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Published ahead of print on August 11, 2004, doi:10.1164/rccm.200405-681OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 1043-1048, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200405-681OC

Original Article

Effects of Anticytokine Therapy in a Mouse Model of Chronic Asthma

Rakesh K. Kumar, Cristan Herbert, Dianne C. Webb, Lily Li and Paul S. Foster

Department of Pathology, University of New South Wales, Sydney; Division of Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra; Discipline of Immunology and Microbiology, Faculty of Health, University of Newcastle, Newcastle, Australia; and Immunobiology Research, Centocor Inc., Malvern, Pennsylvania

Correspondence and requests for reprints should be addressed to Rakesh K. Kumar, M.B.B.S., Ph.D., Department of Pathology, University of New South Wales, Sydney, Australia 2052. E-mail: r.kumar{at}unsw.edu.au


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The relative contribution of Th2 and Th1 cytokines to the pathogenesis of lesions of chronic asthma remains poorly understood. To date, therapeutic inhibition of Th2 cytokines has proved disappointing. We used a clinically relevant model of chronic allergic asthma in mice to compare the effects of administering neutralizing antibodies to interleukin (IL)-13, IL-5, and interferon-{gamma} (IFN-{gamma}) to animals with established disease. As has been observed in clinical studies, anti–IL-5 inhibited both inflammation and remodeling but had no effect on airway responsiveness to methacholine. Anti–IL-13 effectively suppressed eosinophil recruitment and accumulation of chronic inflammatory cells in the airways. This treatment also partially suppressed changes of airway wall remodeling, including goblet cell hyperplasia/metaplasia and subepithelial fibrosis, but had limited ability to inhibit airway hyperreactivity (AHR). In contrast, treatment with anti–IFN-{gamma} markedly suppressed AHR. This antibody inhibited accumulation of chronic inflammatory cells but did not affect eosinophil recruitment or changes of remodeling. We conclude that inhibition of IL-5 is beneficial and that inhibition of IL-13 has considerable potential as a therapeutic strategy in chronic asthma, that IFN-{gamma} may play an important role in the pathogenesis of AHR, and that co-operative interaction between Th2 and Th1 cytokines contributes to the pathogenesis of the lesions of chronic asthma.

Key Words: airway remodeling • bronchial hyperreactivity • interferon-{gamma} • interleukin-5 • interleukin-13

Allergic asthma is characterized by episodes of acute inflammation of the airways superimposed on a background of chronic inflammation, structural changes collectively referred to as airway wall remodeling, and airway hyperreactivity (AHR) to a variety of stimuli (1). The immunologic response is dominated by CD4+ T cells, which exhibit a so-called Th2 profile of cytokine secretion, biased toward production of interleukin (IL)-4, IL-5, IL-9, and IL-13 (2). Studies in animal models of allergic bronchopulmonary inflammation, including investigations in gene-targeted mice deficient in one or more Th2 cytokines, have suggested that the manifestations of asthma may be ameliorated by targeting these mediators (3–11). However, clinical trials involving anti–IL-5 or soluble IL-4 receptor have thus far proved to be disappointing (12–14). This discordance may be related to the failure of animal models involving short-term challenge with high levels of antigen to replicate many of the features of chronic human asthma (15) or to the induction of various compensatory mechanisms in gene-targeted cytokine-deficient animals (16, 17).

Reliable assessment of potential treatments is more likely to be achieved using an experimental model of chronic allergic disease of the airways. We have described such a model in mice that are systemically sensitized to ovalbumin and subjected to inhalational challenge with controlled low levels of aerosolized antigen for 6–8 weeks. This elicits lesions typical of chronic human asthma, including recruitment of eosinophils into the airway epithelium, chronic inflammation in the lamina propria, subepithelial fibrosis, and mucous cell hyperplasia/metaplasia. The exposure protocol is not associated with development of inflammation in the lung parenchyma but instead elicits recruitment of fewer total inflammatory cells and development of lesions confined to the conducting airways (18). In addition, the mice exhibit marked hyperreactivity to an inhaled cholinergic agonist, which is demonstrably of airway rather than parenchymal origin (19). Both the inflammatory response and AHR are CD4+ T-cell dependent (20), and there is evidence of a Th2 pattern of local immune response (21).

