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Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Review Article

Novel treatments of asthma and allergic diseases L. Chini, E. Monteferrario, S. Graziani, V. Moschese * Department of Pediatrics, Policlinico Tor Vergata, University of Rome Tor Vergata, Rome, Italy

EDUCATIONAL AIMS  To revise recent advances on the old therapy of asthma  To summarize the advent of new therapeutic approaches  To introduce the role of new players in the pathogenesis of asthma and their potential implications for future therapies

A R T I C L E I N F O

S U M M A R Y

Keywords: Allergic asthma Anti-IgE antibodies Immunotherapy Anti-cytokine Immunomodulators Monoclonal antibodies

The prevalence of allergic diseases has considerably increased, mostly in industrialized countries (> 20%), and asthma affects approximately 300 million individuals worldwide. Current therapies are able to control symptoms although they do not modulate immunological dysregulation that characterizes allergic diseases. Over the last 30 years, only a few new drugs have been introduced on the market and they all act on Th2-type response which has a critical role in the pathogenesis of allergic diseases. Recently, a new scenario has been opened on Th17-cells, Th1-type cytokines and innate immune system components involved in the inflammatory pathogenesis of asthma and other allergic diseases. These findings suggest a promising therapeutic role of new agents that block the action of specific cytokines. Furthermore, the concept of an intrinsic structural defect in the bronchial epithelium paves the way to innovative therapeutic strategies. In this review we present an update on therapies for allergic diseases with special focus on asthma. ß 2013 Published by Elsevier Ltd.

INTRODUCTION In recent years, the prevalence of allergic diseases has globally increased but, despite wide research, more efforts are needed to understand better the mechanism of allergy development [1]. Among allergic diseases, asthma is very common. Asthma is a chronic inflammatory disease with high incidence, about 300 million people worldwide. Its prevalence is expected to rise particularly in pediatric population [2]. In Europe asthma affects around 30 million people and the total cost of this disease is estimated to be 17.7 billion euro/year with a productivity loss of 9.8 billion euro/year (http://www.efanet.org/asthma/#_ftn7). Particularly, European Lung Foundation (ELF) reports that in UK 3.4 million of people (1:7 in the 2-15 years age group and 1:25 in adults) needs asthma therapy as well as in Germany (http://

* Corresponding author. Department of Pediatrics, Policlinico Tor Vergata, University of Rome Tor Vergata, Viale Oxford, 81- 00133 - Roma. Tel.: +39 0620900525; fax: +39 0620900530. E-mail address: [email protected] (V. Moschese).

www.it.european-lung-foundation.org/431-impatto-in-europa. htm). Epidemiological studies performed in the U.S. population [3] revealed that asthma caused 48% of emergency admissions and approximately 500.000 hospitalizations/year (35% in < 18 years patients). The Center for Disease Control and Prevention (CDC) estimates that children aged 5–17 years with at least one asthma attack missed 10.5 million school days in the past year. In the same age group asthma is responsible for a loss of 10 million school days and 726 million dollars for missed parental work days [3]. Similar data are reported for other industrialized countries [4]. Several studies have demonstrated that genetic, environmental, epigenetic and other factors contribute to asthma heterogeneity [5]. One of these factors is atopy which is not synonymous with asthma. In fact, while 50% of asthmatic population is atopic, only a small proportion of atopic subjects develops asthma supporting the notion that this disease results from a complex and unpredictable combination of factors [6]. Classification of different asthma pheontypes has been based on various types of inflammatory cells with a potential critical role in the pathogenesis of this disease by secreting cytokines and pro-inflammatory molecules. Indeed, Th2 cells

