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Allergology International (2003) 52: 53–63

Review Article Cytokine-directed therapies in asthma

Peter J Barnes National Heart and Lung Institute, Imperial College, London, UK

ABSTRACT Multiple cytokines and have been impli- cated in the pathophysiology of asthma.1 There is now Multiple cytokines play a critical role in orchestrating an intensive search for more specific therapies in and perpetuating inflammation in asthma and several asthma. Inhibitors of cytokines and chemokines figure specific cytokine and inhibitors are now in prominently in these novel therapeutic approaches2 development as future therapy. Anti-interleukin (IL)-5 (Table 1). antibodies markedly reduce peripheral blood and airway eosinophils, but do not appear to be effective in symptomatic asthma. Inhibition of IL-4, despite prom- STRATEGIES FOR INHIBITING CYTOKINES ising early results in asthma, has been discontinued There are several possible approaches to inhibiting and blocking IL-13 may be more effective. Inhibitory specific cytokines. These range from drugs that inhibit cytokines, such as IL-10, interferons and IL-12 are less cytokine synthesis (glucocorticoids, cyclosporine A, promising, because systemic delivery produces side- tacrolimus, rapamycin, mycophenolate, T helper 2 effects. Inhibition of tumor necrosis factor (TNF)-α may (Th2)-selective inhibitors), humanized blocking anti- be useful in severe asthma. Many chemokines are bodies to cytokines or their receptors, soluble receptors involved in the inflammatory response of asthma and to mop up secreted cytokines, small molecule receptor several small molecule inhibitors of chemokine recep- antagonists or drugs that block the signal transduction tors are in development. The CCR3 antagonists (which pathways activated by cytokine receptors. In contrast, block eosinophil chemotaxis) are in clinical develop- there are cytokines that themselves suppress the allergic ment for asthma. Because so many cytokines are inflammatory process and these may have therapeutic involved in asthma, drugs that inhibit the synthesis of potential in asthma.3 multiple cytokines may prove to be more useful; several such classes of drug are now in clinical development and any risk of side-effects with these non-specific INHIBITION OF TH2 CYTOKINES inhibitors may be reduced by the inhaled route. The Th2 lymphocytes play a key role in orchestrating the eosinophilic inflammatory response in asthma, suggest- Key words: chemokines, interleukin-4, interleukin-5, ing that blocking the release or effects of these cytokines interleukin-10, interleukin-12, interleukin-13, tumor may have therapeutic potential. This has been strongly necrosis factor-α. supported by studies in experimental animals, including mice with deletion of the specific Th2 cytokine . INTRODUCTION Anti-interleukin-5 Cytokines play a critical role in the orchestration of chronic inflammation in all diseases, including asthma. Interleukin (IL)-5 plays an essential role in orchestrating the eosinophilic inflammation of asthma.4 In IL-5 knock-out mice, the eosinophilic response to allergen Correspondence: Professor PJ Barnes, Department of Thoracic and the subsequent airway hyperresponsiveness (AHR) Medicine, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK. are markedly suppressed and yet animals have a normal Email: [email protected] survival, validating the strategy to inhibit IL-5. This has Received 18 February 2003. also been achieved using blocking antibodies to IL-5.

54 PJ BARNES

Blocking antibodies to IL-5 inhibit eosinophilic inflam- several weeks and prevents eosinophil recruitment into mation and AHR in animal models of asthma, including the airways after allergen challenge in patients with mild primates.5 This blocking effect may last for up to asthma6 (Fig. 1). However, this treatment has no signifi- 3 months after a single intravenous injection of antibody cant effect on the early or late response to allergen in primates, making treatment of chronic asthma with challenge or on baseline AHR, suggesting that eosin- such a therapy a feasible proposition. Humanized mono- ophils may not be of critical importance for these clonal antibodies to IL-5 have been developed and a responses in humans (Fig. 2). A clinical study in patients single intravenous infusion of one of these antibodies with moderate to severe asthma who had not been (mepolizulab) markedly reduces blood eosinophils for controlled on inhaled corticosteroid therapy confirmed a

