Allergy and Asthma, Small Molecules to Target


Garry M. Walsh, University of Aberdeen, School of Medicine, Aberdeen, Scotland, United Kingdom

doi: 10.1002/9780470048672.wecb676


Current therapies for asthma and allergy are aimed at controlling disease symptoms. For most asthmatics, inhaled anti-inflammatory therapy is effective, but a subset of patients remains symptomatic despite optimal treatment creating a clear unmet medical need. Although considered a less-serious condition than asthma, allergic diseases are common and considerably impact on the quality of life of affected individuals. Innovative disease-modifying therapeutics are needed for both allergy and asthma. Biopharmaceutical approaches may identify small molecules that target key cells and mediators that drive the inflammatory responses that underlie the pathogenesis of allergy and asthma.


Asthma and allergy are important conditions whose complex pathology is influenced by both environmental and genetic factors. Although effective anti-inflammatory therapy is available for both conditions, this therapy is used when symptoms develop and is not always effective in all subjects with asthma and/or allergy. Asthma and allergy share some common pathological features including the overexpression of inflammatory mediators that result in leukocyte accumulation and changes in structural cell function. We have considerable knowledge regarding the cells mediators and factors that control the pathogenic changes in asthma and allergy. This information has informed the identification of small molecules that target aspects of the inflammatory cascade in asthma and allergy. This article will review the background and status of these novel compounds.

Biological Background


Asthma is now one of the most common chronic diseases in developed countries and is characterized by reversible airway obstruction, airway hyper reactivity (AHR), and airway inflammation. Key pathological features include infiltration of the airways by activated lymphocytes and eosinophils; damage to, and loss of, the bronchial epithelium; mast cell degranulation; mucous gland hyperplasia; and collagen deposition in the epithelial sub-basement membrane area. Asthma pathology is associated with the release of myriad proinflammatory substances that include lipid mediators, inflammatory peptides, chemokines, cytokines, and growth factors. In addition to infiltrating leukocytes, structural cells in the airways, which include smooth muscle cells, endothelial cells, fibroblasts, and airway epithelial cells, are all important sources of asthma relevant mediators (1). This complex scenario means that potential targets for therapeutic intervention are many and varied, and the task of successful therapy is challenging.

Anti-inflammatory therapy in asthma is largely reliant on glucocorticoids (GC)—particularly in their inhaled form—with or without the addition of short- or long-acting bronchodilators. The cysteinyl leukotriene-receptor antagonists are also an established part of the asthma armamentarium. Overall, they are less effective than inhaled GC, but some patients show a striking improvement, and a GC-sparing effect has been demonstrated. Although the symptoms of most asthmatics are satisfactorily controlled by regular use of inhaled GC, their use often raises concerns with respect to compliance, particularly in children and adolescents. Increasing evidence shows that long-term use of inhaled GC, especially in high doses, can cause systemic adverse effects, including adrenal suppression, reduced growth and reduced bone-mineral density, as well as local side effects such as dysphonia. Moreover, a significant subgroup of asthmatic patients responds poorly or not at all to high-dose inhaled or systemic GC treatment. As few alternative treatments are available, these patients can be difficult to treat and may require frequent hospitalization (1). Thus, identification of potential targets for therapeutic intervention is an important goal in asthma research.


Allergic inflammation is characterized by an immediate immunoglobulin-E-dependent mast cell and basophil degranulation leading to the release of mediators such as histamine that is responsible for most immediate manifestations of allergic disease. Other mediators include platelet-activating factor, prostaglandins, and cytokines, which include interleukin (IL)-3, IL-4, and tumor necrosis factor-α (TNF-α). Cytokines are particularly important in driving the subsequent late-phase reaction that results in the accumulation of leukocytes at the sites of inflammation. These inflammatory processes lead to various manifestations of allergic disease such as intermittent and persistent allergic rhinitis, conjunctivitis, atopic dermatitis, urticaria, and a degree of airway inflammation observed in allergic (extrinsic) asthma. The burden of allergic disease worldwide is such that it represents a serious public health problem that attracts considerable effort to identify effective and safe therapies.