In this study, we used this model to examine the effect of administering neutralizing anticytokine antibodies to animals with established airway disease. There is currently considerable interest in IL-13 as a potential therapeutic target because in animal models of allergic inflammation it appears to be important in the induction of airway inflammation, subepithelial fibrosis, and AHR (10, 22–27). We therefore sought to compare anti–IL-13 with anti–IL-5. In addition, because we have previously demonstrated that Th1 cytokines such as interferon-{gamma} (IFN-{gamma}) may contribute to the pathogenesis of lesions in chronic asthma in this model (21), we examined the effect of anti–IFN-{gamma}. We specifically wished to assess the contribution of each of these cytokines to airway inflammation, remodeling, and AHR in chronic asthma, as well as the relationship between these abnormalities, as revealed after therapeutic suppression of cytokine activity.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Additional detail about these methods is provided in the online supplement.

Experimental Model
The protocols we employed for sensitization and inhalational challenge of mice have previously been described in detail (18, 28). Briefly, specific pathogen-free female BALB/c mice (aged approximately 8 weeks at the commencement of experimental studies) received intraperitoneal injections of 50 µg of alum-precipitated chicken egg ovalbumin (Sigma Australia, Sydney, Australia) 21 days and 7 days before inhalational exposure. The animals were challenged with aerosolized ovalbumin for 30 minutes/day on 3 days/week for 6 weeks in a whole-body inhalation exposure chamber (Unifab Corporation, Kalamazoo, MI). Particle concentration within the breathing zone of the mice was continuously monitored and maintained at approximately equal to 3 mg/m3, as assessed by a real-time monitor (DustTrak 8520; TSI, St. Paul, MN). Experimental groups each comprised eight animals. All experimental procedures complied with the requirements of the Animal Care and Ethics Committee of the University of New South Wales (reference no. 01/34.1).

Treatment with Neutralizing Anticytokine Antibodies
During the last 2 weeks of antigen challenge (Days 29, 34, 38, and 42 of exposure), mice were administered intraperitoneal injections of protein G–purified rat anti-mouse–IL-13 antibody (C531; Centocor Inc., Malvern, PA; 0.5 mg per injection) or of ammonium sulfate-purified rat anti-mouse–IL-5 monoclonal antibody (TRFK-5, 0.5 mg per injection) (29), anti-mouse IFN-{gamma} (R4–6A2, a generous gift from Dr. James Beck, University of Michigan, 0.35 mg per injection), or isotype control monoclonal antibody (ßGL-113, 0.5 mg per injection). Antibody doses were based on published studies (9, 30–32). Untreated, nonsensitized, nonexposed (i.e., naïve) animals were assessed in parallel.

Histopathology and Morphometry
The approach to histopathologic examination as well as the validity and reliability of the morphometric techniques we employed for quantifying inflammation and remodeling has been documented in previous reports (18, 27, 28). Although changes of inflammation and remodeling are demonstrable in the trachea, main bronchi, and intrapulmonary airways in this model, for convenience, changes were quantified in sections of the longitudinally oriented trachea. Eosinophils within the airway epithelial layer and total numbers of nuclei in the lamina propria were counted in hematoxylin and eosin-stained sections. The thickness of the subepithelial zone of collagenization was measured in reticulin-stained sections. Mucus-secreting goblet cells in intrapulmonary airways were quantified according to a semilogarithmic grading scale in sections stained with Alcian blue-periodic acid-Schiff.

Airway Reactivity
Responsiveness to methacholine (aerosolized from solutions containing 3.125 to 50 mg/ml) was assessed as enhanced Pause (Penh), measured in conscious, unrestrained mice using apparatus and software supplied by Buxco (Troy, NY). Measurement was performed as previously described (28).

Statistical Analysis
Results of morphometry and assessment of airway reactivity are presented as arithmetic mean ± SEM for each experimental group. Analysis of variance followed by Newman-Keuls multiple comparison test was used to examine differences between groups. The proportions of mucin-positive cells in the intrapulmonary airways were assigned grades and are expressed as median values, with comparisons undertaken using a nonparametric Kruskal-Wallis test followed by Dunn's test. The software package GraphPad Prism 4.01 (GraphPad Software, San Diego, CA) was used for all data analysis and preparation of graphs.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
No adverse effects of intraperitoneal injection of antibodies were observed in any of the experimental groups studied.

