Th2 cytokines and asthma The role of interleukin-5 in allergic eosinophilic disease – Respiratory Research

Atopic asthmatic persons have increased expression of Th2-type cytokine (interleukin-2, interleukin-3, interleukin-4, interleukin-5, and GM-CSF) mRNA in both BAL fluid and in bronchial biopsies as compared with healthy volunteers, but there is no difference between the two groups in the expression of Th1-type cytokine mRNA such as interferon-γ [82,83,84,85]. The predominant source of interleukin-4 and interleukin-5 mRNA in asthmatic persons is the T lymphocyte, and the CD4+ and CD8+ T-cell populations express elevated levels of activation markers including interleukin-2 receptor (CD25), human leukocyte antigen-DR, and the very late activation antigen-1 [84,86,87,88,89,90]. These results suggest that atopic asthma is associated with activation of the interleukin-3, interleukin-4, interleukin-5, and GM-CSF gene cluster, a pattern that is consistent with a Th2-like T-lymphocyte response [85]. Interleukin-5 mRNA is also found in activated eosinophils and mast cells in tissues from patients with atopic dermatitis [91,92,93], allergic rhinitis [94,95], and asthma [82,89], raising the possibility that interleukin-5 arises from multiple sources in atopic individuals.

Eosinophil infiltration into the airways after allergen challenge is a consistent feature of atopic asthmatic persons [96,97,98]. Interleukin-5 is predominantly an eosinophil-active cytokine in the late-phase response to antigen challenge [99,100], and is important for the recruitment and survival of eosinophils [57,99]. On the other hand, interleukin-5 is probably not important in the acute response to allergen challenge in asthmatic persons. Indeed, interleukin-5 is not detectable in the BAL fluid of mildly asthmatic persons shortly after allergen provocation [100]. Interleukin-5 may also be important for the recruitment of eosinophils from blood vessels into tissues, because topical administration of recombinant human interleukin-5 to the nasal airway of persons with allergic rhinitis induced eosinophil accumulation into the nasal mucosa [101,102]. Interleukin-5 may also induce activation of eosinophils that are resident to inflamed tissue, but this effect may be secondary to activation of secretory immunoglobulin A [103].

Several studies have demonstrated a correlation between the activation of T lymphocytes, increased concentration of interleukin-5 in serum and BAL fluid, and increased severity of the asthmatic response [87,104,105,106]. In a study of 30 asthmatic persons, Robinson et al [86] found a strong correlation between the number of BAL cells that expressed mRNA for interleukin-5, the magnitude of baseline airflow obstruction (FEV1), and bronchoconstrictor reactivity to methacholine. Furthermore, Zangrilli et al [106] found increased levels of interleukin-4 and interleukin-5 in the BAL fluid of asthmatic persons who had a late-phase response to antigen, but not in asthmatic persons who only demonstrated an early-phase response to antigen challenge. Motojima et al [104] compared serum levels of interleukin-5 in asthmatic patients during an exacerbation and in remission of asthma. Higher levels of serum interleukin-5 were found in each person during exacerbation, and patients with severe asthma had higher levels of serum interleukin-5 than did control individuals or patients with mild asthma. It is interesting to note that interleukin-5 levels were reduced in the serum of patients with moderate-to-severe asthma who were receiving oral glucocorticoids for control of their asthma [104,106]. These results are consistent with in vitro studies that show a potent inhibitory effect of corticosteroids on gene expression and on the release of pro-inflammatory cytokines, including interleukin-5, from inflammatory cells [107].

The link between interleukin-5, eosinophils, and asthma is currently under investigation using two humanized monoclonal antibodies specific for interleukin-5 that have been advanced into the clinic for evaluation as therapies for asthma. SCH55700 (reslizumab) is a humanized monoclonal antibody with activity against interleukin-5 from various species [108]. SB240563 (mepolizumab) is also a humanized antibody with specificity for human and primate interleukin-5 [109,110].

SCH55700 has an affinity for human interleukin-5 of 81 pmol/l and a 50% inhibitory concentration for inhibition of human interleukin-5-mediated TF-1 cell proliferation of 45 pmol/l. The efficacy of SCH55700 was further evaluated preclinically in a number of animal models. In a dose-dependent manner, SCH55700 inhibited total cell and eosinophil influx into BAL fluid, bronchi, and bronchioles of allergic mice for up to 8 weeks after a single 10 mg/kg dose and for 4 weeks after a single 2 mg/kg dose. Additional studies in allergic mice indicated that the combination of SCH55700 with an oral steroid (prednisolone) significantly increased the efficacy over that of either agent administered alone [108]. In allergic guinea pigs, SCH55700 caused a dose-dependent decrease in pulmonary eosinophilia and inhibited the development of allergen-induced airway hyperresponsiveness to substance P. It also inhibited the accumulation of total cells, eosinophils, and neutrophils in the lungs of guinea pigs exposed to human interleukin-5. SCH55700 had no effect on the numbers of inflammatory cells in unchallenged animals or in animals challenged with GM-CSF, and had no effect on the levels of circulating total leukocytes [108]. In cynomolgus monkeys naturally allergic to Ascaris suum, postchallenge pulmonary eosinophilia was significantly decreased for up to 6 months after a single 0.3 mg/kg intravenous dose of SCH55700 [108].

A rising single-dose phase I clinical trial was conducted with SCH55700 in patients with severe persistent asthma who remained symptomatic despite intervention with high-dose inhaled or oral steroids [22]. The two highest doses of SCH55700 significantly decreased peripheral blood eosinophils, with inhibition lasting up to 90 days after the 1 mg/kg dose. There was also a trend toward improvement in lung function at the higher doses 30 days after dosing, with mean FEV1 increasing by 11.2 and 8.6% in the 0.3 and 1.0 mg/kg groups, respectively, versus 4.0% in the placebo group [22].

Preclinical studies with SB240563 in cynomolgus monkeys indicated that peripheral blood eosinophils were decreased as a result of administration of the antibody [109,110]. Interestingly, maximal inhibition of peripheral blood eosinophils (80–90% of baseline) occurred 3–4 weeks after dosing (1 mg/kg subcutaneously), whereas maximal blood levels of the antibody were obtained 2–4 days after dosing, with a half-life of approximately 14 days.

SB240563 has also recently been tested in asthmatic persons in a clinical single-dose safety and activity study [21]. Patients with mild asthma were administered a single intravenous dose of SB240563 at either 2.5 or 10 mg/kg, or placebo. Patients were challenged with allergen 2 weeks before and 1 and 4 weeks after dosing. Peripheral blood and sputum eosinophil levels were measured, and early-phase and late-phase asthmatic responses were assessed by measuring the percentage fall in FEV1 induced by allergen challenge. Both doses of SB240563 caused a significant reduction in peripheral blood eosinophils. Eosinophil counts were reduced in the 10 mg/kg dose group by approximately 75% for up to 16 weeks, and in the 2.5 mg/kg dose group by approximately 65% for up to 8 weeks. Postchallenge sputum eosinophils were also reduced in the 10 mg/kg dose group. Neither dose of SB240563 attenuated the fall in induced by allergen challenge in these mildly FEV1 asthmatic persons.

With both of these antibodies showing acceptable safety profiles, larger studies can be conducted to determine the impact of blocking interleukin-5 on the pathophysiology of asthma and other eosinophil-related diseases. Only when these clinical trials are conducted will we be able to determine whether interleukin-5-based therapy in humans will measure up to the promise that is projected from animal models.