Histamine has a prominent and diverse role in the pathophysiology of allergic disease; therapeutic intervention is therefore commonly focused on blocking its interaction with H1 receptors. The H1 histamine receptor is a heptahelical transmembrane molecule that transduces extracellular signals to intracellular second-messenger systems via G proteins. H1 ntihistamines act as inverse agonists that combine with the H1-receptor, which stabilizes it in the inactive form and shifts the equilibrium toward the inactive state (2). Although effective in the treatment of allergic rhinitis first-generation antihistamines, such as chlorpheniramine and promethazine, had a tendency to cross the blood-brain barrier resulting in unwanted side effects, particularly sedation and impaired psychomotor activity (3). In contrast, the second-generation histamine H1 receptor antagonists are highly effective and well-tolerated treatments for allergic disease and are among the most frequently prescribed drugs in the world (4). More recently, several novel antihistamines, which include fexofenadine, desloratadine, and levocetirizine, have been developed that are either metabolites of active drugs or enantiomers with improved potency, duration, and onset of action, together with increased predictability and safety. Anti-inflammatory effects in vitro and in vivo independent of Hl-receptor blockade have been described for most antihistamines, and these may enhance their therapeutic benefit (3). Other treatments available include anticholinergics, decongestants, intranasal corticosteroids, leukotriene receptor antagonists, or desensitization with modified allergens. It is noteworthy that some of these treatments are often used in combination rather than as monotherapy (e.g. combination of an antihistamine with a nasal decongestant or with a leukotriene antagonist).

Small Molecules in Asthma


Much inflammation in asthma is thought to be a consequence of the inappropriate accumulation of eosinophils and the subsequent release of their potent proinflammatory arsenal that includes such diverse elements as granule-derived basic proteins, mediators, cytokines, and chemokines (5). Interleukin (IL)-5 is crucial to the development and release of eosinophils from the bone marrow, their enhanced adhesion to endothelial cells that line the postcapillary venules, and their persistence, activation, and secretion in the tissues. Several animal models of asthma including the use of primates have provided good evidence that inhibiting the effects of IL-5 using specific mAb-inhibited eosinophilic inflammation and AHR (6). Given its central role in regulating eosinophil development and function, IL-5 was therefore chosen as a potentially attractive target to prevent or blunt eosinophil-mediated inflammation in patients with asthma. However, several clinical trials have reported disappointing clinical outcomes after treatment of asthmatic patients with an anti-IL-5 mAb. The first study was designed to validate the safety of the humanized anti-IL-5 mAb mepolizumab (7); it faced criticism of lack of power (8) and the validity of patient selection (9). A later placebo-controlled study (10) found that treatment of mild asthmatic patients with mepolizumab abolished circulating eosinophils and reduced airway and bone marrow eosinophils, but it reported no significant improvement of clinical measures of asthma. Critically, lung biopsy samples from the treatment group contained intact tissue eosinophils together with large quantities of eosinophil granule proteins; these findings likely explain the lack of clinical benefit after mepolizumab treatment. Similar findings were reported with the anti-IL-5 mAb SCH55700 in patients with severe asthma who had not been controlled by inhaled corticosteroid use. These authors reported profound reduction in circulating eosinophils but no significant improvement in either asthma symptoms or lung function (11). Compared with placebo, treatment of mild atopic asthmatics with mepolizumab significantly reduced the expression of the extracellular matrix proteins tenascin, lumican, and procollagen III in the bronchial mucosal reticular basement membrane. In addition, significant reductions were observed in both airway eosinophils that express mRNA for transforming growth factor-beta (TGF-β1) and the concentration of TGF-β1 in bronchoalveolar lavage (BAL) fluid (12). TGF-β1 is implicated in airway remodeling in asthma, and eosinophils are important sources of this growth factor, which thereby contributes to tissue-remodeling processes in asthma by regulating the deposition of ECM proteins. Mepolizumab may prove useful in preventing this. An alternative to the use of humanized anti-IL-5 mAb is the use of molecular modeling of the IL-5 receptor α-chain to develop specific receptor antagonists. Recently, such a compound (YM-90709) has been shown to be a relatively selective inhibitor of the IL-5R (13), and intravenous injection of YM-90709 inhibited infiltration of eosinophils into the BAL fluid of allergen-challenged BDF1 mice (14).