Table 1 Cytokine modulators for asthma Anti-cytokines Inhibitory cytokines Chemokine inhibitors Cytokine synthesis inhibitors Anti-IL-5 IL-1 receptor antagonist CCR3 antagonists Corticosteroids Anti-IL-4 IL-10 CCR2 antagonists Immunomodulators Anti-IL-13 IL-12 CCR4 antagonists Phosphodiesterase-4 inhibitors Anti-IL-9 Interferons (IFN-α, IFN-γ) CCR8 antagonists NF-κB inhibitors (IKK2 inhibitors) Anti-IL-25 IL-18 CXCR2 antagonists p38 MAPK inhibitors Anti-IL-1 IL-23 CXCR4 antagonists Anti-TNF-α IL, interleukin; TNF-α, tumor necrosis factor-α; IFN, interferon; NF-κB, nuclear factor-κB; IKK, inhibitor of NF-κB kinase; MAPK, mitogen- activated kinase.

Fig. 1 Effect of a humanized monoclonal antibody against interleukin-5 (mepolizumab) on circulating eosinophils in patients with mild asthma, demonstrating a profound and very prolonged inhibitory effect. (), placebo (n = 8); ( ), 2.5 mg/kg mepolizumab (n = 8); (), 10 mg/kg mepolizumab (n = 8). B/L, baseline; D, day; Wk, week. Adapted from Leckie et al.6

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Fig. 2 Effect of a humanized monoclonal antibody against interleukin (IL)-5 (mepomizulab) on (a) the early and late response to allergen (–––, IL-5 antibody; -----, placebo) and (b) airway hyperresponsiveness (, placebo; , IL-5 antibody). FEV1, forced expiratory volume in 1 s. Adapted from Leckie et al.6

profound reduction in circulating eosinophils, but no α-chain and through large-scale throughput screening. significant improvement in either asthma symptoms or One such molecule, YM-90709, appears to be a rela- lung function.7 In both these studies, it would be tively selective inhibitor of IL-5-receptors.10 However, the expected that high doses of corticosteroids would lack of clinical benefit of anti-IL-5 antibodies has made improve these functional parameters.6,7 These surprising this a less attractive approach. It is possible that eosin- results question the critical role of eosinophils in asthma ophils are associated with more chronic aspects of and indicate that other strategies aimed at inhibiting asthma, such as airway remodeling, and, in mice, a eosinophilic inflammation may not be effective. More blocking anti-IL-5 antibody prevents the increased colla- recently, a biopsy study has demonstrated that anti-IL-5 gen deposition in airways associated with repeated aller- antibody, while profoundly reducing eosinophils in the gen exposure. circulation (by over 95%), is less effective at reducing eosinophils in bronchial biopsies (by approximately Anti-IL-4 50%), which may explain why this treatment is not clinically effective.8 Nevertheless, this suggests that Interleukin-4 is critical for the synthesis of IgE by blocking IL-5 is not likely to be a useful approach to B lymphocytes and is also involved in eosinophil recruit- asthma therapy. ment to the airways.11 A unique function of IL-4 is Somewhat similar findings have been reported previ- to promote differentiation of Th2 cells and, there- ously in some studies in mice, where anti-IL-5 antibodies fore, it acts at a proximal and critical site in the allergic reduced eosinophilic responses to allergen, but not AHR, response, making IL-4 an attractive target for inhibition. whereas AHR was reduced by anti-CD4 antibody, which Interleukin-4 blocking antibodies inhibit allergen- depletes Th cells9 and suggests that T cell-derived induced AHR, goblet cell metaplasia and pulmonary cytokines other than IL-5 must be playing a more impor- eosinophilia in a murine model.11 Therefore, inhibition of tant role in AHR. IL-4 may be effective in inhibiting allergic diseases and Non-peptidic IL-5 receptor antagonists would be an soluble humanized IL-4 receptors (sIL-4R) have been alternative strategy and there is a search for such com- tested in clinical trials. A single nebulized dose of sIL-4R pounds using molecular modeling of the IL-5 receptor prevents the fall in lung function induced by withdrawal of

