Abstract
Many drugs are now in development for the treatment of atopic diseases, including asthma, allergic rhinitis and atopic dermatitis. These treatments are based on improvements in existing therapies or on a better understanding of the cellular and molecular mechanisms involved in atopic diseases. Although most attention has been focused on asthma, treatments that inhibit the atopic disease process would have application to all atopic diseases, as they often coincide. Most of the many new therapies in development are aimed at inhibiting components of the allergic inflammatory response, but in the future there are real possibilities for the development of preventative and even curative treatments.
Main
Atopic diseasesFootnote 1 account for a large proportion of health care spending in industrialized countries, as these conditions are common, persistent and currently incurable. There has been an enormous investment by the pharmaceutical companies in the search for new drugs in this profitable market. Current therapies for asthma and rhinitis are effective in most patients, whereas treatment for atopic dermatitis is less effective (Table 1). Anaphylactic shock is treatable with adrenaline (epinephrine) but there is a search for preventive therapies for susceptible patients. There is a need for new treatments to deal with more severe asthma that is currently not well controlled by high doses of inhaled corticosteroids and a need for a safe oral medication that would be effective in all atopic diseases, as they often occur together. The development of safe and effective oral therapies may depend on the discovery of treatments that are more specific for the atopic disease process, in order to avoid side effects.
New therapies for allergic diseases have developed by improving existing classes of drug or by discovering new classes of drug through research. Advances in understanding the molecular mechanisms of atopy have identified several new targets that might lead to new therapies for allergic diseases in the future1.
This review summarizes some of the areas where new drugs are in development for atopic diseases. Most attention is focused on asthma, the atopic disease with the greatest clinical and economic impact, but treatments that are effective against the underlying atopic disease process might be effective against all atopic diseases, which commonly occur together.
Bronchodilators are used for symptom relief in asthma, but have no effect on the underlying inflammatory process. Inhaled β2-adrenergic agonists are safe and highly effective bronchodilators and it has proved impossible to find other classes of drug that are better. They relax airway smooth muscle by increasing the concentration of cyclic AMP and by opening potassium channels. Other classes of drug that mimic these effects, such as phosphodiesterase inhibitors or potassium channel openers, have not proved to be effective as bronchodilators, as side effects have limited the dose that can be administered1. It is unlikely that novel bronchodilators that are more effective than β2-agonists will be developed and all of the attention has switched to the development of treatments that suppress or prevent the atopic inflammatory process.
I begin by discussing corticosteroids, which remain by far the most effective treatment for allergic diseases, as they provide the standard against which new treatments are judged. Many new classes of drug are in development and this very diversity highlights the fact that there are many possible therapeutic targets, most of which are suppressed by corticosteroids. The simplest approach is to develop inhibitors of specific inflammatory mediators and, because many mediators have been implicated in atopic diseases, there are several such drugs in development. Cytokines have a critical role in the allergic inflammatory process and I review drugs that inhibit the cytokines that promote allergic inflammation, as well as cytokines that modulate the inflammatory process. I consider anti-inflammatory drugs with a broader spectrum of action, including broad-spectrum immunosuppressants, followed by drugs that may have a more selective inhibitory effect on the allergic process. Finally, I discuss treatment strategies that may prevent the development of allergic diseases.
Corticosteroids
Corticosteroids are the most effective treatment currently available for atopic diseases and high doses of oral corticosteroids would control almost every atopic patient. However, systemic side effects limit the dose that can be given over long periods, and this led to the development of topical steroids. There is little doubt that inhaled corticosteroids have revolutionized the treatment of asthma and are now first-line treatment for chronic asthma in patients of all ages and severity of disease2. Nasal steroids are also the most effective treatment for allergic rhinitis3. Topical steroids for atopic dermatitis are associated with dermal atrophy, but and this has restricted the use of corticosteroids in the management of eczema. New-generation inhaled corticosteroids for asthma, including budesonide, fluticasone propionate and mometasone furoate, have a high level of anti-inflammatory action with minimal side effects, as the swallowed fraction of drug is largely removed by hepatic metabolism2. However, these drugs are absorbed from the lung or nasal mucosa and so may have some systemic effects at high doses. There has therefore been a search for corticosteroids that are metabolized locally, so that there is less risk of systemic absorption from the respiratory tract or the skin. But these ‘soft steroids’, such as butixocort 21-propionate and tipredane, proved to have poor efficacy in clinical studies, as they are metabolized too rapidly before they exert their anti-inflammatory action. New soft steroids, such as ciclesonide, seem to be more promising4, and corticosteroids that are inactivated in plasma are now in development. Corticosteroids are highly effective in controlling atopic diseases, and there is increasing evidence that if started early they may prevent some of the irreversible airway narrowing in asthma2. However, they do not cure the disease and allergic inflammation recurs when treatment is stopped.