Another cytokine important in eosinophil accumulation is IL-4, which together with its close relative IL-13, is important in IgE synthesis by B cells. Both cytokines signal through a shared surface receptor, IL-4Rα, which then activates the transcription factor STAT-6 (15). Studies with soluble IL-4R given in a nebulized form demonstrated that the fall in lung function induced by withdrawal of inhaled corticosteroids was prevented in patients with moderately severe asthma (16). However, despite these promising findings subsequent trials have not been as successful; consequently, this treatment is no longer being developed. Other approaches for blocking the IL-4 receptor include administration of antibodies against the receptor and mutant IL-4 proteins. For example, a peptide-based vaccine for blocking IL-4 was recently developed by antigenic prediction and structure analysis of IL-4/receptor complex. Vaccine construction involved a truncated hepatitis B core antigen as carrier with the peptide inserted using gene engineering methods. Compared with control animals, immunized allergen-challenged ovalbumin (OVA)-sensitized mice had significant reductions in Immunoglobulin-E (IgE), eosinophil accumulation in BAL, goblet-cell hyperplasia, tissue inflammation, and methacoline-induced respiratory responses (17).


IL-13 has been found in BAL after allergen provocation of asthmatic subjects, which strongly correlated with the increase in eosinophil numbers. mRNA expression for IL-13 was detected in bronchial biopsies from both allergic and nonallergic asthmatic subjects. In animal models, IL-13 mimics many proinflammatory changes associated with asthma (18). It is therefore another potential therapeutic target for the resolution of airway inflammation. Two receptors for IL-13 have been described—IL-13 Rα1 and IL-13 Rα2. The latter exists in soluble form, has a high affinity for IL-13, and can thus “mop up” secreted IL-13. In mice, IL-13 Rα2 blocked the actions of IL-13, which included IgE production, pulmonary eosinophilia, and AHR (19). A humanized IL-13 Rα2 is now in clinical development as a novel therapy for asthma. Another mouse-based study reported that intratracheal administration of human IL-13 induced leukocyte infiltration in the lung, AHR, and goblet-cell metaplasia with allergic eosinophilic inflammation in the esophagus. An antihuman IL-13 IgG4 mAb (CAT-354) significantly reduced many of these parameters. In contrast, another study using mice sensitized by intranasal application of ovalbumin as a model of asthma/allergy found that the inhibition of the IL-4/IL-13 system efficiently prevented the development of the asthmatic phenotype, which includes goblet-cell metaplasia and airway responsiveness to methacholine, but it had little effect on established asthma (20). A humanized anti-IL-13 mAb called IMA638 significantly reduced eosinophils, neutrophils, eotaxin, and RANTES in BAL fluid from cynomolgus monkeys sensitized to Ascaris suum after segmental antigen challenge, compared with levels observed in control animals (21). IMA-638 also gave dose-dependent inhibition of the antigen-induced late responses and airway hyperresponsiveness in a sheep model of allergic asthma that used animals with natural airway hypersensitivity to Ascaris suum antigen (22).