56 PJ BARNES inhaled corticosteroids in patients with moderately severe where concentrations of IL-13 are much higher than asthma.12 Subsequent studies have demonstrated that those of IL-4. Humanized IL-13Rα2 is now in clinical weekly nebulization of sIL-4R improves asthma control development as a therapeutic approach for asthma. over a 12 week period.13 However, subsequent studies in patients with milder asthma proved disappointing Anti-IL-9 and this treatment has now been withdrawn. Another Interleukin-9 is a Th2 cytokine that may enhance approach is blockade of IL-4 receptors with a mutated Th2-driven inflammation and amplify mast cell mediator form of IL-4 (BAY 36-1677), which binds to and blocks release and IgE production.18 Interleukin-9 may also IL-4Rα and IL-13Rα1, thus blocking both IL-4 and enhance mucus hypersecretion. Interleukin-9 and its IL-13.14 This treatment has also been withdrawn. receptors show an increased expression in asthmatic Interleukin-4 and the closely related cytokine IL-13 airways.19 A blocking antibody to IL-9 inhibits airway signal through a shared surface receptor, namely IL-4Rα, inflammation and AHR in a murine model of asthma.20 which activates a specific transcription factor, signal Strategies to block IL-9, including blocking humanized transducers and activators of transcription (STAT)-6.15 antibodies, are now in development.21 Deletion of the STAT-6 gene has a similar effect to IL-4 gene knock-out. This has led to a search for inhibitors of Anti-IL-25 STAT-6 and, although peptide inhibitors that interfere with the interaction between STAT-6 and Janus kinase Interleukin-25 is a newly described cytokine that stimu- (JAK) linked to IL-4Rα have been discovered, it will be lates the release of Th2 cytokines IL4, IL-5 and IL-13, difficult to deliver these intracellularly. An endogenous suggesting that it may play a role in allergic inflam- inhibitor of STAT, suppressor of cytokine signaling mation.22 It is released from mast cells via an IgE- (SOCS-1), is a potent inhibitor of IL-4 signaling pathways dependent mechanism and is, therefore, a possible and offers a new therapeutic target.15 target for inhibition in the treatment of asthma.23

Anti-IL-13 INHIBITION OF PRO-INFLAMMATORY CYTOKINES There is increasing evidence that IL-13 in mice mimics many of the features of asthma, including AHR, mucus Pro-inflammatory cytokines, particularly IL-1β and tumor hypersecretion and airway fibrosis, independently of necrosis factor (TNF)-α, may amplify the inflammatory eosinophilic inflammation.16 It potently induces the response in asthma and may be linked to disease secretion of eotaxin from airway epithelial cells and severity. This suggests that blocking IL-1β or TNF-α may transforms airway epithelium into a secretory phenotype. have beneficial effects, particularly in severe airway Knocking out the IL-13, but not the IL-4, gene in mice disease. prevents the development of AHR after allergen, despite a vigorous eosinophilic response, and the increase in Anti-IL-1 AHR induced by IL-13 is only seen when the expression Interleukin-1 expression is increased in asthmatic 16 of STAT-6 is lost in airway epithelial cells. Interleukin- airways24 and activates many inflammatory genes that 13 signals through the IL-4Rα, but may also activate are expressed in asthma. There are no small molecule different intracellular pathways via activation of IL- inhibitors of IL-1, but a naturally occurring cytokine, the 15 13Rα1, so that it may be an important target for the IL-1 receptor antagonist (IL-1ra), binds to IL-1 receptors development of new therapies. A second specific IL-13 to block the effects of IL-1. In experimental animals receptor, IL-13Rα2, exists in soluble form and has a high IL-1ra reduces AHR induced by allergen. However, affinity for IL-13, thus acting as a decoy receptor for human recombinant IL-1ra does not appear to be secreted IL-13. Soluble IL-13Rα2 is effective in blocking effective in the treatment of asthma.25 the actions of IL-13, including IgE generation, pulmo- nary eosinophilia and AHR in mice.17 In the murine Anti-TNF model, IL-13Rα2 is more effective than IL-4-blocking antibodies,16 highlighting the potential importance of Tumor necrosis factor-α is expressed in asthmatic IL-13 as a mediator of allergic inflammation. Blocking airways and may play a key role in amplifying asthmatic IL-13 may be more important in established asthma, inflammation, through the activation of nuclear factor