Airway Inflammation
Whereas eosinophils are rarely identifiable within the tracheal epithelium of normal BALB/c mice, sensitized mice treated with control antibody ßGL-113 exhibited recruitment of numerous intraepithelial eosinophils (p < 0.001 compared with nonexposed control animals; Figure 1). Treatment with anti–IL-13 markedly reduced the accumulation of eosinophils (p < 0.01 compared with ßGL-113–treated control animals) as did treatment with anti–IL-5 (p < 0.01). In contrast, treatment with anti–IFN-{gamma} had no effect on eosinophil recruitment.



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  		Figure 1. Accumulation of eosinophils in the tracheal epithelium of sensitized, chronically challenged mice treated with neutralizing anticytokine antibodies. Significant differences compared with naive animals shown as ### p < 0.001; significant differences compared with mice treated with the control antibody shown as **p < 0.01. IFN = interferon; IL = interleukin.

 
Sensitized chronically exposed BALB/c mice treated with the control antibody developed widespread multifocal accumulation of lymphocytes, plasma cells, and other chronic inflammatory cells in the lamina propria of the trachea, leading to a marked increase in the number of cells in this compartment (Figure 2) (p < 0.001 compared with nonexposed control animals). Accumulation of lamina propria cells was significantly diminished in mice treated with anti–IL-13 or anti–IFN-{gamma} (p < 0.01 for both) and was also reduced in mice treated with anti–IL-5 (p < 0.05).



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  		Figure 2. Inflammatory cells in the lamina propria of the trachea of sensitized, chronically challenged mice treated with neutralizing anticytokine antibodies. Significant differences compared with naive animals shown as # p < 0.05, ## p < 0.01, ### p < 0.001; significant differences compared with mice treated with the control antibody shown as *p < 0.05, **p < 0.01.

 
Airway Wall Remodeling
Mucus-secreting goblet cells, which are virtually absent in the intrapulmonary airways of naïve mice, were strikingly increased in sensitized exposed mice treated with the control ßGL-113 antibody, with a median grade of 4 (Figure 3) (p < 0.001 compared with nonexposed control animals). In mice treated with anti–IL-13, there were substantially fewer mucous cells, with a median grade of 2. This was significantly decreased compared with ßGL-113–treated control animals (p < 0.05) but was no longer significantly greater than nonexposed control animals. Treatment with anti–IL-5 led to a modest reduction in the proportion of goblet cells in the airways, but this was not statistically significant. Treatment with anti–IFN-{gamma} had no significant effect on the number of mucous cells.



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  		Figure 3. Mucous cell hyperplasia/metaplasia in the intrapulmonary airways of sensitized, chronically challenged mice treated with neutralizing anticytokine antibodies. Significant differences compared with naive animals shown as # p < 0.05, ### p < 0.001; significant difference compared with mice treated with the control antibody shown as *p < 0.05.

 
Sensitized mice exposed to antigen and treated with the control antibody exhibited accumulation of subepithelial collagen (Figure 4), leading to significant thickening of the reticulin-stained zone (p < 0.001 compared with nonexposed control animals). There was diminished subepithelial fibrosis in mice treated with anti–IL-13 or with anti–IL-5, although only the latter was statistically significant (p < 0.05) (Figure 4). Treatment with anti–IFN-{gamma} had no effect on subepithelial fibrosis.



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  		Figure 4. Subepithelial collagenization in the trachea of sensitized, chronically challenged mice treated with neutralizing anticytokine antibodies. Significant differences compared with naive animals shown as ## p < 0.01, ### p < 0.001; significant difference compared with mice treated with the control antibody shown as *p < 0.05.

 
Airway Responsiveness
Animals treated with control ßGL-113 antibody exhibited a left-shifted Penh dose–response curve and increased maximal reactivity to methacholine, characteristic of AHR (Figure 5). Treatment with anti–IL-13 led to a modest decrease in airway responsiveness, but this was statistically significant only at a methacholine concentration of 50 mg/ml. Anti–IL-5 had virtually no effect on airway responsiveness. In contrast, animals treated with anti–IFN-{gamma} demonstrated statistically significant reductions in Penh at all methacholine concentrations above 3.125 mg/ml (Figure 5).



