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(Chest. 2006;130:244-250.)
© 2006 American College of Chest Physicians

Cytokines or Their Antagonists for the Treatment of Asthma*

Paul M. O’Byrne, MB, FCCP

* From McMaster University, Hamilton, ON, Canada.

Correspondence to: Paul M. O’Byrne, MB, FCCP, Department of Medicine, McMaster University Medical Center, 1200 Main St West, Hamilton, ON, L8N 3Z5 Canada; e-mail: obyrnep{at}mcmaster.ca

Abstract

T helper (Th) type 2 cytokines, particularly interleukin (IL)-4, IL-5, and IL-13, may be important in the development of allergic asthma. Humanized monoclonal antibodies (MoAbs) against IL-5 and a recombinant human soluble IL-4 receptor (sIL-4R) have been developed as possible treatments. These approaches have not yet proven to be successful in patients with persistent asthma. This may suggest that neither IL-4 nor IL-5 is important in asthma pathogenesis. There is, however, insufficient information about the efficacy of sIL-4R and the anti-IL-5 MoAbs in asthma to draw any firm conclusions about the importance of these Th2 cytokines. Also, the administration of the potentially antiinflammatory cytokines IL-12 and interferon-{gamma} has not shown benefit in asthmatic patients. By contrast, the treatment of severe oral steroid-dependent asthma with soluble tumor necrosis factor-{alpha} receptor has demonstrated very promising results, suggesting that this cytokine plays an important role in the persistence of severe asthma.

Key Words: airway hyperresponsiveness • asthma • interferon-{gamma} • interleukin-4 • interleukin-5 • interleukin-13 • tumor necrosis factor-{alpha}

Over the past 20 years, there has been an enormous increase in the understanding of the pivotal role of cytokines in the initiation and persistence of allergic inflammation in asthma, and in causing the airway structural changes and associated physiologic abnormalities that characterize this disease. This research originated from the important findings of Parish and Luckhurst,1 who reported that T cells from airways, but not from peripheral blood, that were obtained from asthmatic subjects released mediators that promoted eosinophil chemokinesis and chemotaxis, but not neutrophil chemokinesis and chemotaxis. Subsequently, a seminal study by Mosmann and colleagues2 identified subsets of T-helper (Th) cells (designated Th1 and Th2) in mice by identifying a different array of cytokines that the cells were producing and suggested that these subsets played different roles in the induction of allergic inflammation. The cytokines produced by Th2 cells (which subsequently came to be known as Th2 cytokines) were interleukin (IL)-3, IL-4, IL-5, and IL-13, the so-called Th1 cytokines were IL-10 and interferon (IFN)-{gamma}, while other cytokines, such as IL-12 and granulocyte-macrophage colony-stimulating factor, were produced by both subsets (Fig 1 ). More recently, it has become clear that these designations, which are possible to make using mouse T cells, are much more complicated in humans. This information, however, had important implications for the pathogenesis of allergic asthma, as the IL-4 levels that are necessary for IgE isotype switching,3 for the up-regulation of vascular cell adhesion molecule-1,4 and for Th cell commitment are increased in the airways of allergic asthmatic subjects5 and might also be involved in causing allergen-induced airway eosinophilia.6 In addition, the biological activity of IL-5 is very specifically focused on the development, differentiation, recruitment, activation, and survival of eosinophils.7 Allergen inhalation increases the production of IL-5 in the airways as measured in airway mucosal T cells8 and induced sputum.9 Allergen inhalation also increases the number of peripheral blood eosinophils and lymphocytes containing intracellular IL-510 and increases the proportion of bone marrow CD34+ progenitor cells expressing the {alpha} subunit of the IL-5 receptor,11 suggesting that the responsiveness of the bone marrow to IL-5 is a determinant of the magnitude of the eosinophilic responses to inhaled allergens. In addition, IL-13, which stimulates the same receptor as IL-4, is necessary for allergen-induced airway hyperresponsiveness (AHR)12 in mouse models of allergic airway responses. Subsequently, Th2 cells were identified in the airway mucosa of allergic asthmatic subjects.13 This information resulted in the hypothesis that the up-regulation of Th2 cells, with an associated down-regulation of Th1 cells, is responsible for the development of allergic asthma (Fig 1).


Figure 1
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  		Figure 1. A schematic representation of the induction of Th1 and Th2 responses and their associated cytokines by viruses and allergen. The Th2 cytokines IL-4, IL-5, and IL-13 play important roles in IgE production, eosinophil production, and in survival and increases in AHR, respectively.