CYTOKINE-DIRECTED THERAPIES IN ASTHMA 57

(NF)-κB, activating protein (AP)-1 and other transcription tolerated, there are hematological side-effects. In the factors.26 In rheumatoid arthritis and inflammatory bowel future, drugs that activate the unique signal transduction disease, blocking humanized monoclonal antibodies to pathways activated by the IL-10 receptor or drugs that TNF-α (infliximab) and soluble TNF receptors (etaner- increase endogenous production of IL-10 may be devel- cept) have produced remarkable clinical responses, oped. In mice, drugs that elevate cAMP increase IL-10 even in patients who are relatively unresponsive to production, but this does not appear to be the case in steroids. Such TNF inhibitors are a logical approach human cells.35 to asthma therapy, particularly in patients with severe disease, and clinical trials are now underway. Interferons Because of the problems associated with antibody based therapies that have to be given by injection, there Interferon (IFN)-γ inhibits Th2 cells and should, there- is a search for small molecule inhibitors of TNF. Tumor fore, reduce atopic inflammation. In sensitized animals, necrosis factor-α-converting enzyme (TACE) is a matrix nebulized IFN-γ inhibits eosinophilic inflammation induced metalloproteinase-related enzyme critical for the release by allergen exposure and adenovirus-mediated gene of TNF from the cell surface. Small molecule TACE inhib- transfer of IFN-γ inhibits allergic inflammation in mice.36 itors are in development as oral TNF inhibitors.27 However, administration of IFN-γ by nebulization to asthmatic patients did not significantly reduce eosi- nophilic inflammation, possibly due to the difficulty in ANTI-INFLAMMATORY CYTOKINES obtaining a high enough concentration locally in the Some cytokines have anti-inflammatory effects in inflam- airways.37 Interestingly, allergen immunotherapy increases mation and, therefore, have therapeutic potential.3 IFN-γ production by circulating T cells in patients with Whereas it may not be feasible or cost-effective to clinical benefit38 and increases the numbers of IFN-γ- administer these as long-term therapy, it may be expressing cells in nasal biopsies of patients with allergic possible to develop drugs in the future that increase the rhinitis.39 A preliminary report suggests that IFN-α may release of these endogenous cytokines or activate their be useful in the treatment of patients with severe asthma receptors and specific signal transduction pathways. who have reduced responsiveness to corticosteroids.40

Interleukin-10 Interleukin-12 Interleukin-10 is a potent anti-inflammatory cytokine that Interleukin-12 is the endogenous regulator of Th1 cell inhibits the synthesis of many inflammatory proteins, development and determines the balance between Th1 including cytokines (TNF-α, granulocyte–macrophage and Th2 cells.41 Interleukin-12 administration to rats colony stimulating factor (GM-CSF), IL-5, chemokines) inhibits allergen-induced inflammation and inhibits and inflammatory enzymes (inducible nitric oxide syn- sensitization to allergens. Interleukin-12 releases IFN-γ, thase) that are overexpressed in asthma.28 Indeed, there but has additional effects on T cell differentiation. may be a defect in IL-10 transcription and secretion from Interleukin-12 levels released from whole blood cells are macrophages in asthma, suggesting that IL-10 may be lower in asthmatic patients, indicating a possible reduc- defective in atopic diseases.29,30 In sensitized animals, tion in IL-12 secretion.42 IL-10 is effective in suppressing the inflammatory Recombinant human IL-12 has been administered to response to allergen31 and CD4+ cells engineered to humans and has several toxic effects that are diminished secrete IL-10 suppress airway inflammation in a murine by slow escalation of the dose.43 In patients with mild model of asthma.32 Specific allergen immunotherapy asthma, weekly infusions of human recombinant IL-12 in results in increased production of IL-10 by Th cells and escalating doses over 4 weeks caused a progressive fall this may contribute to the beneficial effects of immuno- in circulating eosinophils and a reduction in the normal therapy.33 rise in circulating eosinophils after allergen challenge44 Recombinant human IL-10 has proved to be effective (Fig. 3). There was a concomitant reduction in eosin- in controlling inflammatory bowel disease and psoriasis, ophils in induced sputum. However, there was no reduc- where similar cytokines are expressed, and may be given tion in either the early or late response to inhaled allergen as a weekly injection.34 Although IL-10 is reasonably well challenge or any reduction in AHR (as with anti-IL-5 58 PJ BARNES