As stated above, IL-4Rα is the signaling component of the heterodimeric receptor complex shared by both IL-4 and IL-13. Therefore, it represents an attractive target to antagonize the effects of both cytokines, as this approach may be more effective than targeting either IL-4 or IL-13 alone (23). Recently, a recombinant human IL-4 variant pitrakinra (Aerovant) was developed that competitively inhibits the IL-4 Ra receptor complex to interfere with the actions of both IL-4 and IL-13. In two independent small-scale parallel-group Phase IIa randomized, double-blind, placebo-controlled clinical trials, patients with atopic asthma were treated with pitrakinra or placebo given either as a single subcutaneous dose or via nebulization twice daily. Active or placebo treatments were given for 4 weeks before the patients were given an inhaled inhalation challenge. Compared with placebo, allergen challenge-induced decreases in FEV1 were significantly attenuated after 4 weeks of inhalation of pitrakinra. The frequency of spontaneous asthma attacks that required rescue medication use was also diminished in the study in which pitrakinra was given subcutaneously (24). These important findings support the hypothesis that dual inhibition of IL-4 and IL-13 can affect the course of the late asthmatic response after experimental allergen challenge. More large-scale clinical trials on patients with day-to-day asthma are required to establish fully whether pitrakinra is an effective and safe asthma treatment.


Another TH2 cytokine, IL-9, and its receptor are found in asthmatic airways in increased levels (25). IL-9 has several proinflammatory effects on eosinophils, which includes enhancement of eosinophil IL-5 receptor expression, differentiation in the bone marrow, and prolonged survival through inhibition of apoptosis (26). Transgene expression of IL-9 in the lungs of mice resulted in lymphocytic and eosinophilic infiltration of the lung, airway epithelial hypertrophy with mucus production, and mast cell hyperplasia, as well as production of IL-4, IL-5, and IL-13 (27). Treatment of OVA-challenged mice with an anti-IL-9 antibody significantly prevented AHR in response to a methacholine challenge together with reductions in numbers of eosinophil and levels of IL-4, IL-5, and IL-13 in BAL (28).

Tumor necrosis factor-α

TNF-α is expressed in asthmatic airways and may play a key role in amplifying airway inflammation through activation of transcription factors such as NF-KB and AP-1. TNF-α has proinflammatory effects on eosinophils, neutrophils, T cells, and endothelial cells. It is thought to contribute to AHR, airway remodeling, and GC resistance in asthma; therefore, it represents a potential target for therapy. Humanized anti-TNF mAb (infliximab) and soluble TNF receptor blockers (etanercept) have been developed, and preliminary clinical studies have shown significant improvements in lung function, airway hypereactivity, and exacerbation rate, particularly in patients with severe asthma refractory to GC treatment. However, some clinical studies reported negative findings, so heterogeneity seems to exist in response to TNF-α antagonism. In addition, concerns exist regarding potential side effects in some subjects treated with anti-TNF therapy, which include higher rates of solid organ malignancies or latent TB reactivation (29). Small-molecule inhibitors of TNFα-converting enzyme have also been synthesized; and these inhibitors may be attractive therapeutic targets for asthma (30).

Immunoglobulin-E inhibitors

IgE plays a central role in the pathogenesis of diseases associated with immediate hypersensitivity reactions, which include allergic asthma. IgE-dependent biological actions are a result of it binding to high-affinity (FcεRI) receptors on mast cells and basophils and to low-affinity (FcεRII) receptors on macrophages, dendritic cells, and B lymphocytes. Allergen molecules then crosslink adjacent Fab components of IgE on the cell surface, which thereby activates intracellular signal transduction. In mast cells, this action leads to the release of preformed mediators and the rapid synthesis and release of other mediators responsible for bronchoconstriction and airway inflammation. Therefore, blocking the action of IgE using blocking antibodies that do not result in cell activation is an attractive approach.