Advances in understanding how corticosteroids suppress inflammation at a molecular level may lead to the development of safer steroids, or drugs that mimic their key anti-inflammatory actions. Corticosteroids bind to a cytosolic glucocorticoid receptor which translocates to the nucleus and binds as a homodimer to DNA to activate genes. The principal action of corticosteroids is to suppress multiple inflammatory genes, including cytokines, inflammatory enzymes, adhesion molecules and inflammatory mediator receptors, and this is why corticosteroids are so effective in complex inflammatory conditions. Most of the anti-inflammatory actions of corticosteroids can be accounted for by inhibiting transcription factors, such as activator protein-1 (AP-1), nuclear factor-κB (NF-κB) and nuclear factor of activated T cells (NF-AT), that regulate inflammatory gene expression5. These effects are mediated, at least in part, by inhibition of core-histone acetylation
New corticosteroids. Systemic side effects of corticosteroids are mediated largely through DNA binding, so that it may be possible to dissociate the anti-inflammatory effects, mainly mediated by transcription-factor inhibition, from their side effects (Fig. 1). Several dissociated corticosteroids have now been synthesized and a separation between trans-activation (DNA binding) and trans-repression (transcription-factor inhibition) has been demonstrated in gene reporter systems and in intact cells in vitro6. Whether this will translate to in vivo differences has not yet been determined and because all corticosteroids have to bind to a single class of glucocorticoid receptor, a large separation of effects may not be possible. Identification of the major targets for corticosteroid action, such as NF-κB, activation of cAMP-response element binding protein (CREB)-binding protein (CBP) or acetylation of core histones, may be a more promising approach in the future.
Corticosteroids bind to glucocorticoid receptors (GR) which dimerize to bind to DNA and increase transcription (trans-activation) and this mediates the systemic side effects of corticosteroids. Most of the anti-inflammatory effects of corticosteroids are mediated by inhibition of expression of inflammatory genes that are regulated by transcription factors, such as activator protein-1 (AP-1), nuclear factor-κB (NF-κB) and nuclear factor of activated T cells (NF-AT), by interaction of GR monomers with these transcription factors (trans-repression). Some corticosteroids (‘dissociated steroids’) are able to selectively inhibit trans-repression to a greater extent than trans-activation.
Mediator antagonists
Many inflammatory mediators are involved in atopic diseases, and in asthma over 50 different mediators have been identified7. This implies that inhibitors of single mediators would be unlikely to be of major clinical benefit. Yet some mediator antagonists have been found to be useful in treating atopic diseases, indicating that these may have a more dominant role.
Antihistamines. Histamine H1-receptor antagonists have a long history in the treatment of atopic diseases. Older antihistamines such as promethazine and chlorpheniramine, which caused sedation, have now been replaced by a new generation of antihistamines such as loratadine and fexafenadine, which are much less likely to sedate. These drugs are effective in rhinitis and reduce itch in atopic dermatitis, but have no clear benefit in asthma8. New antihistamines, such as cetirizine, ebastine and astemizole, have been claimed to have additional anti-asthma effects that are not mediated through H 1-receptor blockade. These effects include an inhibitory effect on eosinophil chemotaxis and adherence to endothelial cells, and inhibition of eosinophil recruitment into asthmatic airways after allergen challenge.
Antileukotrienes. Cysteinyl leukotrienes, generated from the rate-limiting enzyme 5′-lipoxygenase (5-LO), are potent bronchoconstrictors and inducers of plasma exudation, and there is some evidence that they may promote eosinophilic inflammation9. 5-LO inhibitors (zileuton) and cysteinyl-leukotriene receptor (Cys-LT1) antagonists (pranlukast, zafirlukast and montelukast) have been developed for the treatment of asthma, and possibly other atopic diseases. In challenge studies they reduce allergen- and exercise-induced asthma, as well as several other challenges. In clinical trials they improve asthma symptoms, lung function and reduce the need for rescue bronchodilator treatment9. A major advantage is that they are effective orally and, so far, there are no serious class-specific effects, although headache occurs in some patients. However, they are only weakly effective in asthma, although some patients (even with severe disease) may have a striking improvement. It is not yet possible to predict which patients will respond best, although there is some evidence that patients with aspirin-sensitive asthma do well, as may be expected form studies showing increased leukotriene production in these patients10. It is possible that genetic polymorphisms in the 5-LO pathway or Cys-LT1 receptors might predict responders in the future11. Although there are some reasons for thinking that antileukotrienes may have efficacy in allergic rhinitis, recent clinical studies have shown no benefit compared with nasal corticosteroids12.