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and their cytokines predominate in mild to moderate asthma, whereas steroid-resistant asthma has a mixed Th2/Th1 phenotype with a Th17 component [7,8]. Furthermore, cells of innate immunity (neutrophils, macrophages, natural killer cells, dendritic cells, smooth muscle cells) have recently been involved in the pathogenesis of asthma because of the secretion of several cytokines that contribute to the different features of asthma [9]. Recently, bronchial epithelium has been identified not only as an important player in asthma but also as a regulator of immune function [10]. In contrast to the significant health and economic impact of asthma, only two novel classes of controller medications have been introduced on the market in the last decades. One class is the antileukotrienes with zafirlukast, montelukast and zileuton. The second group is represented by anti-IgE monoclonal antibody, omalizumab. Other new drugs have been introduced in the marketplace but they are advanced versions of historical drugs (inhaled steroids, beta2 agonists, anticholinergic and their various combination) [6]. These ‘‘old’’ classes of anti-asthmatic drugs have been updated to ensure greater specificity and efficacy as well as greater convenience of use in order to increase and improve patient compliance. However, there is still concern about the use of inhaled corticosteroids (ICS) and long-acting bronchodilators because of the fear of long-term side effects, worst acceptance of inhaled medications than those with oral administration and exacerbation of symptoms when the treatment is discontinued. Also, in 5–10% of patients we usually observe a control failure despite adequate compliance to the therapy [11]. Thus, the requirement of new therapies, that act on the immunological mechanisms of allergic diseases, including suppression of disease associated cytokines, is critical. In this review we will discuss recent advances on the ‘‘old’’ drugs and on new potential immunomodulators to combat asthma and allergic diseases. Furthermore, the crucial function of the airway epithelium in asthma and related implications will be presented. ASTHMA PATHOGENESIS: THE TRADITIONAL CONCEPT AND THE REVOLUTIONARY SCENARY Asthma is considered a typical Th2 cell-mediated disorder. IL-4, IL-13, IL-9 and IL-5 have been identified as main cytokines involved in airway inflammation. Recently, Th1, Th17, regulatory T (Treg) cells, cytotoxic CD8+ T cells, natural killer T cells and gd T cells have been involved in the asthma process [6]. All these mechanisms contribute to differentiate asthma phenotypes. Particularly, mild to moderate allergic asthma is prevalently characterized by Th2 cells, eosinophil infiltrates, mucus secreting cells hyperplasia and metaplasia, remodeling airway wall and airway hyperresponsiveness [9]; conversely, severe asthma is characterized by a prevalent involvement of both Th2 and Th1 cells, with a Th17 cells cooperation. In severe asthma neutrophilic inflammation and infiltration, induced by the production of particular cytokines, such as TNFa, INFg, IL-17 and IL-27 [12], might account for the development of corticosteroid resistance. Molecular mechanisms implicated in this resistance might be activation of p38 MAPK activity, increased expression of a mutated glucocorticoid receptor GRb, increased concentration of macrophage migratory inhibitory factor (MIF) and reduced expression of histone deacetylase-2 [13]. Thus, all of them might represent a potential therapeutic target to overcome corticosteroid resistance and treat severe asthma phenotypes. Until few years ago asthma has been considered only a Th2 cell mediated disease and many studies concentrated on adaptive immunity and its mediators. Nowadays, the new