Omalizumab (rhuMab-E25) is a humanized monoclonal antibody directed to the FcεRI binding domain of human IgE. It inhibited early-phase and late-phase allergen-induced asthmatic reactions and reduces serum-free IgE concentrations to less than 5% of baseline; it has now progressed through clinical development (31). A large Phase II trial studied fortnightly intravenous administration of omalizumab for 20 weeks in 317 patients (32), whereas two Phase III trials, which included over 500 patients each, studied omalizumab given subcutaneously every 2-4 weeks for 12 months (33, 34). Ayres and colleagues (35) examined the effects of Omalizumab in patients with moderate-to-severe allergic asthma whose symptoms were poorly controlled by high doses of inhaled GC. Omalizumab was administered for 12 months and benefited these patients as shown by a 50% reduction in their asthma deterioration-related incidents. Another study reported that Omalizumab treatment of subjects with both persistent rhinitis and difficult-to-treat asthma resulted in significantly reduced asthma exacerbations and improved quality of life in those patients who received anti-IgE therapy over the 28-week study period (36). Omalizumab has also been shown to be beneficial as an add-on therapy in patients who have inadequately controlled, severe persistent asthma (37). Consistent findings from these trials showed that omalizumab is an effective therapy for patients with symptomatic moderate to severe allergic asthma despite treatment with GC and rescue medication. It reduced the frequency of exacerbations and improved symptom control while allowing a reduction in the use of GC and β2-agonists. It also improved patient quality of life and produced a significant improvement in lung function as measured by PEFR and FEVi. Omalizumab seems to be well tolerated with few side effects reported in these studies with no reports of circulating antibodies against omalizumab. Although more long-term studies are needed to elucidate the benefit and safety of anti-IgE therapy in asthma, its niche may be in the treatment of patients with severe asthma who are dependent on oral corticosteroids.


Chemokines are a family of small, secreted proteins that control migration of monocytes, lymphocytes, neutrophils, eosinophils, and basophils. Eotaxin is an inducible, secreted chemokine that promotes selective recruitment of eosinophils from the blood into inflammatory tissues. It was first described in 1993 when intradermal injection of naive guinea pigs with BAL fluid from antigen-challenged guinea pigs resulted in the recruitment of eosinophils (38). Uniquely, the major characteristic of eotaxin is its selective ability to act on eosinophils. CCR3, which is a seven-transmembrane-spanning G protein-coupled receptor for eotaxin-1, is highly expressed on eosinophils and mediates the biological effects of other eosinophil chemokines, such as eotaxin-2, eotaxin-3, MCP-3, MCP-4, and RANTES. Furthermore, CCR3 is expressed not only on eosinophils but also on basophils (39), mast cell subpopulations (40), and activated Th2 cells (41), which might explain the coordinated recruitment of these cell types to sites of allergic inflammation. CCR3 is also expressed by airway epithelial cells (42), and although the bronchial epithelium consists of structural nonmigratory cells, expression of the CCR3 receptor may represent an autoregulatory feedback mechanism to monitor chemokine production. Furthermore, eotaxin produced by the epithelium may be sequestered by the CCR3 receptor and presented to infiltrating cells, which thereby enhances their activation; this phenomenon is observed with IL-8 and its receptor. Several clinical studies have suggested a pivotal role for CCR3 ligands/CCR3 in the eosinophilic inflammation characteristic of atopic dermatitis, asthma, and allergic rhinitis; thus, blockade of this receptor may have pronounced beneficial effects in these diseases (43). Several small-molecule CCR3 antagonists have been described. In this regard, N-(ureidoalkyl)-benzpiperidines have been identified as potent CCR3 antagonists, which inhibit eosinophil chemotaxis and calcium mobilization in the micromolar to nanomolar concentration range (44). The small-molecule selective CCR3 antagonist YM-344031 potently inhibited the binding of eotaxin-1 and RANTES to human cells transfected with CCR3, ligand-induced Ca2+ flux, and chemotaxis, together with inhibition of eotaxin-1-induced eosinophil shape change. Furthermore, both immediate and late-phase allergic skin reactions in a mouse model were significantly inhibited by orally administered YM-344031 (45). Another small-molecule selective CCR3 antagonist YM-355179 inhibited eotaxin-induced intracellular Ca2+ influx, chemotaxis, and eosinophil degranulation. It also inhibited eosinophil infiltration into airways of cynomolgus monkeys after segmental bronchoprovocation with eotaxin (46). The effect of a low molecular weight CCR-3 antagonist on chronic experimental bronchial asthma was examined using BALB/c mice intraperitoneally sensitized with OVA subsequently chronically challenged with OVA aerosol to induce chronic airway inflammation and airway remodeling. CCR-3 antagonist treatment resulted in a marked reduction of eosinophils in the bronchoalveolar lumen and in airway wall tissue, whereas infiltration of lymphocytes or macrophages remained unchanged. Furthermore, antagonizing CCR-3 reduced AHR, goblet-cell hyperplasia, and airway remodeling as defined by subepithelial fibrosis, and it increased accumulation of my- ofibrocytes in the airway wall of chronically challenged mice. Therefore, antagonizing CCR-3 represents a novel approach and promising asthma or allergy therapy (47). Furthermore, evidence from animal models suggests that IL-5 and eotaxin may work in a synergistic fashion to promote the release of mature eosinophils from the bone marrow (48). Thus, it might be that combination therapies of CCR3 antagonist and humanized anti-IL-5 mAb might prove an effective approach to limit or prevent eosinophil toxicity in the asthmatic lung.