Fig. 3 Effect of interleukin (IL)-12 on peripheral blood eosinophils in patients with mild asthma. (), placebo (n = 20); ( ), IL-12 (n = 19) IL-12 was given in progressively increasing doses as an intravenous injec- tion. Adapted from Bryan et al.44 therapy). Furthermore, most patients suffered from different surface receptors.50 Chemokine receptors malaise and one of the 12 subjects had an episode of belong to the seven transmembrane receptor super- cardiac arrhythmia. This suggests that IL-12 is not a suit- family of G-protein-coupled receptors and this makes it able treatment for asthma. In mice, administration of an possible to find small molecule inhibitors, which has not IL-12–allergen fusion protein results in the development yet been possible for classic cytokine receptors.51 Some of a specific Th1 response to the allergen, with increased chemokines appear to be selective for single chemok- production of an allergen-specific IgG2, rather than the ines, whereas others are promiscuous and mediate the normal Th2 response with IgE formation.45 This indicates effects of several related chemokines (Fig. 4). Chemok- the possibility of using local IL-12 together with specific ines appear to act in sequence in determining the final allergens to provide a more specific immunotherapy, inflammatory response and so inhibitors may be more or which may even be curative if applied early in the course less effective depending on the kinetics of the response. of the atopic disease. CCR3 inhibitors Interleukin-18 and IL-23 Several chemokines, including eotaxin, eotaxin-2, Interleukin-18 was originally described as IFN-γ- eotaxin-3, RANTES and macrophage chemoattractant releasing factor, but has a different mechanism of action protein (MCP)-4, activate a common receptor on eosi- 46 to IL-12. Interleukin-12 and IL-18 appear to have a nophils designated CCR3.52 A neutralizing antibody synergistic effect on inducing IFN-γ release and for against eotaxin reduces eosinophil recruitment into the 47 inhibiting IL-4-dependent IgE production and AHR, but lung after allergen and the associated AHR in mice.53 no clinical studies have been reported so far. There is increased expression of eotaxin, eotaxin-2, Interleukin-23 is structurally related to IL-12 and MCP-3, MCP-4 and CCR3 in the airways of asthmatic shares some of its biological effects, so should have a patients and this is correlated with increased AHR.54 48 protective function in asthma. Its clinical potential has Several small molecule inhibitors of CCR3, including not yet been explored. UCB35625, SB-297006 and SB-328437, are effective in inhibiting eosinophil recruitment in allergen models of asthma55,56 and drugs in this class are currently under- CHEMOKINE INHIBITORS going clinical trials in asthma. Although it was thought Many chemokines are involved in the recruitment of that CCR3 were restricted to eosinophils, there is some inflammatory cells in asthma.49 Over 50 different chem- evidence for their expression on Th2 cells and mast cells, okines are now recognized and they activate up to 20 so that these inhibitors may have a more widespread CYTOKINE-DIRECTED THERAPIES IN ASTHMA 59

Fig. 4 antagonists in asthma. Several chemokines are likely to be involved in the pathophysiology of asthma. There are three major chemokine receptor targets in asthma: CCR3, which is most advanced in terms of small molecule inhibitor development, but also CCR2, CCR4/8, and CXCR4, for which small molecule inhibitors are now in development. MCP, macro- phage chemoattractant protein; MDC, monocyte-derived chemokine; TARC, thymus and activation-dependent chemokine.