 
Another cytokine that may play a role in the initiation or persistence of inflammation in asthma is tumor necrosis factor (TNF)-{alpha}, which is important in the persistence of inflammation in other inflammatory diseases such as rheumatoid arthritis14 and inflammatory bowel disease.15 However, not all cytokines are proinflammatory. For example, animal models of allergic asthma IL-1016 and IFN-{gamma}17 have been demonstrated to attenuate or prevent allergen-induced airway inflammation.

Cytokines Antagonists

An important implication of the research that supported a central role for IL-4, IL-5, and IL-13, or for other potentially important cytokines, such as TNF-{alpha} and transforming growth factor (TGF)-ß,18 in the development of allergic airway responses is that blocking their action may be a useful therapeutic approach in asthma patients. Other possibilities considered were to treat asthmatic patients with cytokines that may down-regulate allergic inflammation, such as IL-10, IL-12, or IFN-{gamma}. Thus, it was necessary to develop antagonists for some cytokines or to administer others directly into asthmatic airways. Efforts to do this resulted in the development of humanized monoclonal antibodies (hMoAbs) that were directed against IL-5, of a recombinant human soluble IL-4 receptor (IL-4R) as an IL-4 antagonist, and a soluble TNF-{alpha} receptor-IgG1Fc fusion protein as an anti-TNF-{alpha}. In addition, IL-12 and IFN-{gamma} have been administered to asthmatic patients to evaluate their efficacy. A summary of the results of the trials using cytokine antagonists is provided in Table 1 .


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  		Table 1. Summary of Human Studies Examining the Efficacy of Cytokine Antagonists in the Treatment of Asthma*

 
Soluble IL-4R

Two studies have been published on the efficacy of soluble IL-4R (sIL-4R), administered by nebulization, as treatment in asthmatic patients. Nebulized sIL-4R has a serum half-life of about 1 week and has been studied in patients with moderate-to-severe asthma. In one study,19 two doses of IL-4R (500 or 1,500 µg) were compared to placebo in patients in whom therapy with inhaled corticosteroids had been discontinued. The study demonstrated that the sIL-4R (particularly the higher dose) was significantly better than placebo for most indexes of asthma control, which deteriorated with inhaled corticosteroid therapy withdrawal in patients in the placebo arm of the study. In another, slightly larger study,20 62 patients with moderate asthma requiring therapy with inhaled corticosteroids were studied. Once again, the highest dose of sIL-4R studied (3,000 µg) prevented both a decline in FEV1 and an increase in asthma symptoms, which occurred in the placebo group, when therapy with inhaled corticosteroids was withdrawn. Concerns have been raised about the poor patient retention in these studies, and there have been, as yet, no published reports confirming these promising results in patients with persistent asthma in larger clinical trials.

Anti-IL-5 hMoAbs

The most extensively evaluated approach using anticytokines has been made using anti-IL-5 hMoAb. The first such study21 examined the effects of treatment with an anti-IL-5 hMoAb (mepolizumab) on allergen-induced airway responses and inflammation. In this study, 24 subjects with mild allergic asthma were treated with one of two doses of anti-IL-5 (2.5 or 10 mg/kg given as a single IV infusion) or placebo. The effects of treatment on the levels of blood and airway eosinophils (measured in induced sputum) were examined, as were the effects on the responses to an inhaled allergen challenge administered at 1 week and 4 weeks after the treatment. The study demonstrated that treatment with the anti-IL-5 hMoAb significantly reduced the number of blood eosinophils and sputum eosinophils for at least 4 weeks. This was important information, as it confirmed a central role for IL-5 in the development of blood and airway eosinophilia following allergen inhalation, but the hMoAb did not have any significant effect on allergen-induced late responses or on histamine airway responsiveness measured either before or after inhaled allergen. However, the investigators could not demonstrate any effect of allergen inhalation on histamine airway responsiveness on two of the three occasions when this was measured at baseline in the treatment arms. The inability to demonstrate significant changes in allergen-induced AHR makes the interpretation of the effects of active treatment on allergen-induced AHR impossible. Therefore, this study cannot be used to support or refute an important role for eosinophils in causing allergen-induced changes in AHR.

Another reason why the anti-IL-5 hMoAb may not have been fully effective in this clinical model of asthma was identified by Flood-Page et al.22 These investigators demonstrated that, while treatment with mepolizumab reduced the number of circulating and sputum eosinophils markedly, it reduced the number of airway tissue eosinophils by only 55% and the number of bone marrow eosinophils by 52% over 20 weeks of treatment, and did not normalize eosinophil numbers in either compartment. This suggests that there is redundancy in this (as in many) biological system and that other cytokines, such as IL-3 have a role in eosinophilopoesis,23 while others,24 such as granulocyte-macrophage colony-stimulating factor, are important in eosinophil survival and persistence in tissues. Another study25 has demonstrated that treatment with mepolizumab reduced the levels of extracellular matrix proteins tenascin, lumican, and procollagen III in the bronchial mucosal reticular basement membrane in airway biopsy specimens of asthmatic subjects, and was associated with a significant reduction in the number of airway eosinophils expressing messenger RNA for TGF-ß and with decreases in the concentration of TGF-ß in BAL fluid, implying the existence of a role for eosinophil release of TGF-ß in airway remodeling in patients with allergic asthma.