Targeting Inflammatory Cell Accumulation

Asthma pathology is characterized by excessive leukocyte infiltration that leads to tissue injury. Leukocyte extravasation, migration within the interstitium, cellular activation, and tissue retention are controlled by cell-adhesion molecules (i.e. selectins, integrins, and members of the immunoglobulin superfamily). Numerous animal studies have demonstrated essential roles for these cell-adhesion molecules in lung inflammation, which include L-selectin, P-selectin, and E-selectin, ICAM-1, and VCAM-1, together with many of the β1 and β2 integrins. For example, compared with wild-type mice, inhaled allergen challenge of P-selectin deficient mice resulted in fewer eosinophils in BAL fluid with significant reductions in AHR. In a sheep model of allergic asthma, pretreatment with an L-selectin monoclonal antibody significantly reduced both the early and late airway response and significantly reduced AHR (49). Therefore, these therapies represent potentially important therapeutic targets and these families of adhesion molecules have been under intense investigation by the pharmaceutical industry for the development of novel therapeutics.


Selectins are responsible for the early “rolling” adhesive events between leukocytes and the endothelial cells that line the postcapillary venules. The small-molecule selectin antagonist Bimosiamose (TBC1269) is a synthetic computer-designed selectin antagonist targeted against all three selectins in vitro and has proven to be efficacious in mouse, rat, rabbit, guinea pig, and sheep models of allergic asthma (50). For example, in a sheep model of allergy, inhaled TBC1269 potently inhibited allergic airway responses, histamine levels in BAL, and tissue kallikrein and neutrophilic inflammation (51). In patients with asthma, a single intravenous dose of TBC1269 had only a minor effect on sputum eosinophils or inhaled allergen-induced late asthmatic reactions (52). In contrast, inhaled TBC1269 significantly reduced late-phase asthmatic reactions by approximately 50% compared with placebo in mild asthmatic subjects (53). Thus, the inhaled route of TBC1269 may offer advantages over systemic delivery in terms of both efficacy and safety. Because selectins are also vital in early adhesive neutrophil interactions with the endothelium, TBC1269 may also prove an effective therapy for COPD.