concept of asthma as an epithelial disease with structural and functional damages [14] could revise the pathophysiological knowledge of this disease. Indeed, recent genetic studies disclosed many epithelial genes and innate immune pathways involved in asthma process [15]. Particularly, an intrinsic structural defect in the bronchial epithelium, due to impaired formation of tight junctions and aberrant barrier function, might contribute to the pathogenetic basis of asthma, leading to the airway remodeling [14]. In allergic diseases the pathogenetic role of epithelium damage has been described in atopic dermatitis with a potential link to subsequent development of asthma as in ‘‘atopic march’’ [16]. Moreover, recent studies have also highlighted an impaired innate immune response, as expressed by a deficiency of Toll-like receptor 3 response to rhinovirus infections in epithelial cells and a reduced airway interferon response, with an altered airway microbiome in asthmatic patients [17,18]. These exciting findings pave the way for strategies acting on epithelium reconstruction widening the therapeutic armamentarium. THE (G)OLD THERAPY OF ASTHMA Corticosteroids Inhaled Corticosteroids (ICS) represent the milestone of asthma controller therapy. Several ICS, with similar clinical efficacy but different pharmacodynamic properties and systemic exposure, are now available for clinical use. Since patients with severe asthma may require high doses of ICS, research is focusing on the development of new molecules with low risk of side effects, like ciclesonide, a newly licensed steroid (for children > 12 years and adults). Its little activation in the oropharynx [19] explains few systemic side effects since the prodrug is converted in the lungs into the active principle des-ciclesonide by esterases. Since side effects mainly derive from transactivation and binding of the glucocorticoid receptors to DNA, whereas pharmacological effects are mediated through transrepression of transcription factors through a non-genomic effect [20], current attempt is ‘‘to dissociate’’ side-effect mechanisms of steroids from their pharmacological effect. Indeed, ‘‘Dissociated’’ steroids are designed to act predominantly on modulation of transactivation than on transrepression with an excellent cost-benefit ratio [21]. Further improvement is now obtained with the use of pressurized inhalers containing hydrofluoroalkane 134a rather than chlorofluorocarbons as propellant with smaller particle sizes deposited in peripheral airways [22]. Bronchodilators Bronchodilators are effective in reducing symptoms in patients with asthma because they relieve and prevent obstruction. Safety of long acting bronchodilators (LABA) is matter of debate and current guidelines recommend their combined use with ICS, as controller medications, to limit severe exacerbations and mortality [23]. Alternative classes of bronchodilators, such as vasoactive intestinal peptide analogs and potassium-channel openers are under investigation. They seem to have more potent vasodilator than bronchodilator effects. In murine models agonists of bitter taste receptors (TAS2Rs), such as quinine, chloroquine and saccharin, appear to be more effective than b-agonists, although further studies are needed to test their efficacy in humans [24]. New other molecules with a bronchodilator effect, such as selective agonists of prostaglandin, are being evaluated. Particularly, EP4selective agonists might be useful both in bronchodilatation and in the control of coughing induced by PGE2 through EP3 receptors on sensory nerve endings [25].

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3

HOW THERAPY IS EVOLVING

Immunomodulation of Th1 response

Blocking critical effector molecules

Allergy Immunotherapy with native allergens Allergy Immunotherapy (AIT), introduced by Noon and Freeman about a century ago, has been an important therapeutic strategy in reducing symptoms and drug consumption in allergic diseases. AIT acts reducing Th2 and stimulating Th1 response through regulatory T cells [39]. These cells inhibit allergic inflammation through IL-10 and TGF-b release. IL-10 shifts allergen specific IgE in IgG4, while TGF-b increases allergen specific IgA levels. Therefore AIT reduces seasonal production of IgE and increases protective allergen specific IgG4 [40]. To date, AIT is effective in allergic rhinitis, asthma and hymenoptera venom allergy [40], even if emerging studies suggest that it may be effective in other allergic conditions such as atopic dermatitis, food allergy and venom severe reactions [41]. Although the beneficial effects of AIT, only an estimated 5% of the allergic population in Europe and US subscribe to it [42]. Actually, the only two routes for AIT administration are subcutaneous (SCIT) and sublingual (SLIT). Both require a multiyear treatment and the selected route depends on many factors, but extract availability, costs, age and patient preference usually guide this choice [41]. Of note, SCIT should be administered in a medical centre with staff and tools to address the emergency of anaphylaxis whereas SLIT requires higher doses than SCIT with an increased cost [41].