Mepolizumab has also been evaluated in patients with persistent asthma in a study that, as yet, has been reported only in abstract form. The study included > 300 patients with poorly controlled asthma, and treatment with mepolizumab did not improve any indexes of asthma control; however, the higher dose of mepolizumab did significantly reduce the risk of the development of a severe asthma exacerbation by about 50%. A second anti-IL-5 hMoAb (SCH55700) has also been evaluated26 in a group of patients with severe asthma who were not responding to conventional asthma treatment, including high doses of inhaled or oral corticosteroids. The study demonstrated that the antibody reduced the number of circulating eosinophils and provided a small, but significant, improvement in FEV1 after treatment with the lower dose, but no other clinical improvement was seen.

Soluble TNF Receptor

Two recently published studies have evaluated a possible role for TNF-{alpha} in the pathogenesis of severe asthma. The first study27 demonstrated that TNF-{alpha} levels in BAL fluid, TNF-{alpha} gene expression, and immunoreactive mast cell numbers were increased in patients with severe oral corticosteroid-dependent asthma. A subsequent open-label study27 was then undertaken in 17 of these patients with the soluble TNF-{alpha} receptor-IgG1Fc fusion protein etanercept, 25 mg administered twice weekly over 12 weeks of treatment, which improved asthma symptoms, lung function (a 0.24-L improvement in FEV1 and a 0.33-L improvement in FVC), and AHR in these patients with severe asthma.

These impressive, albeit uncontrolled, results have been confirmed by a second study28 using etanercept (25 mg twice weekly over 10 weeks of treatment) in 10 patients with refractory asthma, but this time in a placebo-controlled, double-blind, crossover study. Once again, the study demonstrated that, compared with patients with mild-to-moderate asthma and control subjects, patients with refractory asthma had increased expression of membrane-bound TNF-{alpha}, TNF-{alpha} receptor 1, and TNF-{alpha}-converting enzyme in peripheral blood monocytes. Therapy with etanercept was associated with a significant increase in methacholine AHR (mean improvement, 3.5 doubling concentration), an improvement in the asthma-related quality-of-life score, and a 0.32-L increase in post-bronchodilator treatment FEV1.

Other Cytokine Antagonists Under Development
Several other cytokines have been identified as possible targets for intervention in asthma patients. These include IL-9, which is produced by T cells, eosinophils, neutrophils, and mast cells, and which has important roles in mast cell development29 and accumulation into tissues,30 as well as mucous gland hyperplasia,30 airway eosinophilia,31 and AHR3031 in mice. Similarly, the Th2 cytokine IL-13 has a critical role in mediating allergen-induced AHR and mucous metaplasia in mice, and there have been associations described between airway IL-13 levels or abnormalities in the IL-13 gene with asthma.32 Another potential candidate is the pleotropic cytokine IL-1, which has been shown to play a role in allergic airway responses in rodent models.33 IL-1 receptor type I-deficient mice have demonstrated reduced airway eosinophilia and reduced AHR in ovalbumin-sensitized mice.34 As yet, however, there have been no reports of clinical trials with hMoAb or other approaches directed against these cytokines; although these studies are anticipated with great interest.

Cytokines to Treat Asthma
Two cytokines with the potential for attenuating or preventing the development of allergic inflammation have been evaluated in human subjects. These are IL-12 and IFN-{gamma}. Bryan et al35 evaluated the benefits of subcutaneous (SC) recombinant human IL-12 in a double-blind, randomized, study, in which patients with mild allergic asthma were given weekly injections of SC recombinant human IL-12 at increasing doses of 0.1, 0.25, and 0.5 µg/kg or placebo. The responses to the inhaled allergen were measured before the first injection and after the final injection. IL-12 treatment resulted in a significant decrease in counts of blood eosinophils and sputum eosinophils 24 h after the allergen challenge. IL-12 also resulted in a nonsignificant trend toward improvement in allergen-induced AHR but had no significant effect on the late asthmatic response. However, after the administration of IL-12, two subjects had to withdraw from the study with cardiac arrhythmias.

