma is a phenotypeof the condition characterized by increasedblood or sputum eosinophils whose num-bers correlate with disease severity. Releaseof their potent pro-inflammatory arsenalby infiltrating tissue eosinophils, includinggranule-derived basic proteins, mediators,cytokines and chemokines, contributesto airway inflammation, and lung tissueremodeling that includes airway thick-ening and fibrosis. More recent evidencesuggests that in addition to their role asdegranulating effector cells, eosinophilshave the capacity to act as antigenpresenting cells resulting in T cell pro-liferation and activation (Blanchard andRothenberg, 2009). Eosinophil extrava-sation from the post-capillary venules,migration within the interstitium, cel-lular activation and tissue retention arecontrolled by cell adhesion molecules,i.e., selections, integrins and members ofthe immunoglobulin superfamily (Barthelet al., 2008; Barnes, 2011). The expres-sion and function of these adhesionmolecules and the subsequent chemotac-tic attraction and activation of infiltratingpro-inflammatory cells are controlled bya myriad of cytokines, chemokines andmediators with the Th2 cytokines IL-4,IL-5, and IL-13 representing essential andcentral coordinators of asthmatic inflam-mation (Barrett and Austen, 2009; Walsh,2010). Thus, modulating the cytokinenetwork in asthma with biological ther-apy targeted to patients with particulareosinophilic phenotypes represents aplausible paradigm for treatment of thisimportant condition (Petsky et al., 2007;Barnes, 2008; Desai and Brightling, 2009;Walsh, 2011).INTERLEUKIN-5The crucial role of IL-5 in the develop-ment and release of eosinophils from thebone marrow, their enhanced adhesion toendothelial cells lining the post-capillaryvenules and their activation and secre-tion in the tissues has been known formany years (Egan et al., 1996). IL-5 wasidentified as a target to prevent or blunteosinophil-mediated inflammation inpatients with asthma, leading to the devel-opment of humanized anti-IL-5 mAb suchas mepolizumab, reslizumab and benral-izumab (Long, 2009; Molfino et al., 2012).Early clinical trials with mepolizumab(GlaxoSmithKline plc) reported signif-icant reductions of blood and sputumeosinophils but clinical outcomes were dis-appointing (Leckie et al., 2000; Flood-Pageet al., 2003; Kips et al., 2003; Flood-Page et al., 2007). However, these studiesall used subjects recruited on the basisof clinical and physiological character-istics not associated with the presenceof eosinophilic airway inflammation(O’Byrne, 2007). Two more recent studiesin highly selected asthma patient pop-ulations with a demonstrable sputumeosinophila reported that mepolizumabtreatment not only reduced eosinophilnumbers in the blood and sputum but alsogave a significant reduction in asthmaexacerbations and also demonstratedthat mepolizumab attenuates aspects ofeosinophil-induced airway inflammationrefractive to glucocorticoid (GC) therapy(Haldar et al., 2009; Nair et al., 2009).A recent randomized, placebo-controlledtrial evaluated intravenous reslizumab inpatients with poorly controlled asthma, asputum eosinophilia greater than 3% andwho were taking high-dose inhaled GC.The reslizumab group exhibited a signifi-cant decrease in sputum eosinophilia witha non-significant trend toward improve-ment in asthma control with a significantimprovement in lung function as assessedby the Asthma Control Questionnairescore. In patients with concomitant nasalpolyposis, reslizumab treatment wasassociated with a significant improve-ment in asthma symptoms. There was anon-significant reduction in asthma exac-erbations in the reslizumab group whilethe adverse-event profile for reslizumaband placebo were similar (Castro et al.,2011). Benralizumab is a novel human-ized afucosylated IgG1κ mAb indicatedfor the potential treatment of asthmaand COPD that binds to a distinct epi-tope within the extracellular domain ofrecombinant human IL-5Rα (Ghazi et al.,2012). Afucosylation is associated withenhanced antibody-dependent cell cyto-toxicity and benralizumab was found topotently induce apoptosis in eosinophilsand basophils (Kolbeck et al., 2010).Tissue eosinophils in bronchial biopsies ofpatients with mild atopic asthma exhibitedintense immune