The discovery of IgE by Ishizaka, Bennich and Johansson represents a milestone in the allergology field. This class of immunoglobulins has led not only to development of new diagnostic tools, but also to the identification of new treatments, such as monoclonal anti-IgE antibodies [26]. Actually, omalizumab is the only anti-IgE monoclonal antibody approved for asthma treatment but its use may be extended to other allergic diseases [26]. Omalizumab prevents activation of IgE receptors on mast cells, basophils and dendritic cells binding the Fc portion of IgE. Consequently, it reduces release of mediators involved in allergic reactions. Omalizumab has been approved in Europe since 2005 [27] and actually is used in patients older than 6 years of age with severe persistent allergic asthma [26]. Recent guidelines recommend omalizumab in patients with elevated serum IgE and asthmatic symptoms poorly controlled by ICS. It is administered subcutaneously every 2 to 4 weeks, according to total IgE values [28]. However, few data are available on adequate doses and period of treatment. Patients with a serum IgE levels between 70 and 300 IU/ml showed a good clinical response but biological markers are required to monitor the therapeutic effects. Despite its safety omalizumab may cause from mild to moderate side effects, such as reactions at the injection site (pain, swelling, itching and redness), headache and fever. Rare, but more severe side effects are represented by sudden allergic reactions up to anaphylaxis (http:// www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/ human/medicines/000606/human_med_001162.jsp&mid= WC0b01ac058001d124). Several clinical trials confirmed the efficacy of omalizumab in reducing the dose of inhaled and oral steroids and clinical exacerbations in adults and pediatric patients with severe asthma [25]. Indeed, significant improvements of PEF and FEV1 have been observed [29]. Particularly, in patients with severe allergic asthma treated with subcutaneous immunotherapy (SCIT), pre-treatment with omalizumab induces a significant reduction of SCIT side effects. These results are encouraging for a maintenance dose in a greater number of patients [30]. Since few years ago little data were available about long-term effects of biologic therapy. In a recent study, Nopp et al. reported that in patients with severe allergic asthma treated with anti-IgE (Xolair) for 6 years, asthma symptoms were mild or stable after 3 years since its withdrawal [31]. Intrinsic asthmatic patients are not treated with omalizumab even if the observation of a local IgE production [32] might favor the investigation of these drugs in this cohort of patients. Anti-IgE antibodies application has been reported as a therapeutic option in other allergic diseases such as intermittent and persistent rhinitis, chronic rhinosinusitis [28], atopic dermatitis, urticaria and food allergy [26]. Leung et al., in food allergy, have highlighted the safety and efficacy of anti-IgE antibodies treatment in peanut allergic patients because of an increased tolerance threshold in case of accidental ingestion [33]. Sampson et al confirmed these data [34]. In allergic rhinitis, the combined therapy of omalizumab and SCIT showed a decrease of SCIT side effects and a better control of symptoms [35]. Recently, the efficacy of anti-IgE therapy has been monitored through the quantification of the sensitivity of allergen-specific basophil activation (CD63 up- regulation) as expressed by CD-sens [36]. CD-sens is defined as the inverted value for allergen concentration giving a 50% of maximum CD63% up-regulation multiplied by 100 [36]. The higher CDsens value means an elevated basophil allergen sensitivity [37]. Moreover, CD-sens value has been suggested as a predictive factor of tolerance in food allergy [38].

Recombinant allergens Recombinant DNA technologies have been applied for molecular cloning and sequencing of most important allergens. Recently, these knowledge allowed to develop recombinant hypoallergenic allergens to limit the IgE-mediated side effects induced by allergen extracts [43]. The reduced IgE reactivity allows administration of higher doses than the natural allergen [43]. Moreover, recombinant wild-type allergens were produced to mimic the properties of native allergens with regard to fold and presence of IgE and T cell epitopes [43]. Actually, the most studied allergens are the major birch pollen, Bet v1, and the major grass pollen allergen, Phl p5 and Phl p6. Peptides The use of allergen-derived peptides containing T cell epitopes represents another strategy to significantly reduce the ability to crosslink allergen specific IgE and the adverse effects [44]. This formulation of AIT is thought to induce T-cell tolerance through IL10 secretion by regulatory T-cells [45]. To date, efforts have focused on two major allergens: the main cat allergen, Fel d1, and the main bee venom allergen, Api m1. Several studies demonstrated that this therapy increases the quality of life and the ability to tolerate natural allergen exposure [44]. New routes of administration of AIT The ideal route of AIT administration should induce high concentration of dendritic cells, important effectors of desired effects after allergen presentation and low concentration of basophils and mast cells, responsible of side effects [41]. New routes of administration are developing in this way. While intranasal and intrabronchial immunotherapy are not currently used because of associated local symptoms [40], oral immunotherapy (OIT) is a promising route. It has been used, in several trials, for food desensitization to common food like egg, milk and peanut. Several studies showed that OIT reduces the severity of accidental food ingestion in most patients and might control food allergy in some patients [46]. Conversely, safety of OIT is still doubtful since mild and severe reactions occurred during this therapy. Moreover, an effective therapeutic protocol for OIT lacks