IFN-{gamma} has also been evaluated as a possible treatment for severe steroid-dependent asthma. This was supported by evidence that the treatment of patients with severe atopic dermatitis with recombinant IFN-{gamma} resulted in clinical improvement as well as a reduction in the number of circulating eosinophils.36 Patients were treated with daily SC injections of IFN-{gamma} or placebo, 0.05 mg/m2, for 90 days.37 While total circulating eosinophil counts decreased after treatment with IFN-{gamma}, the oral prednisone dose, FEV1, and peak expiratory flow rates did not differ between the two groups.

Conclusions

Treatment approaches directed against IL-4 or IL-5 have not been reported to have striking success in patients with persistent asthma. The reasons for this likely include the possibility that neither IL-4 nor IL-5 is important in the pathogenesis of asthma. This is plausible, because asthmatic patients, even those who are atopic, have triggers other than allergens causing symptoms, such as viruses and atmospheric pollutants. Also, eosinophils do not appear to be required for all of the clinical manifestations of asthma. Studies of the airway inflammatory responses during asthma exacerbations have shown that only 50 to 60% of exacerbations are associated with an increase in the number of airway eosinophils.38 In addition, the pathoimmunology of asthma is complex with many different cytokines, chemokines, and lipid mediators involved in different aspects of the disease, and with redundancy in the biological activities of these mediators. For example, IL-13 is also important in IgE production, and many mediators have been implicated in eosinophil migration. Therefore, it is unlikely that targeting a single cytokine will be beneficial in all patients. It is worth noting, however, that studies that have reported using sIL-4R and mepolizumab have both prevented asthma deterioration at the time of inhaled corticosteroid therapy withdrawal and have reduced the number of asthma exacerbations, events that have been associated in some patients with increases in the number of airway eosinophils. Finally, it is probable that not all asthma patients will respond to these treatment interventions. Inhaled and/or oral corticosteroids are very effective, in many patients, in reducing or eliminating airway eosinophilia, and this is associated with improvements in asthma control. The patients studied in the anti-IL-5 hMoAb trials, which have evaluated efficacy in patients with persistent asthma, have been those with moderate-to-severe asthma who are already using a large amount of antiasthma medication. It is not obvious from these reports whether these patients had airway eosinophilia that was associated with poor asthma control. If not, it is difficult to envisage how the hMoAb would be expected to improve asthma control.

If these observations with anti-IL-5 hMoAb or sIL-4R are supported in future studies, would this be enough evidence to conclude that the Th2 cytokines are not important in the pathogenesis of asthma? Not necessarily. Indeed, there would be a fundamental flaw in reaching this conclusion. This is that the blockade of Th2-mediated events will not necessarily rapidly reverse the physiologically relevant pathology that was in fact directly caused by Th2 mediators. Early evidence from mouse models of chronic allergen challenge suggest that altering the pattern of Th2 cytokines could have major effects on the development of functionally important remodeling of the airway wall. Therefore, it is important to keep in mind that the lack of a rapid clinical effect should not be taken as evidence that a specific cytokine is not involved in asthma pathogenesis. Rather, it might be an indication that therapy needs to be started much earlier in the course of the disease. The study designs required to evaluate the roles of IL-4 or IL-13, which do not have direct effects on airway eosinophil accumulation, in asthma patients will be more difficult to develop and may require a longer duration treatment if the benefits achieved are through a reduction of IgE or improvements in AHR in asthmatic patients.

In contrast to the rather equivocal results, to date, of treatment with anti-IL-5 hMoAb or sIL-4R, the results of two studies2728 using the soluble TNF-{alpha} receptor etanercept have been very promising; particularly, as populations of patients with asthma that was very difficult to manage were studied. These studies strongly support an important role for TNF-{alpha} in causing severe, steroid-resistant asthma and would support the development of other treatment approaches that target TNF-{alpha} or its intracellular signaling mechanisms. Finally, using cytokines for treatment that may attenuate or prevent allergic inflammatory responses, such as IL-12 or IFN-{gamma} have, to date, not been very promising.

Footnotes

Abbreviations: AHR = airway hyperresponsiveness; hMoAb = human monoclonal antibody; IFN = interferon; IL = interleukin; IL-4R = interleukin-4 receptor; sIL-4R = soluble interleukin-4 receptor; TGF = transforming growth factor; Th = T helper; TNF = tumor necrosis factor

For 2003–2006, Dr. O’Byrne is or has been a consultant for Altana, AstraZeneca, GSK, Roche, and Topigen, and has received speaker’s fees from Altana, AstraZeneca, GSK, and Ono. He also holds grants from Altana, AstraZeneca, Aventis, Boeringher Ingleheim, Biolipox, GSK, IVAX, and Pfizer.

Received for publication April 13, 2006. Accepted for publication April 19, 2006.

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