positivity for benral-izumab in contrast to resident mast cells,which were negative. Other anti-IL-5 mAbact by neutralizing the effects of IL-5. Incontrast, benralizumab targets effectorcells, mainly eosinophils, and basophils.A phase-1 study in subjects with mildasthma demonstrated that intravenousbenralizumab rapidly induced near totaldepletion of peripheral blood eosinophilswhile exhibiting an adequate safety profileand dose-proportional pharmacokinetics(Busse et al., 2010).www.frontiersin.org November 2012 | Volume 3 | Article 197 | 1Walsh Eosinophil accumulation antagonismINTERLEUKIN-4 AND -13Both IL-4 and IL-13 are important ineosinophil accumulation and are key fac-tors in IgE synthesis by B cells (Wills-Karpet al., 1998) together with direct effectson airway epithelial cells (Kuperman et al.,2002). Several clinical trials of anti-IL-13biologics reported disappointing clini-cal outcomes although this cytokine iswidely regarded as central to asthmaticinflammation. However, the latter conclu-sion is almost exclusively based on stud-ies that used animal-models of asthma.Indeed, out of around 3000 peer-reviewedpublications implicating IL-13 as a cen-tral mediator in asthma, only four relateto direct evidence in human asthma(Holgate, 2010). Importantly, in two ofthese studies, elevated levels of IL-13 werepresent in the sputum of around halfof asthmatic patients tested with no sig-nificant association with disease severity(Berry et al., 2004; Saha et al., 2008). Itis not surprising therefore that anti-IL-13proved to be disappointing in asthma ther-apy given that only half of the patientsrecruited to a given clinical trial haveany likelihood of responding to this bio-logic. The anti-IL-13 mAb lebrikizumab(Genentech/Chugai Pharmaceutical) hasrecently been demonstrated to signifi-cantly improve lung function in patientswith inadequately controlled asthma, butonly in a subgroup defined on the basisof high serum levels of periostin (Correnet al., 2011). The latter is a cellular matrixprotein that is released by airway epithe-lial cells stimulated with IL-13. Periostinexhibits effects on epithelial cells andfibroblasts that may contribute to airwayremodeling in asthma (Takayama et al.,2006; Sidhu et al., 2010) and may proveto be useful as a biomarker to iden-tify those subjects most likely to give apositive clinical response to IL-13 antago-nism. The recombinant human IL-4 vari-ant, pitrakinra (Aerovant) competitivelyinhibits the IL-4Ra receptor complex tointerfere with the actions of both IL-4and IL-13 and initial clinical trials indi-cated that such an approach may provebeneficial in patients with atopic asthma(Walsh, 2012). For example, a placebo-controlled trial of inhaled pitrakinra in 534patients with uncontrolled, moderate-to-severe asthma reported significant effectson exacerbations rates and symptomscores in patients with an elevated bloodeosinophilia (Wenzel et al., 2010). In con-trast, a study that examined AMG 317,a fully humanized mAb to IL-4Rα, inpatients with moderate to severe asthmareported no significant effects on primaryor secondary clinical endpoints. However,clinically significant effects were observedin those patients who had the most uncon-trolled or symptomatic asthma (Correnet al., 2010). It is interesting to notethat analysis of single nucleotide polymor-phisms leading to for amino acid changesin the 3′ end of the IL-4R α gene identifieda sub-group of patients with moderate-to-severe asthma who were significantly moreresponsive to pitrakinra therapy (Slageret al., 2012).TUMOUR NECROSIS FACTOR-αTumour necrosis factor (TNF)-α, animportant cytokine in innate immuneresponses, has been implicated in severalchronic inflammatory diseases includ-ing rheumatoid arthritis and Crohn’sdisease with anti-TNFα therapy provinguseful in these conditions. It is pro-duced principally by macrophages whileother pro-inflammatory cells includingmonocytes, dendritic cells, B lympho-cytes, T cells, neutrophils, mast cellsand eosinophils, together with the struc-tural cells fibroblasts, epithelial cells, andsmooth muscle cells represent significantsources. TNF-α has pro-inflammatoryeffects on eosinophils, neutrophils, T cells,epithelial cells and endothelial cells andmay play a key role