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and the real mechanism of OIT is not yet fully understood [46]. So, further studies are needed to perform AIT for routine treatment of food allergy [41]. In the last years intralymphatic allergen administration (ILIT) showed good results. Senti et al. demonstrated that ILIT compared to SCIT led to a marked reduction of dose and number of injections required to induce allergen tolerance in patients with hay fever due to grass pollen [47]. In a recent study on ILIT in pollen-allergic rhinitis patients, Hylander et al. agree with these findings. Moreover, they state that ILIT can provide socioeconomic benefits since its cost is tenfold less [48]. Since some patients do not accept SCIT and ILIT because of the injections, epicutaneous allergen specific therapy (EPIT) by patches has been developed to bypass this problem. In 2009 the first randomized double-bind placebo-controlled study testing EPIT in grass pollen-allergic patients [49] showed a statistically significant

improvement of symptoms in 70% of EPIT patients versus 20% of placebo group patients, without severe adverse reactions [50]. Agostinis et al. demonstrated similar results in grass pollen allergic children, underlying EPIT safety and efficacy. Moreover, a pilot study using EPIT in children with cow’s milk protein allergy, showed a major tolerance to cow milk proteins during the provocation test [51]. Thus, EPIT could represent a good therapeutic strategy especially in paediatric population where injections represent a big obstacle to SCIT. Toll-like receptors Toll-like receptors (TLRs) are innate immune receptors that recognize molecular patterns of several pathogens and induce Th1 and regulatory T-cell response [52]. Immunomodulation by these molecules has been investigated in allergy and they seem to

Figure 1. Immunologic effectors of the allergic manifestations.

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Table 1 New immunomodulatory drugs Mechanism of Action

Route of administration

Pascolizumab

IL-4 antagonist

Intravenous

Phase II

Unfavorable data

Altrakincept

Blocks interaction between IL-4 and its cellular receptors IL-4Ra

Nebulized

Phase III

Poor effectiveness in moderate persistent asthma

Mepolizumab

IL-5 antagonist

Intravenous

Phase II

Potential efficacy on specific eosinophilic refractory asthma subphenotype

Lebrikizumab

IL-13 antagonist

Subcutaneous

Phase II/III

Pitrakinra

Antagonist of IL4 and IL13 through Blocking IL-4Ra

Nebulized or Subcutaneous

Phase III

Suplatast Tosilate

Presumed block of Th2 cytokines (IL-4, IL-5, IL13)

Oral

Approved in Japan since 1995

R0498991

OX40L inhibition

Subcutaneous

Phase II

Omalizumab

Anti IgE

Subcutaneous

Since 2003 and 2005 approved in USA and Europe, respectively

AMG-853 OC000459

PGD2 receptor (CRTH2) Antagonist

Oral

Phase II

Masitinib

Inhibits c-Kit and PDGF receptors.

Oral

Phase II/III

Syk ASO R112 R343

Inhibit tyrosine kinase Syk

Nebulized Intranasal Nebulized

Phase II

Reduced tracheal smooth muscle contraction and lung inflammation.