Other mediator inhibitors. Several other inhibitors of inflammatory mediators have been tested in asthma and rhinitis with disappointing effects, including inhibitors and receptor antagonists of thromboxane synthesis, antagonists of platelet activating factor, and bradykinin and tachykinin antagonists. Inhibitors of other mediators relevant to atopic diseases are in development. There is increased production of nitric oxide (NO) in asthma and rhinitis, with evidence for increased expression of inducible NO synthase (iNOS). NO may contribute to vasodilatation and plasma exudation and has been implicated in eosinophil recruitment and survival13. Selective inhibitors of iNOS are now in development but have not yet reached clinical studies. Endothelins have been implicated in bronchoconstriction, smooth muscle hyperplasia and fibrosis, with effects mediated by endothelin-A and endothelin-B receptors14. Mixed endothelin antagonists have now been developed although they have not yet been tested in asthma; but if their principal effect is to inhibit airway remodelling they may prove difficult to test in clinical studies.
Tryptase inhibitors. Mast-cell tryptase has several effects on airways, including increasing responsiveness of airway smooth muscle to constrictors, increasing plasma exudation, potentiating eosinophil recruitment and stimulating fibroblast proliferation. Some of these effects are mediated by activation of the proteinase-activated receptor, PAR2. A tryptase inhibitor APC366 is effective in a sheep model of allergen-induced asthma15, but was only poorly effective in asthmatic patients16. More potent tryptase inhibitors and PAR2 antagonists are now in development.
Cytokine modulators
Multiple cytokines have been implicated in the pathophysiology of atopic diseases, although some cytokines have a more critical role in atopic inflammation17. There are several possible approaches to inhibiting specific cytokines. These include the use of drugs that inhibit cytokine synthesis (glucocorticoids, cyclosporin A and tacrolimus), humanized blocking antibodies to cytokines or their receptors, soluble receptors that ‘mop up’ secreted cytokines to receptor antagonists and drugs that block the signal-transduction pathways activated by cytokines (Fig. 2). On the other hand, there are cytokines that suppress the allergic inflammatory process and these may have therapeutic potential.
Strategies used to inhibit the production or effects of cytokines.
Anti-IL-5. Interleukin (IL)-5 is crucial in orchestrating the eosinophilic inflammation of asthma18 (Fig. 3). Blocking antibodies to IL-5 inhibit eosinophilic inflammation and airway hyperresponsiveness (AHR) in animal models of asthma, including primates. This blocking effect may last for up to 3 months after a single injection, making treatment of chronic asthma with such a therapy a feasible proposition. Humanized monoclonal antibodies to IL-5 have now been developed and a single injection reduces blood eosinophils for several weeks and prevents eosinophil recruitment into the airways after allergen challenge19. However, this treatment has no effect on the early or late response to allergen challenge or on AHR, indicating that eosinophils may not be critical for these responses. Similar findings have been reported previously in mice where anti-IL-5 antibodies reduced eosinophil responses to allergen, but not AHR, whereas AHR is reduced by anti-CD4 antibody, which depletes helper T cells (Th cells)20. Long-term clinical studies are now in progress, particularly in patients with more severe disease. Non-peptidic IL-5-receptor antagonists would be an attractive alternative and there is a search for such compounds using molecular modelling of the IL-5-receptor α-chain and through large-scale throughput screening.
Several strategies are possible to inhibit eosinophilic inflammation in tissues, including immunomodulators, inhibitors of driving cytokines (IL-4 and IL-5), inhibition of critical adhesion molecules (VLA4, selectins and ICAM-1), blockade of chemokine receptors on eosinophils (CCR3) and induction of apoptosis.