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  		Figure 5. Airway reactivity of sensitized, chronically challenged mice treated with neutralizing anticytokine antibodies, assessed by change in Penh in response to increasing concentrations of aerosolized ß-methacholine. Significant differences compared with naive animals shown as ## p < 0.01, ### p < 0.001; significant differences compared with mice treated with the control antibody shown as *p < 0.05, **p < 0.01.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we employed a clinically relevant experimental model that replicates most of the features of chronic human asthma with high fidelity (15), to assess the effect of treatment with neutralizing antibodies against IL-13, IL-5, and IFN-{gamma}. We have previously shown that in this model, changes of inflammation and airway wall remodeling are established by 4 weeks and progress with continuing antigenic challenge (18). The therapeutic regimen was therefore also clinically relevant and allowed us to examine whether the antibodies could inhibit progression of lesions and/or reverse them. The three antibodies had strikingly different effects in this model of chronic asthma.

Treatment with anti–IL-5 had significant antiinflammatory effects, decreasing the numbers of both intraepithelial eosinophils and chronic inflammatory cells in the airway wall, yet failed to inhibit AHR. These observations closely parallel the findings in clinical trials in which humanized monoclonal antibodies were administered to subjects with asthma (12, 13). The data, which are in contrast to the findings in a short-term model in which there was partial inhibition of AHR (8), reinforce the similarity between our chronic challenge model and the human disease. However, the lack of inhibition of AHR by treatment with anti–IL-5 differs from our earlier findings in IL-5–/– mice (28), which might be a consequence of associated cytokine disturbances in the gene-targeted animals; for example, there is evidence of deficient production of IL-13 in IL-5–/– mice (33). Anti–IL-5 partially inhibited the mucous cell response, as others have previously reported in IL-5–/– mice (34). In addition, administration of the antibody significantly inhibited the development of subepithelial fibrosis. This result is consistent with an earlier study in mice (30) and directly supports recent observations in humans (35), indicating that IL-5 plays a role in the development of airway wall remodeling.

Anti–IL-13 was also a potent antiinflammatory agent, significantly reducing the accumulation of intraepithelial eosinophils and of chronic inflammatory cells in the lamina propria of the airways. In addition, anti–IL-13 effectively inhibited mucous cell hyperplasia/metaplasia and caused a diminution in thickness of the reticulin-stained zone, although the latter response did not achieve statistical significance in a multiple comparison. Mice treated with anti–IL-13 still had evidence of AHR, but there was significant inhibition at the highest concentration of methacholine tested. Whereas studies in IL-13–/– mice have yielded conflicting data (9, 10, 27), these results clearly demonstrate that treatment with anti–IL-13 had a combination of beneficial effects.

Our findings emphasize the potential of inhibition of IL-13 as a therapeutic strategy in chronic asthma. They are also consistent with data from two previously reported studies in models of chronic asthma, in which treatment with anti–IL-13 significantly inhibited eosinophil recruitment (32), collagen deposition in the lungs, and mucous cell hyperplasia/metaplasia (26, 32). However, the results of those studies are not directly comparable, as both models were associated with marked parenchymal inflammation progressing to pulmonary fibrosis, which may impact interpretation of the data. The presence of parenchymal disease also makes it difficult to draw direct comparisons between the modest effect on AHR that we observed after administration of anti–IL-13 and the partial (26) or complete (32) inhibition of AHR demonstrated in those models.

In our model of chronic asthma, we have previously demonstrated virtually complete absence of subepithelial fibrosis in IL-13–/– mice (27). The lesser effect after treatment with anti–IL-13 might be related to the dosage of antibody employed or the duration for which it was administered, although in previous experiments, we have shown that glucocorticoids or other antiinflammatory agents could inhibit changes of remodeling when administered over a similar period (36).