TPI-ASM8

Blocks CCR3 chemokine and b chain of GM-CSF

Nebulized

Phase II

Reduced early inflammation and sputum hypereosinophilia

Drug

Development status

regulate IFN-g levels but not allergic airway response [53]. Recently these molecules are investigated to improve the efficacy of immunotherapy but their effectiveness has been shown comparable to ICS [28]. ASTHMA THERAPY: FUTURE CHALLENGES The goal of asthma therapy would be blocking both synthesis and receptors of over than 100 mediators involved in the inflammatory process. Cytokines play a key role in chronic inflammation and airway remodeling and are considered important therapeutic targets, particularly in patients with severe disease not controlled by high doses of ICS (Figure 1) [54]. Currently, research is focusing on different sets of cytokines, such as those involving Th1 and Th17 cells. In particular, Th17 cells not only have been implicated in the pathogenesis of severe asthma, but also in corticosteroid resistance [25]. Anti-Th2 cytokine therapy IL-4 Antagonists IL-4 is a cytokine produced by Th2 cells, activated by mast cells and eosinophils, involved in the differentiation of Th2 cells and in the suppression of Th1 cell development [55]. This cytokine promotes isotype switching to IgE production, growth and development of mast cells and the recruitment of eosinophils. It also contributes to maintain the inflammatory response to antigens and the production of eotaxins [56]. IL-4, such as IL-13, induces its effects through the IL4 receptor (IL-4R) a/ IL-13 receptor (IL-13R) a1 complex. However, several clinical trials on the use of soluble recombinant human IL4Ra (altrakincept) and humanized anti-IL4 neutralizing antibody

Clinical efficacy

Improvement of FEV1 in moderate-to-severe asthma with poor responsiveness to ICS. Improvement of FEV1 and reduction of asthma exacerbations

Decreased peripheral blood eosinophils and eosinophil cationic levels in serum and sputum. Reduced allergen-induced globet cell metaplasia. Reduced ICS doses. Decreased allergic symptoms Reduced asthma exacerbations Improvement of PEF and FEV1 Reduced onset of allergic reactions combined to SCIT Reduced vasodilator and bronchoconstrictor effect

Reduced bronchial inflammation and airway remodeling

(pascolizumab) were not encouraging [57] (Table 1). Therefore, recent approaches are focusing on drugs whose action suppresses the activity of both IL4 and IL13, because of their redundant mechanisms in the IgE production [58]. Recently, a variant of IL-4 (pitrakinra) that blocks IL-4 receptor a, common to IL-4 and IL-13, has been developed. This molecule, in patients with moderate but not with severe asthma, significantly reduces delayed response to inhaled allergens when administered subcutaneously or by nebulization devices, and induces a significant improvement in FEV1 and a reduction of spontaneous asthma attacks requiring rescue medications [59]. (Table 1). Less data are available on side effects of these drugs [9]. IL-13 Antagonists IL-13 is a Th2 cytokine with a key role in asthma pathogenesis, i.e. allergic inflammation, persistence of eosinophilic inflammation, airway remodeling and development of bronchial hyper-responsiveness [60]. Many IL-13 antagonists are undergoing or have completed Phase II human clinical trials, although results have not yet been published (Table 1). Recently, it has been observed that ICS resistant asthmatic patients have elevated levels of IL-13, therefore this cytokine has been supposed to be responsible of drug resistance [61]. Interestingly, IL-13 induces production of periostin, a protein of the cellular matrix secreted by bronchial epithelial cells, that contributes to remodeling of bronchial tree. A recent study on lebrikizumab, an inhibitor of IL-13 that completed Phase II clinical trials, showed an higher efficacy in patients with elevated levels of periostin supporting its possible role as predictive biomarker of therapeutic response [62]. Little data are available about side effects of anti-IL-13. Recently the MILLY trial reported that musculoskeletal side effects occurred slightly more often in the group of patients treated with

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lebrikizumab [63]. Furthermore, human IL-13 neutralizing antibodies appeared to be safe and well tolerated in patients with asthma [64]. IL-5 Inhibitors IL-5 is critical in differentiation and maturation of eosinophils in the bone marrow and in their entry into the circulation. Currently, several IL-5 inhibitors, such as mepolizumab and reslizumab, are being investigated. However, these encouraging results obtained from experimental models were not matched to human clinical trials, where these drugs reduce hypereosinophilia only in a small group of subjects [65]. Although no serious risk or adverse effects associated with the administration of mepolizumab were reported, it is important to continue pharmacovigilance since eosinophils depletion induced by this drug could favour helminth, viral and fungal infections [65]. Suplatast tosilate In 1995 Suplatast tosilate, a sulphur-containing compounds, was introduced in Japan where it is still used in treatment of moderate-severe asthma. In 2006, the Japanese Asthma Prevention and Management Guidelines, classified suplatast as a Th2 cytokines inhibitor [66], but recently it has been considered as a ‘‘regulator of immune mechanism’’ [67] (Table 1). Its effects reduce airway hyper-responsiveness with improvement of the clinical course of patients with mild asthma [68]. Suplatast has also an anti-inflammatory effect since its association to ICS seems to allow a dose reduction in patients receiving high doses of steroids [69]. Moreover, since no significant adverse reactions have been reported [67] suplatast is considered safe in < 3 years old children and can be administered for long periods [70]. Further studies are needed to highlight its mechanism of action. OX40L Antagonists