Anti-IL-4. IL-4 is critical for the synthesis of immunoglobulin E (IgE) by B lymphocytes and is also involved in eosinophil recruitment to the airways (see review by Corry & Kheradmand, this supplement). IL-4-receptor blocking antibodies inhibit allergen-induced AHR, goblet-cell metaplasia and pulmonary eosinophilia in a murine model21. Inhibition of IL-4 may therefore be effective in inhibiting allergic diseases, and soluble IL-4 receptors are in clinical development as a strategy to inhibit IL-4, with some preliminary evidence of efficacy by nebulization in moderate asthma22. IL-4 and the closely related cytokine IL-13 signal through a shared surface receptor that activates a specific transcription factor, signal transducer and activator of transcription 6 (Stat-6); deletion of the Stat-6 gene has a similar effect to knock-out of the IL-4 gene23. This has led to a search for inhibitors of Stat-6, although it will be difficult to deliver these intracellularly. An endogenous inhibitor of STATs, suppressor of cytokine signalling (SOCS-1), is a potent inhibitor of IL-4 signalling pathways and offers a new therapeutic target24.
Anti-IL-13. There is increasing evidence that IL-13 in mice mimics many of the features of asthma, including AHR and mucus hypersecretion, independently of eosinophilic inflammation25. It is also a potent inducer of eotaxin secretion from airway epithelial cells26. IL-13 signals through the IL-4-receptor α-chain, but may also activate different intracellular pathways27, so that it may be an important target for the development of new therapies.
Anti-TNF. Tumour-necrosis factor (TNF)-α is expressed in asthmatic airways and may be important in amplifying asthmatic inflammation, through the activation of NF-κB, AP-1 and other transcription factors. In rheumatoid arthritis and inflammatory bowel disease a blocking antibody to TNF-α (infliximab) has produced remarkable clinical responses, even in patients who are relatively unresponsive to steroids28. Such antibodies or soluble TNF receptors are a logical approach to asthma therapy, particularly in patients with severe disease. There is also a search for small-molecule inhibitors of TNF, of which the most promising are inhibitors of TNF-α converting enzyme as these could be given orally.
Chemokine inhibitors. Chemokines are chemoattractant cytokine molecules. Chemokines such as RANTES, MCP-3, MCP-4 and eotaxin may be crucial in the recruitment of eosinophils in atopic patients; all of these chemokines act on a common receptor, the CCR3 receptor, that is expressed predominantly on eosinophils29. An antibody to human CCR3 blocks the chemotactic response of human eosinophils to all chemokines30. The modified chemokine met-RANTES similarly blocks CCR3 receptors and inhibits eosinophil chemotactic responses to chemokines31. Chemokine receptors are G-protein-coupled receptors with the typical seven-transmembrane-spanning segments and are therefore have a simpler structure than the receptors for other cytokines. Non-peptide inhibitors of CCR3 receptors are now in development and should be relatively safe as the distribution of CCR3 receptors is restricted to eosinophils, Th2 cells and basophils.
Anti-inflammatory cytokines. Some cytokines have anti-inflammatory effects in atopic inflammation and therefore have therapeutic potential32. Although it may not be feasible or cost-effective to administer these proteins as long-term therapy, it may be possible to develop drugs that increase the release of these endogenous cytokines or activate their receptors and specific signal-transduction pathways. IL-1-receptor antagonist (IL-1ra) binds to IL-1 receptors and blocks the action of IL1β. In experimental animals it reduces AHR33 and clinical studies are underway.
IL-10 is a potent anti-inflammatory cytokine that inhibits the synthesis of many inflammatory proteins, including cytokines (TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-5 and chemokines) and inflammatory enzymes (iNOS) that are overexpressed in asthma34. Indeed, there may be a defect in IL-10 transcription and secretion from macrophages in asthma35,36. In sensitized animals, IL-10 is effective in suppressing the inflammatory response to allergen, indicating that IL-10 might be defective in atopic diseases. Recombinant human IL-10 has proved to be effective in controlling inflammatory bowel disease, where similar cytokines are expressed, and may be given as a weekly injection37. In the future, drugs that active the unique signal-transduction pathways activated by the IL-10 receptor or drugs that increase endogenous production of IL-10 may be developed. In mice, drugs that elevate cAMP increase IL-10 production, but this does not seem to be the case in human cells38.
Interferon-γ (IFN-γ) inhibits Th2 cells and should therefore reduce atopic inflammation. In sensitized animals, nebulized IFN-γ inhibits eosinophilic inflammation induced by allergen exposure39 (see review by Corry & Kheradmand, this supplement). But administration of IFN-γ by nebulization to asthmatic patients did not significantly reduce eosinophilic inflammation, although this may be due to the difficulty in obtaining a high enough concentration locally in the airways40. Allergen immunotherapy increases IFN-γ production by circulating T cells in patients with clinical benefit41 and it increased the number of cells expressing IFN-γ in nasal biopsies of patients with allergic rhinitis42.