Good evidence from animal models indicates that α4β1 (VLA-4) is a viable drug target for asthma. Monoclonal antibodies (mAb) against the α4 subunit of VLA-4 have proven efficacious in asthma models in five different species. For example, in a mouse model of asthma, intravenously administered anti-α4 mAb eliminated eosinophilia but did not affect AHR. In contrast, when delivered intranasally, the mAb blocked both airway inflammation and AHR (54). The small-molecule VLA-4 antagonist (2S)-3-(4-Dimethylcarbamoyloxyphenyl)-2-{((4R)-5, 5-dimethyl-3-(1-methyl-1 H-pyrazole-4sulfonyl)thiazolidine-4-carbonyl)amino}propionic acid (WAY103) was assessed for its effects on eosinophil VLA-4-dependent functions, which include adhesion, migration, respiratory burst, and degranulation. WAY103 inhibited eosinophil adhesion to VCAM-1, transendothelial migration, and VCAM-1-stimulated eosinophil superoxide generation. However, it also enhanced cytokine- activated eosinophil-derived neurotoxin degranulation, which generated concerns that it might promote eosinophil activation in certain circumstances (55). More recently, a potent and selective, small-molecule VLA-4 inhibitor, (2S)-3-(2',5’-dichlorobiphenyl-4-yl)-2-({(1-(2-methoxybenzoyl)piperidin-3-yl) carbonyl}amino) propanoic acid, blocked VLA-4 dependent functions on a variety of cell types and also inhibited eosinophil infiltration in a dose-dependent manner by up to 80% in an air-pouch mouse model (56). Overall, several small-molecule integrin α4β1 antagonists have been developed, but most of these have proved to be ineffective in preventing the clinical symptoms of asthma. However, a recent clinical trial of an oral α4β1 antagonist valategrast demonstrated significant positive effects on lung function and rates of exacerbation in asthma patients who had their inhaled GC therapy withdrawn prior to treatment with valategrast (57).


Asthma and allergy are manifestations of an imbalance in cytokine and signaling pathways that mediate inflammatory and structural changes within the affected tissues. Developing treatments include strategies to alter the cytokine/chemokine balance or to skew the cytokine profile away from T helper2 (Th2) responses and toward Th1 responses. Immunotherapy may potentially attenuate symptoms by disease modification through the induction of tolerance to common environmental allergens rather than by suppressing inflammation. A major advantage is the potential for a positive effect to remain for several years after the end of the treatment period. The use of allergen-specific immunotherapy is not a new approach to asthma therapy, and until relatively recently the crude nature of the allergen extracts available meant that its use was limited by unwanted side effects, such as anaphylaxis. Strategies to overcome these problems include the use of hypoallergenic isoforms, recombinant allergens, or DNA vaccines (58). For example, in mice with chronic airway inflammation maintained by repeated ovalbumin inhalation, mucosal administration of CpG DNA oligonucleotides significantly reversed airway hyperreactivity together with both acute and chronic markers of inflammation (59). Another approach is the use of short, synthetic, allergen-derived peptides that induce T cell tolerance but cannot crosslink IgE on mast cells or basophils and induce anaphylaxis. The main effect seems to be a shift from a Th2 to Th1 profile and induction of regulatory cytokines such as IL-10 and TGB-β. One study that used patients with asthmatic reactions to cats demonstrated that treatment with a desensitising vaccine based on many short, overlapping, HLA-binding, T-cell peptides derived from Fel d 1 inhibited both early- and late-phase reactions to a subsequent whole-allergen challenge. Changes in immunological parameters included modulation of the proliferation of blood mononuclear cells together with their production of IL-4, IL-10, and IL-13, and of interferon-y (60). A more recent study from the same group demonstrated that treatment of cat-allergic asthmatic subjects with Fel d 1-derived T-cell peptides significantly improved clinically relevant outcome measurements, which include reductions in late asthmatic reactions to inhaled whole cat dander and significant improvements in asthma-related quality of life (61). Although the results from these studies are encouraging, we require larger, dose-ranging studies before firm conclusions on clinical efficacy of peptide allergen therapy can be made. Although it is conceivable that targeting T cells may induce Th1-type autoimmune pathology in humans, to date no evidence indicates that this occurs. In addition, nonallergic mechanisms are also likely to be important in the pathogenesis of asthma; thus, it is possible that novel treatments targeted at the allergy fraction of the phenotype may not be as efficacious as hoped.


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See Also

Small Molecule Inhibitors, Design and Selection of

Small Molecule Drugs that Target Chronic Obstructive Pulmonary Disease (COPD)


Integrin signalling