Inhibiting key effector cells Mast cells inhibitors Blocking mast cells has long been a challenge for the design of new drugs. Chromones were very effective in blocking mast cells activation as a result of exercise or allergen exposure; nevertheless their short acting effects (12 hours) limited their use in long term control therapy. Their mechanism of action has not been identified yet; they might influence mast cell function by acting on surface chloride ion channels and mimicking the diuretic effect of furosemide. Further pharmacodynamic studies are needed to develop new drugs with longer action [11]. The mast cell survival is promoted by the interaction between c-Kit receptor and stem cell factor (SCF) [73]. The pharmacological blockade of both SCF and c-Kit has been proven effective in controlling asthma in animal models, suggesting that this pathway might be an excellent target for the development of new drugs. For example Masitinib, a monoclonal antibody that blocks c-Kit, is able to reduce symptoms in patients with severe asthma (Table 1) [11]. The tyrosine kinase Syk is an intracellular enzyme activated by binding of IgE on mast cell membrane leading to release of preformed mediators and synthesis of lipid mediators [74]. Recently, Stenton et al. have demonstrated that an antisense oligodeoxynucleotide anti-Syk (Syk ASO), administered by inhalation, reduces tracheal smooth muscle contraction and lung inflammation [75]. R112, another Syk inhibitor, administered intranasally, has also proved its efficacy in reducing symptoms in patient with seasonal rhinitis [76]. Further new molecules, such as R343 and Bay 613-606, are being analyzed to reduce its systemic side effects due to interacting of Syk, presented in neuronal cells [11]. These studies might provide the basis for development of new therapeutic strategies.

OX40L and its receptor OX40 belong to the TNF and TNF receptor superfamilies, respectively. B and T lymphocytes, macrophages, dendritic and endothelial cells express OX40L on their surface. In the absence of IL-12, activated dendritic cells upregulate OX40L that binds OX40 and triggers Th2 immune responses and memory cell expansion [71]. The observation that the onset of asthma after allergen stimulation is significantly lower in transgenic mice lacking OX40L than in wild-type mice [72], has led to trials with inhibitor of this ligand, R0498991, a humanized monoclonal antibody (Table 1). Phase II clinical trials are in progress to assess the safety of its subcutaneous administration in subjects with allergic rhinitis. Intravenous formulation is still being investigated to attenuate bronchial responses in asthmatic patients [28].

Eosinophil inhibitors Several molecules, including cytokine inhibitors, immunomodulants and adhesion molecule inhibitors, have been developed to block eosinophilic inflammation. TPI-ASM8 is a nebulized drug containing two modified phosphorothioate antisense oligonucleotides: the first blocks CCR3 chemokine and the second targets the common b chain of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3 and IL-5 receptors [28]. In mild asthma TPIASM8 was effective in reducing early inflammation response and sputum hypereosinophilia [77]. Moreover, in mice models TPIASM8 has a synergic effect with inhaled budesonide in reducing monocytes chemotactic protein-1 (MCP-1) and IL-13 levels in bronchoalveolar lavage, so this molecule may be an efficient adjunctive treatment in asthma. In 2010 a phase II study on the effect of TPI-ASM8 in mild asthmatic patients started (Table 1) [28].

The block of lipid mediators

New ‘‘light’’ on bronchial remodeling

Leukotrienes are lipid molecules that contribute to inflammatory process in asthma. To date, antileukotrienes (LTRA) represent the only class of drug that inhibits these lipid mediators, blocking cysteinyl leukotriene receptors. Unfortunately, these molecules are less effective than ICS, especially in severe asthma [25]. Prostaglandin D2 (PGD2) production is increased in severe asthma and the binding to its receptor (CRTH2) leads Th2 cells and eosinophils chemotaxis. Currently, many CRTH2 antagonists, such as AMG-853 and OC000459, are promising for the treatment of asthma and rhinitis (Table 1) [18]. Moreover, the inhibition of PGD synthase might both block the synthesis of PGD2 and avoid the bronchoconstrictor effects of PGD2 via thromboxane receptors on airway smooth muscle [11].