IL-12 is the endogenous regulator of Th1-cell development and determines the balance between Th1 and Th2 cells43. IL-12 administration to rats inhibits allergen-induced inflammation44 and inhibits sensitization to allergens. IL-12 releases IFN-γ, but has additional effects on T-cell differentiation. Recombinant human IL-12 has been administered to humans and has several toxic effects which are diminished by slow escalation of the dose. In mice, administration of an IL-12-allergen fusion protein results in the development of a specific Th1 response to allergens rather than the normal Th2 response with IgE formation45. This indicates the possibility of using IL-12 to provide a more specific immunotherapy, which might even be curative if applied early in the course of the atopic disease.
New anti-inflammatory drugs
There has been an intensive search for anti-inflammatory treatments that are as effective as glucocorticoids but with fewer side effects. Whereas one approach is to seek corticosteroids with a greater therapeutic effect, other approaches involve developing different classes of anti-inflammatory drugs.
Phosphodiesterase-4 inhibitors. Phosphodiesterases (PDEs) break down cyclic nucleotides that inhibit cell activation and at least nine families of enzymes have now been discovered. Theophylline, long used as an asthma treatment, is a weak but non-selective PDE inhibitor. PDE4 is the predominant family of PDEs in inflammatory cells, including mast cells, eosinophils, T lymphocytes, macrophages, and structural cells such as sensory nerves and epithelial cells46. This has suggested that PDE4 inhibitors would be useful as an anti-inflammatory treatment in atopic disease, particularly as there is some evidence for over-expression of PDE4 in cells of atopic patients47. In animal models of asthma, PDE4 inhibitors reduce eosinophil infiltration and AHR responses to allergen46. Several PDE4 inhibitors have been tested in asthma, but with disappointing results. One PDE4 inhibitor, CDP840, had a marginal inhibitory effect on the late response to allergen, but is not being further developed48. However, most of the PDE4 inhibitors so far tested clinically have had unacceptable side effects, particularly nausea and vomiting, and such side effects have limited the use of theophylline.
Several steps may be possible to overcome these problems. It is possible that vomiting is due to inhibition of a particular subtype of PDE4. At least four human PDE4 genes have been identified and each has several splice variants46,49. This raises the possibility that subtype-selective inhibitors may be developed that may preserve the anti-inflammatory effect, while having less propensity to side effects. PDE4D seems to be of particular importance in inflammatory cells, such as T lymphocytes and eosinophils, and may be a more specific target50; subtype-selective PDE4 inhibitors are now in development.
Transcription-factor inhibitors. Transcription factors, such as NF-κB and AP-1, are important in the orchestration of asthmatic inflammation51,52 and this has prompted a search for specific blockers of these transcription factors. NF-κB is inhibited naturally by the inhibitory protein IκB, which is degraded after activation by specific kinases. Inhibitors of IκB kinases or the proteasome, the multifunctional enzyme that degrades IκB, would thus inhibit NF-κB and there is a search for such inhibitors. There are some naturally occurring inhibitors of NF-κB, such as the fungal product gliotoxin, although this compound is toxic. There are concerns that inhibition of NF-κB may cause side effects such as increased susceptibility to infections, which as been observed in gene-disruption studies when components of NF-κB are inhibited51.
Cyclosporin A and tacrolimus inhibit T-lymphocyte function by blocking the transcription factor NF-AT by blocking activation of calcineurin. This results in suppression if IL-2, IL-4, IL-5 and GM-CSF and so offers therapeutic potential in atopic diseases (see below).
MAP kinase inhibitors. There are three major mitogen-activated protein (MAP) kinase pathways and there is increasing recognition that these pathways are involved in chronic inflammation53. There has been particular interest in the p38 MAP kinase pathway that is blocked by a new class of drugs, the cytokine suppressant anti-inflammatory drugs (CSAIDs), such as SB203580 and RWJ67657. These drugs inhibit the synthesis of many inflammatory cytokines, chemokines and inflammatory enzymes. They appear to have a preferential inhibitory effect on synthesis of Th2 compared with Th1 cytokines, indicating their potential application in the treatment of atopic diseases54. Furthermore, p38 MAP kinase inhibitors have also been shown to decrease eosinophil survival by activating apoptotic pathways55. Whether this new class of anti-inflammatory drugs will be safe in long-term studies remains to be established.