effect than on eosinophils alone, making them poten- A neutralizing antibody to MCP-1 blocks the development tially more valuable in asthma treatment. of AHR in response to allergen.58 Macrophage chemo- RANTES, which shows increased expression in asth- attractant protein-1 levels are increased in broncho- matic airways, also activates CCR3, but also has effects alveolar lavage fluid of patients with asthma.59 This has on CCR1 and CCR5, which may play a role in T cell led to a search for small molecule inhibitors of CCR2. recruitment. Modification of the N-terminal of RANTES (met-RANTES) has a blocking effect on RANTES by inhib- Other CCR inhibitors iting these receptors.57 CCR4 and CCR8 are selectively expressed on Th2 cells and are activated by the chemokines monocyte-derived CCR2 inhibitors chemokine (MDC) and thymus and activation-dependent Macrophage chemoattractant protein-1 activates CCR2 chemokine (TARC).60 Therefore, inhibitors of CCR4 and on monocytes and T lymphocytes. Blocking MCP-1 with CCR8 may inhibit the recruitment of Th2 cells and, thus, neutralizing antibodies reduces recruitment of both T persistent eosinophilic inflammation in the airways. cells and eosinophils in a murine model of ovalbumin- CCR8 gene deletion does not have any effects on induced airway inflammation, with a marked reduction allergic inflammation in mice, suggesting that this recep- in AHR.53 Macrophage chemoattractant protein-1 also tor may not be an effective target.61 In addition, CXC recruits and activates mast cells, an effect that is medi- receptor (CXCR) 4 is selectively expressed on Th2 cells ated via CCR2. Macrophage chemoattractant protein-1 and a small molecule inhibitor (AMD3100) inhibits instilled into the airways induces marked and prolonged allergen-induced inflammation in a murine model of AHR in mice, associated with mast cell degranulation. asthma.62 60 PJ BARNES

CCR7 plays a role in the migration of dendritic cells to when given orally. More selective Th2 selective drugs regional lymph nodes and, therefore, blocking this recep- may be safer for the treatment of asthma in the future. tor may suppress antigen presentation.63 An inhibitor of Th2 cytokines, namely suplatast tosilate,68 provides clinical benefit in asthma.69 CXCR inhibitors Phosphodiesterase 4 inhibitors CXC receptors mediate the effects of CXC chemokines, which act predominantly on neutrophils and monocytes. Phosphodiesterase (PDE) 4 inhibitors inhibit the release Neutrophils are not a prominent feature of inflammation of cytokines and chemokines from inflammatory cells via in patients with chronic asthma and inflammation is an increase in intracellular cAMP.70 Their clinical use is dominated by eosinophils. However, there is evidence limited in asthma by side-effects, such as nausea. In for increased neutrophils in biopsies and induced contrast with corticosteroids, PDE4 inhibitors have a sputum of patients with severe asthma who are treated potent inhibitory effect on neutrophils, indicating that with high doses of inhaled or oral corticosteroids, and they may be useful anti-inflammatory treatments in more the levels of IL-8 are increased.64,65 It is not certain severe asthma. whether this neutrophilic inflammation contributes to pathophysiology, but it is possible that CXCR2 inhibitors Nuclear factor-κB inhibitors may have a therapeutic role in severe asthma. Nuclear factor-κB regulates the expression of many cytokines and chemokines involved in asthma.71 There OTHER APPROACHES TO CYTOKINE INHIBITION are several possible approaches to inhibition of NF-κB, including gene transfer of the inhibitor of NF-κB (IκB), Although there have been several attempts to block inhibitors of IκB kinase-2 (IKK2), NF-κB-inducing kinase specific cytokines, this may not be adequate to block (NIK) and IκB ligase, which regulate the activity chronic inflammation in asthma, because so many of NF-κB, and the development of drugs that inhibit the cytokines are involved and there is considerable redun- degradation of IκB.72 One concern about this approach dancy of effects. This has suggested that the develop- is that effective inhibitors of NF-κB may result in immune ment of drugs that have a more general effect on suppression and impair host defences, because knock- cytokine synthesis may be more successful. However, out mice that lack NF-κB proteins succumb to septi- these drugs also affect other inflammatory processes, so cemia.72 However, there are alternative pathways of their beneficial effects cannot necessarily be ascribed to NF-κB activation that may be more important in inflam- inhibition of cytokine synthesis alone. matory disease. Several small molecule inhibitors of IKK2 are now in development. Corticosteroids Corticosteroids are, by far, the most effective treatments P38 mitogen-activated protein kinase for asthma and part of their efficacy is due to inhibition inhibitors of inflammatory cytokine expression. This is mediated via an effect on glucocorticoid receptors to reverse the Mitogen-activated protein kinases (MAPK) play a key acetylation of core histones, which is linked to increased role in chronic inflammation and several complex expression of inflammatory genes, such as those encod- enzyme cascades have now been defined. One of these, ing cytokines and chemokines.66 the p38 MAPK pathway, is involved in the expression of inflammatory cytokines and chemokines.73 Small mole- cule inhibitors of p38 MAPK, such as SB 203580, Immunomodulatory drugs SB 239063 and RWJ 67657, also known as cytokine Cyclosporine A, tacrolimus and rapamycin inhibit the synthesis anti-inflammatory drugs (CSAIDS), have now transcription factor nuclear factor of activated T cells been developed and these drugs have a broad range (NF-AT), which regulates the secretion of IL-2, IL-4, IL-5, of anti-inflammatory effects.74 There may be issues of IL-13 and GM-CSF by T lymphocytes.67 Although it has safety, because p38 MAPK are involved in host defence. some reported beneficial steroid-sparing effects in asthma, However, it is possible that the inhaled route of delivery the toxicity of cyclosporine A limits its usefulness, at least may reduce the risk of side-effects. CYTOKINE-DIRECTED THERAPIES IN ASTHMA 61