Airway remodeling is an important process reducing lung function in patients with chronic asthma. Anti-inflammatory action of ICS has limited effects on smooth muscle hyperplasia and subepithelial fibrosis of lung remodeling [78]. Asthma severity and lung function impairment are also related to peribronchial smooth muscle mass [79]. It has been reported that bronchial remodeling is the result of a complex interaction between immune cells and bronchial structural cells, driven by a network of cytokines and growth factors, including TGF-b and IL-13 [7,80]. Dhoerty et al. studied LIGHT (also called TNFSF14; an inducible ligand homologous to lymphotoxins that competes with HSV glycoprotein D for herpes virus entry mediator HVEM, a receptor expressed by T lymphocytes) a ligand that belongs to TNF family and seems to control key aspects of asthma inflammatory process and airway

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remodeling in murine models [78]. These authors demonstrated that the block or the absence of LIGHT reduces subepithelial fibrosis, hypertrophy and hyperplasia of smooth muscle and bronchial hyperactivity without affecting the eosinophils number in the airway. They also observed that bronchial remodeling, directed by LIGHT cascade, is highly dependent on production of TGF-b and IL-13, secreted by macrophages and eosinophils, respectively. These findings suggest that LIGHT might be an intriguing pharmacological target for airway remodeling treatment since, currently, there are no effective drugs that act specifically on such mechanism [78]. THE EVOLUTIONARY PROCESS OF THERAPY The recent notion that respiratory epithelium is central to asthma pathogenesis paves the way to new therapeutic strategies. The fragility of airway epithelium of asthmatic patients favours the passage of bacteria, viruses, aeroallergens and other organic and inorganic substances. The observation that bronchial epithelium of asthmatic patients is characterized not only by fewer intercellular adhesion junctions but also by a reduced expression of adhesion proteins, such as E-chaderin and zonula occludens 1 [81] with reduced transepithelial electrical resistance [82] is intriguing. Moreover, epidermal growth factor (EGF) has been shown to restore barrier function of the airway epithelium after a damage, raising the potential therapeutical use of growth factors in asthma. Actually, the role of innate immunity represents another emerging concept in asthma research. Indeed, if in the past the bronchial tree was considered sterile, recently an endogenous microbiome has been identified which differs in asthmatic and healthy patients [83]. Individual populations of microbes and their innate immune responses could contribute to mucosal inflammation in allergy and asthma. Beneficial effects of macrolides and other antibiotics might arise from their anti-inflammatory properties and activity on the microbiome. New insights into the dynamic host’s immune response to microbes and other environmental stimuli might explain the different asthmatic phenotypes. This will provide additional information to the diverse pathways causing asthma and to development of targeted treatment. Of note, surfactant protein-D (SP-D), produced by alveolar type II cells and nonciliated Clara cells, seems to modulate adaptive immune responses in asthma. In animal models, the absence of this protein causes enhanced allergic airway responses which are controlled by the administration of SP-D [84]. Accordingly, a therapeutic approach that restores surfactant and its components may be of value. In conclusion, future advances in understanding the complex mechanisms involved in allergic inflammation and/or asthma will provide the basis for new treatments. Most of the molecules cited in this review have been used in clinical trials on animal models and/or adults. However, in children drugs might be absorbed, distributed and eliminated in a different way, resulting sometimes toxic at the doses used in adulthood [85]. More pediatric clinical trials are urgent and indispensable since children are not little adults. A coordinated effort of academic institutions, patients’ organizations and pharmaceutical companies will near a personalized approach in the treatment of allergy disease and asthma. Acknowledgment This study is part of the educational activity of the Master in Advanced Pediatric Allergy and Immunology, University of Rome Tor Vergata.

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