Tyrosine kinase inhibitors. Syk kinase is a protein tyrosine kinase that has a pivotal role in signalling of the high-affinity IgE receptor (FcεRI) in mast cells. In syk-deficient mice, mast-cell degranulation is inhibited, indicating that this might be an important potential target for the development of mast-cell stabilizing drugs56. Syk is also involved in antigen-receptor signalling of B and T lymphocytes and in eosinophil survival in response to IL-5 and GM-CSF57, so that syk inhibitors might have several useful beneficial effects in atopic diseases. Another tyrosine kinase lyn is upstream of syk, and an inhibitor of lyn kinase, PP1, has an inhibitory effect on inflammatory and mast-cell activation58. But as lyn and syk are widely distributed in the immune system, there are doubts about the long-term safety of selective inhibitors.
Immunosuppressants. T lymphocytes may be important in initiating and maintaining the inflammatory process in atopy through the release of cytokines that result in eosinophilic inflammation, indicating that T-cell inhibitors may be useful in controlling asthmatic inflammation. The non-specific immunomodulator cyclosporin A reduces the dose of oral steroids needed to control asthma in patients with severe asthma59, but its efficacy is very limited60, and side effects, particularly nephrotoxicity, limit its clinical use. The possibility of using inhaled cyclosporin A is now being explored, as in animal studies the inhaled drug is effective in inhibiting the inflammatory response in experimental asthma61. Immunomodulators, such as tacrolimus (FK506) and rapamycin, seem to be more potent but are also toxic and may offer no real advantage. Topical tacrolimus seems to be effective in atopic dermatitis and is well tolerated62. Novel immunomodulators that inhibit purine or pyrimidine pathways, such as mycophenolate mofetil, leflunomide and brequinar sodium, may be less toxic and therefore of greater potential value in asthma therapy63.
One problem with these non-specific immunomodulators is that they inhibit both Th1 and Th2 cells, and therefore do not restore the imbalance between these cells in atopy. They also inhibit suppresser T cells (Tc1 cells) that may modulate the inflammatory response. Selective inhibition of Th2 cells may be more effective and better tolerated and there is now a search for such drugs.
Cell adhesion blockers. Infiltration of inflammatory cells into tissues is dependent on adhesion of blood-borne inflammatory cells to endothelial cells before migration to the inflammatory site64. This depends upon specific glycoprotein adhesion molecules, including integrins and selectins, on both leukocytes and endothelial cells, which may be upregulated or show increased binding affinity in response to various inflammatory stimuli such as cytokines or lipid mediators. Monoclonal antibodies which inhibit these intracellular adhesion molecules (ICAMs) may prevent inflammatory cell infiltration. Thus a monoclonal antibody to ICAM-1 on endothelial cells prevents the eosinophil infiltration into airways and the increase in bronchial reactivity after allergen exposure in sensitized primates65, although this has not been found in other species66. The interaction between very late antigen (VLA)-4 and vascular cell-adhesion molecule (VCAM)-1 is important for eosinophil inflammation and humanized antibodies to VLA-4 (α4α1) have been developed67 (Fig. 3). Small-molecule peptide inhibitors of VLA-4 have been developed which are effective in inhibiting allergen-induced responses in sensitized sheep68. Inhibitors of selectins, particularly L-selectin, based on the structure of sialyl-Lewisx, inhibit the influx of inflammatory cells in response to inhaled allergen in sensitized sheep69 and inhibit adhesion of human eosinophils in vitro 70. Although blocking adhesion molecules is an attractive new approach to the treatment of inflammatory disease, there may be potential dangers in inhibiting immune responses leading to increased infections and increased risks of neoplasia.
Specific anti-allergic drugs
Although corticosteroids are effective in controlling atopic diseases, there are continuing concerns about systemic side effects when high doses are needed. This has prompted a search for more selective anti-inflammatory agents that would selectively target the atopic disease process.
Cromones. The cromones (sodium cromoglycate and nedocromil sodium) are the most specific anti-allergic drugs so far discovered. Topical application is effective in asthma, rhinitis and allergic conjunctivitis, but the effects are less marked that seen with topical steroids and they are effective only in mild disease. Cromones seem to have a specific action on allergic inflammation, yet their molecular mechanism of action remains obscure. Although it was believed that the primary mode of action of cromones involved inhibiting mast-cell mediator release, it has now been shown that they affect several other inflammatory cells and sensory nerves, including certain types of chloride channels that are expressed in mast cells71. Sodium cromoglycate phosphorylates moesin, a specific cytoskeletal protein in mast cells, indicating a possible mechanism that may inhibit degranulation72. Both cromoglycate and nedocromil sodium must be given topically and all attempts to develop orally active drugs of this type have been unsuccessful, possibly suggesting that topical administration is critical to their efficacy.
