Cytokines or Their Antagonists for the Treatment of Asthma*

CHEST Translating Basic Research Into Clinical Practice
Cytokines or Their Antagonists for the
Treatment of Asthma*
Paul M. O’Byrne, MB, FCCP
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-␥ has not
shown benefit in asthmatic patients. By contrast, the treatment of severe oral steroid-dependent
asthma with soluble tumor necrosis factor-␣ receptor has demonstrated very promising results,
suggesting that this cytokine plays an important role in the persistence of severe asthma.
(CHEST 2006; 130:244 –250)
Key words: airway hyperresponsiveness; asthma; interferon-␥; interleukin-4; interleukin-5; interleukin-13; tumor
necrosis factor-␣
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
ver the past 20 years, there has been an enorO mous
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 me*From McMaster University, Hamilton, ON, Canada.
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.
Manuscript received April 13, 2006; revision accepted April 19,
2006.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
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:[email protected]
DOI: 10.1378/chest.130.1.244
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diators 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)-␥, 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 molTranslating Basic Research Into Clinical Practice
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.
ecule-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 ␣ 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).
Another cytokine that may play a role in the
initiation or persistence of inflammation in asthma is
tumor necrosis factor (TNF)-␣, which is important in
the persistence of inflammation in other inflammawww.chestjournal.org
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tory 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-␥17 have
been demonstrated to attenuate or prevent allergeninduced 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-␣ and transforming growth factor (TGF)-␤,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-␥. 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-␣ receptor-IgG1Fc fusion protein
as an anti-TNF-␣. In addition, IL-12 and IFN-␥
have been administered to asthmatic patients to
CHEST / 130 / 1 / JULY, 2006
245
evaluate their efficacy. A summary of the results of
the trials using cytokine antagonists is provided in
Table 1.
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 ␮g) 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 ␮g) 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
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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-␤ and
with decreases in the concentration of TGF-␤ in
BAL fluid, implying the existence of a role for
eosinophil release of TGF-␤ 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
Translating Basic Research Into Clinical Practice
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CHEST / 130 / 1 / JULY, 2006
247
62
24
26
24
17
10
Borish et al20
Leckie et al21
Kips et al26
Flood-Page et al25
Howarth et al27
Berry et al28
Daily Asthma Medications
Severe
Severe
Mild
Severe
Mild
DB, R, Pl
DB, R, Pl
DB, R, Pl
DB, R, Pl
DB, R, Pl
Trial
Design
High-dose ICs, and most
OCSs and LABAs
Intervention
None
FEV1, symptoms, and
safety
Outcomes
SCH 55700, 0.3 mg/kg
Mepolizumab, 2.5 mg/kg,
10 mg/kg IV
Etanercept, 25 mg SC 2
times/wk for 10 wk
Etanercept, 25 mg SC 2
times/wk for 12 wk
Improved FEV1 and
symptoms for 1.5-mg
dose
No decline in FEV1 or
symptoms for 3.0-mg
dose
Attenuated blood and
sputum eos; no effect
on other outcomes
Improved FEV1 at 24 h
after 0.3 mg/kg dose
Results
Reduction in eos in bone
marrow by 52%, in
tissue by 55%
Symptoms, lung function, Improved symptoms, lung
QOL, AHR, FeNO, and
function, and AHR
induced sputum
Symptoms, lung function, Improved symptoms, lung
AHR, FeNO, and
function, QOL, and
induced sputum
AHR
Blood and sputum eos,
symptoms, and lung
function
Blood, bone marrow, and
tissue eos
Blood and sputum eos;
EAR, LAR, and AHR
Inhaled IL-4R, 0.75, 1.5,
FEV1, symptoms, and
safety
and 3.0 mg/wk ⫻ 12 wk
Inhaled IL-4R, 0.5 and
1.5 mg in single dose
Treatment
Blood and bone marrow, Mepolizumab, 750 mg ⫻
airway biopsies
3 over 20 wk
None
Allergen challenge
Steroid withdrawal
Steroid withdrawal
DB, R, Pl, CO None
High-dose ICSs, and most Open label
OCSs and LABAs
None
ICSs and/or OCSs
None
Moderate ICSs
Moderate ICSs
Asthma
Severity
*ICS ⫽ inhaled corticosteroid; OCS ⫽ oral corticosteroid; LABA ⫽ long-acting ␤ 2-agonist; DB ⫽ double blind; R ⫽ randomized; Pl ⫽ placebo controlled; CO ⫽ crossover; EAR ⫽ early asthmatic
response; LAR ⫽ late asthmatic response; eos ⫽ eosinophils; QOL ⫽ quality of life; FeNO ⫽ fractional exhaled nitrous oxide.
Borish et al
25
Patients,
No.
19
Study
Table 1—Summary of Human Studies Examining the Efficacy of Cytokine Antagonists in the Treatment of Asthma*
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-␣ in the pathogenesis of
severe asthma. The first study27 demonstrated that
TNF-␣ levels in BAL fluid, TNF-␣ gene expression,
and immunoreactive mast cell numbers were increased in patients with severe oral corticosteroiddependent asthma. A subsequent open-label study27
was then undertaken in 17 of these patients with the
soluble TNF-␣ 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-␣,
TNF-␣ receptor 1, and TNF-␣-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 asthmarelated 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 AHR30,31 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
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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-␥. 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 ␮g/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-␥ 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-␥ 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-␥ or placebo, 0.05 mg/m2, for 90 days.37
While total circulating eosinophil counts decreased
after treatment with IFN-␥, 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
Translating Basic Research Into Clinical Practice
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 moderateto-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.
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In contrast to the rather equivocal results, to date,
of treatment with anti-IL-5 hMoAb or sIL-4R, the
results of two studies27,28 using the soluble TNF-␣
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-␣
in causing severe, steroid-resistant asthma and would
support the development of other treatment approaches that target TNF-␣ or its intracellular signaling
mechanisms. Finally, using cytokines for treatment that
may attenuate or prevent allergic inflammatory responses, such as IL-12 or IFN-␥ have, to date, not been
very promising.
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