The effects of anti–IFN-{gamma} were in marked contrast to the other two neutralizing antibodies. Although anti–IFN-{gamma} had no effect on eosinophil accumulation, it significantly diminished the accumulation of chronic inflammatory cells in the lamina propria. It had no apparent effect on remodeling, but very effectively suppressed AHR in our model of chronic asthma. This was an unexpected finding but is consistent with numerous published reports implying a role for Th1 cytokines and especially for IFN-{gamma} in the pathogenesis of AHR, both in patients with asthma (37–41) and in animal models (42–44). IFN-{gamma} may be particularly important in the development of AHR in models of chronic asthma, which involve distinctly different pathogenetic mechanisms as compared with short-term models of allergic bronchopulmonary inflammation. This has been well demonstrated in a model of fungal asthma (45) and in our model of chronic aerosol challenge (21): in both of these models, AHR is demonstrable in signal transducer and activator of transcription (STAT)6-deficient animals (which exhibit impaired Th2 cytokine signaling), whereas this deficiency abrogates AHR in short-term challenge models. We have also shown that in our model, AHR is regulated independently of airway inflammation or remodeling and can develop in animals deficient in IL-4, IL-13, or signaling via the IL-4 receptor {alpha} chain (reviewed in 15), which may be relevant to the observed pattern of response to antibody treatment. However, the molecular mechanisms regulating AHR clearly differ in other murine models of chronic allergen challenge. For example, models involving high-dose chronic aerosol exposure frequently exhibit downregulation of AHR (46), which has been demonstrated to be associated with a shift to a Th1 profile and induction of IFN-{gamma} (47). In contrast, models involving chronic intranasal challenge usually exhibit persistent AHR (48, 49), which is abrogated in mice deficient in either IL-4 or IL-13 (50).

This study provides the first direct demonstration of the potential importance of IFN-{gamma} in AHR in chronic asthma. In interpreting this finding, consideration needs to be given to the method we employed to assess airway responsiveness. Measurement of Penh by unrestrained plethysmography does not provide direct assessment of a specific physiologic variable, and its limitations are well documented (51–53). However, Penh can be used to monitor airway function empirically. In our chronic challenge model, we have previously shown that the observed changes in Penh closely correlate with increased specific airway resistance as measured by the forced oscillation technique and that the animals exhibit hyperreactivity, which originates from the airways and not the pulmonary parenchyma (19).

Although the cellular source of the IFN-{gamma} that contributes to AHR in our model has not yet been defined, the absence of AHR in mice depleted of CD4+ T lymphocytes (20) suggests that these cells may either be the source of IFN-{gamma} or may regulate other cells producing this cytokine. In human asthma, both CD4+ and CD8+ T cells are important sources of IFN-{gamma} (38, 54, 55). That production of IFN-{gamma} by chronic inflammatory cells might play a key role in AHR provides a logical explanation for some of the striking differences in airway reactivity between acute and chronic antigenic challenge models (27, 28, 45). Investigators have previously suggested that IFN-{gamma} may contribute to airway hyperresponsiveness by modulating the contractile responses of airway smooth muscle cells to leukotrienes (56). Treatment with anti–IFN-{gamma}, which has long been recognized to inhibit lymphocyte accumulation at the site of an immunologic response (57), might also contribute to suppression of AHR by depletion of a relevant population of chronic inflammatory cells and/or their mediators.

In the context of our previously published studies in this model, the results of this study strongly support the notion that the pathogenesis of the lesions of asthma, and especially of AHR, involves a cooperative interaction between Th2 and Th1 cytokines (21, 58). Although targeting single cytokines or signaling pathways in therapy is unlikely to effectively control all of the manifestations of the disease, our observations suggest that inhibition of IL-5 may be beneficial in chronic asthma, that inhibition of IL-13 is a potentially useful therapeutic strategy, and that consideration should be given to inhibiting IFN-{gamma} in parallel as an approach to combination therapy.


   FOOTNOTES
 
Supported by grants from Asthma New South Wales and the National Health and Medical Research Council of Australia and by a gift of anti–IL-13 antibody from Centocor Inc.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Conflict of Interest Statement: R.K.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.C.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.L. is an employee of Centocor, Inc. (a Johnson & Johnson company) and holds Johnson & Johnson stock options; P.S.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Centocor is interested in the therapeutic area in asthma.

Received in original form May 27, 2004; accepted in final form August 6, 2004


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 DISCUSSION
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