The diuretic furosemide shares many of the actions of cromones in inhibiting indirect bronchoconstrictor challenges (such as allergen, exercise, cold air, adenosine and metabisulphite) but not direct bronchoconstriction (such as histamine and methacholine) when given by inhalation73. The mechanism of action of furosemide is not shared by the more potent loop-diuretic bumetanide, indicating that some other mechanism than the inhibition of the Na+/K+/Cl- co-transporter must be involved. This probably involves inhibition of the same chloride channel that is inhibited by cromones. Furosemide itself does not seem to be particularly effective when given regularly by metered dose inhaler in asthma74, but it is possible that more potent and long-lasting chloride-channel blockers might be developed in the future.
Co-stimulation inhibitors. Co-stimulatory molecules may be crucial in augmenting the interaction between antigen-presenting cells (APCs) and CD4+ T lymphocytes (see review by Corry & Kheradmand, this supplement). The interaction between B7 and CD28 may determine whether a Th2-type cell response develops, and there is some evidence that B7-2 (CD86) skews towards a Th2 response (Fig. 4). Blocking antibodies to B7-2 inhibit the development of specific IgE, pulmonary eosinophilia and AHR in mice, whereas antibodies to B7-1 (CD80) are ineffective75. A molecule on activated T cells, CTL4, seems to act as an endogenous inhibitor of T-cell activation and CTLA4-Ig, a soluble fusion-protein construct, is also effective in blocking AHR in a murine model of asthma76. Anti-CD28, anti-B7-2 and CTLA4-Ig also block the proliferative response of T cells to allergen77, indicating that these are potential targets for new therapies that should be effective in all atopic diseases.
Therapies are based on inhibition of co-stimulatory molecules (B7-2 and CD28), inhibition of IgE-driven APCs, and the use of non-selective immunomodulators or cytokines that tip the balance away from Th1 cells towards Th2 cells
Th2-cell inhibitors. Non-selective T-cell suppressants, such as cyclosporin A and tacrolimus, may be relatively ineffective in asthma as they inhibit all types of T cell. CD4+ T cells have been implicated in asthma and a chimaeric antibody directed against CD4+ (keliximab), which reduces circulating CD4+ cells, seems to have some beneficial effect in asthma78, although long-term safety of such a treatment might be a problem. Furthermore, there is increasing evidence that CD8+ cells (Tc2 cells), through release of IL-5 and other cytokines, might also be involved in atopic diseases, particularly in response to infections with certain viruses79. There has been a search for selective inhibitors of Th2 cells by identifying features that differentiate Th1 and Th2 cells. The transcription factor GATA-3 seems to be of particular importance in murine and human Th2 cells80,81 and may be a target for selective immunomodulatory drugs. However, an argument against strategies to control atopic disease by targeting Th2 cells is that chronic stimulation (by exposure to allergen) results in cells that are relatively resistant to immune suppression82.
Anti-IgE. Because release of mediators from mast cells in asthma is IgE-dependent (see review by Turner & Kinet, this supplement), an attractive approach is to block the activation of IgE using blocking antibodies that do not result in cell activation. A humanized murine monoclonal antibody directed to the FcεRI-binding domain of human IgE (rhuMAb-E25) reduces allergen-specific IgE after intravenous administration83. RhuMAb-E25 also reduces early and late responses to inhaled allergen and eosinophil counts in induced sputum84. Although a reduction in early response to allergen, which is due to mast-cell activation through bound IgE, is expected, the reduction in the late response and in sputum eosinophils is unexpected, but it may be explained by blocking the effect of IgE on low-affinity IgE receptors (CD23) on APCs. Anti-IgE in mice inhibits Il-4 and IL-5 secretion and pulmonary eosinophilia by blocking Th2-cell activation in response to allergen, and this is mimicked by an anti-CD23 antibody85. Clinical studies with rhuMAb-E25 are now in progress86. Although injections of antibody may not be feasible for the long-term treatment of mild asthma, this could be a realistic therapy for patients with more severe forms of asthma or atopic dermatitis, in whom high IgE levels may be found.
Preventive strategies
Atopy seems to be due to immune deviation from Th1 to Th2 cells, which may arise because of a failure to inhibit the normal Th2 preponderance at birth, which in turn may result from environmental factors such as the Th1 response to infectious agents (see review by Holt et al., this supplement).