in amplifying air-way inflammation through activation oftranscription factors such as NF-κB andAP-1. TNF-α is expressed in biopsiesand lavage fluid from asthmatic air-ways, particularly in patients with severeasthma compared with those with well-controlled disease. TNF-α is thought tocontribute to AHR, airway remodelingand GC resistance in asthma and thereforerepresents a potential target for ther-apy (Walsh, 2011). Humanized murineanti-TNF mAb (infliximab) and solu-ble TNF receptor linked to human IgG1(etanercept) have been developed and pre-liminary clinical studies in asthma didshow significant improvements in lungfunction, airway hypereactivity and exac-erbation rate, particularly in patients withsevere asthma refractory to GC treatment(Brightling et al., 2008). However, a morerecent clinical trial in 132 subjects withmoderate-to-severe persistent asthmareported no significant differencesbetween etanercept and placebo for anyefficacy end-points although etanerceptwas well-tolerated. In addition, the anti-TNF biologic golimumab in patients withsevere uncontrolled persistent asthmaalso reported negative clinical findings.Importantly, this study was terminatedearly due to unacceptable adverse eventsincluding frequent serious infections,eight malignancies and one death inthe active-treatment group comparedwith the placebo group (Wenzel et al.,2009). Overall it appears that TNF-αinhibitors are effective in a sub-group ofpatients with asthma, and again identifi-cation of the correct patient populationmay improve clinical outcomes (Materaet al., 2010). However, the unfavorablerisk/benefit ratio exhibited by golimumabdoes cast doubt on the future of anti-TNFtherapy in severe asthma.CONCLUSIONThe development of novel asthma anti-inflammatory therapy based on target-ing cytokines for the most part initiallyproved to be disappointing. The major-ity of biologics have proven inadequate inthe clinical setting in asthma even thoughthey were highly effective in animal mod-els of asthma, most likely because theartificially-induced airway inflammationin the latter is not a true representation ofthe wide spectrum of pathology observedin asthmatic patients. The developmentof discriminatory biomarkers and geneticprofiling may identify patients with par-ticular sub-phenotypes of asthma allowingtherapy to be targeted to those most likelyto exhibit beneficial effects. This com-bined with the development of biologicsaimed at the antagonism of more than onecytokine, as exemplified by pitrakinra, mayprove a more effective approach.REFERENCESBarnes, P. J. (2008). Cytokine networks in asthmaand chronic obstructive pulmonary disease. J. Clin.Invest. 118, 3546–3556.Barnes, P. J. (2011). Pathophysiology of allergicinflammation. Immunol. Rev. 242, 31–50.Barrett, N. A., and Austen, K. F. (2009). Innate cellsand T helper 2 cell immunity in airway inflamma-tion. Immunity 31, 425–437.Frontiers in Pharmacology | Experimental Pharmacology and Drug Discovery November 2012 | Volume 3 | Article 197 | 2Walsh Eosinophil accumulation antagonismBarthel, S. R., Johansson, M. W., McNamee, D. M.,and Mosher, D. F. (2008). 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Science282, 2258–2260.Received: 17 October 2012; accepted: 02 November2012; published online: 22 November 2012.Citation: Walsh GM (2012) Antagonism of cytokine-induced eosinophil accumulation in asthma. Front.Pharmacol. 3:197. doi: 10.3389/fphar.2012.00197This article was submitted to Frontiers in ExperimentalPharmacology and Drug Discovery, a specialty ofFrontiers in Pharmacology.Copyright © 2012 Walsh. This is an open-accessarticle distributed under the terms of the CreativeCommons Attribution License, which permits use,distribution and reproduction in other forums, pro-vided the original authors and source are creditedand subject to any copyright notices concerning anythird-party graphics etc.www.frontiersin.org November 2012 | Volume 3 | Article 197 | 3

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Antagonism of cytokine-induced eosinophil accumulation in asthma

Garry M. Walsh

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Antagonism of cytokine-induced eosinophil accumulation in asthma

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