CONCLUSIONS only partially depletes numbers in asthmatic airways. Am. J. Respir. Crit. Care Med. 2003; 167: 199–204. There are several specific cytokine and chemokine 9 Hogan SP, Matthaei KI, Young JM, Koskinen A, inhibitors now in development for the treatment of Young IG, Foster PS. A novel T cell-regulated mechanism asthma. Inhibition of IL-4 with sIL-4R in asthma showed modulating allergen-induced airways hyperreactivity in promising early results, but this was not confirmed in BALB/c mice independently of IL-4 and IL-5. J. Immunol. 1998; 161: 1501–9. larger trials and IL-13 inhibition is more promising. Anti- 10 Morokata T, Ida K, Yamada T. Characterization of YM- IL-5 antibody is very effective at inhibiting peripheral 90709 as a novel antagonist which inhibits the binding of blood and airway eosinophils, but does not appear to interleukin-5 to interleukin-5 receptor. Int. Immunophar- be effective in symptomatic asthma. Inhibitory cytokines, macol. 2002; 2: 1693–702. such as IL-10, interferons and IL-12, are less promising, 11 Steinke JW, Borish L. Interleukin-4: Its role in the patho- because systemic delivery produces side-effects and it genesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir. Res. may be necessary to develop inhaled delivery systems. 2001; 2: 66–70. Inhibition of TNF-α may be useful in the treatment of 12 Borish LC, Nelson HS, Lanz MJ et al. Interleukin-4 recep- severe asthma. Many chemokines are involved in the tor in moderate atopic asthma. A phase I/II randomized, inflammatory response of asthma and small molecule placebo-controlled trial. Am. J. Respir. Crit. Care Med. inhibitors of chemokine receptors are now in develop- 1999; 160: 1816–23. 13 Borish LC, Nelson HS, Corren J et al. Efficacy of soluble ment. The CCR3 antagonists are now being developed IL-4 receptor for the treatment of adults with asthma. for the treatment of asthma. Because so many cytokines J. Allergy Clin. Immunol. 2001; 107: 963–70. are involved in these complex diseases, drugs that inhibit 14 Shanafelt AB, Forte CP, Kasper JJ et al. An immune cell- the synthesis of multiple cytokines may be more success- selective interleukin 4 agonist. Proc. Natl Acad. Sci. USA ful. Several such classes of drug are now in clinical 1998; 95: 9454–8. development, including PDE4, p38 MAPK and IKK2 15 Jiang H, Harris MB, Rothman P. IL-4/IL-13 signaling beyond JAK/STAT. J. Allergy Clin. Immunol. 2000; 105: inhibitors. The risk of side-effects in these non-specific 1063–70. inhibitors may be reduced by an inhaled route of 16 Wills-Karp M, Chiaramonte M. Interleukin-13 in asthma. delivery. Curr. Opin. Pulmon. Med. 2003; 9: 21–7. 17 Wills-Karp M, Luyimbazi J, Xu X et al. Interleukin-13: Central mediator of allergic asthma. 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