Specific allergen vaccination (immunotherapy). Subcutaneous injection of small amounts of purified allergen has been used form many years in the treatment of allergy. It is effective in the treatment of insect venom anaphylaxis and hay fever, and may induce prolonged remission87, but is less effective in asthma. The molecular mechanism of desensitization is unknown. Cloning of several common allergen genes has made it possible to prepare recombinant allergens for injection, although this purity may detract from their allergenicity as most natural allergens contain several proteins. Intramuscular injection of rats with plasmid DNA expressing house dust mite allergen results in its long-term expression and prevents the development of IgE responses to inhaled allergen88. This suggests that allergen gene immunization might be a useful therapeutic strategy in the future. The major allergens of peanuts, which are responsible for an increasing number of severe anaphylactic reactions, has been cloned and oral administration of microparticles of DNA complexed to chitosan in mice produces intestinal epithelial expression of the allergen and prevention of anaphylaxis after oral challenge89.
Peptide immunotherapy. Small peptide fragments of allergen (epitopes) are able to block allergen-induced T-cell responses without inducing anaphylaxis90. T-cell-derived peptides from cat allergen (fel d1) seem to be effective in blocking allergen responses to cat dander91, but may induce an isolated late response to allergen by direct T-cell activation92.
Vaccination. A relative lack of infections may be a factor that influences the development of atopy in genetically predisposed individuals. This leads to the concept that vaccination may induce protective Th1 responses to prevent sensitization and thus prevent the development of atopic diseases (see review by Holt et al., this supplement). Bacille Calmette-Guérin (BCG) vaccination has been associated with a reduction in atopic diseases in Japan93, but this has not been confirmed in a Swedish population94. BCG inoculation in mice, delivered 14 days before allergen sensitization, reduced the formation of specific IgE in response to allergen and the eosinophilic response and AHR responses to allergen, with an increase in production of IFN-γ95. This has prompted several clinical trials of BCG to prevent the development of atopy. Similar results have been obtained in mice with the a single injection of heat-killed Mycobacterium vaccae, another potent inducer of Th1 responses96, and with Listeria. Lactobacillus acidophilus in yoghurt, another potential means of tipping back the balance from Th2 to Th1 cells, weakly increases IFN-γ formation in adult asthmatic patients97. Immunostimulatory DNA sequences, such as unmethylated cytosine–guanosine dinucleotide-containing oligonucleotides (CpG ODN), are also potent inducers of Th1 cytokines and, in mice, administration of CpG ODN increases the ratio of Th1 to Th2 cells, decreases formation of specific IgE and reduces the eosinophilic response to allergen, an effect that lasts for over 6 weeks98. These promising animal studies encourage the possibility that vaccination might prevent or cure atopic diseases in the future.
Gene therapy
Because atopic diseases are polygenic, it is unlikely that gene therapy will be of value in long-term therapy (see review by Cookson, this supplement). However, identifying the genes involved in atopic diseases and in disease severity may identify new molecular targets and may also predict the response to different forms of therapy (pharmacogenetics). Transfer of anti-inflammatory genes may provide specific anti-inflammatory or inhibitory proteins in a convenient manner and gene transfer has been shown to be feasible in animals using viral vectors99. Anti-inflammatory proteins relevant to asthma include IL-10, IL-12 and IκB. Antisense oligonucleotides may switch off specific genes, but there are considerable problems in getting these molecules into cells. An inhaled antisense oligonucleotide directed against the adenosine A1-receptor has been shown to reduce AHR in a rabbit model of asthma, demonstrating the potential of this approach in treating asthma100. Suitable target genes may be IL-4 or IL-5. Considering the practical problems encountered by gene therapy, this approach is unlikely in the foreseeable future, other than for proof-of-concept studies.
Conclusions
Many different therapeutic approaches to the treatment of atopic diseases may be possible, yet there have been few new drugs that have reached the clinic. Topical glucocorticoids are particularly effective as chronic treatment in atopic diseases and suppress the underlying inflammatory process. Advances in therapy would be facilitated through the development of more specific anti-allergic drugs that lack side effects. If these treatments can be taken orally this would treat asthma, rhinitis and eczema, which often coincide. The possibility of developing a ‘cure’ for atopy is remote, but strategies to inhibit the development of sensitization in early childhood offer such a prospect in the future.
Notes
*Terms in italic are defined in the glossary on p. 39.
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Barnes, P. Therapeutic strategies for allergic diseases. Nature 402, 31–38 (1999). https://doi.org/10.1038/35037026
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DOI: https://doi.org/10.1038/35037026
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