The role of interleukin 5 in asthma

KEYWORDS:

• IL5
• asthma
• eosinophils
• interleukins
• monoclonals

Eosinophils were first named in 1879 by Paul Ehrlich, who described their capacity to be stained by eosin, a bright red synthetic dye [1]. Ehrlich speculated correctly that cytoplasmic granules of eosinophils contained secretory products and described several causes of eosinophilia including asthma, skin diseases, helminthes, and reactions to drugs. Ehrlich’s use of eosin was a landmark contribution, which heralded modern studies on eosinophils [2].

Due to their rarity (±1% of peripheral blood leukocytes), eosinophils have been erroneously neglected for decades. Because of their striking and esthetically pleasing appearance by light microscopy, eosinophils have episodically attracted the interest of morphologists and immunologists. Eosinophils were initially considered only a necessary and ubiquitous host defense against helminthic parasite infections [2]. Paradoxically, in the 1980s, eosinophil pathophysiological role in allergy, particularly asthma, was doubted [3,4]. In recent decades, several observations called these cells to the attention of several groups of investigators, leading to a revolution in their pathophysiological roles. Allergists and researchers of immediate hypersensitivity were attracted to eosinophils for several reasons: appreciation that these cells represent repositories of a wide spectrum of potent mediators such as several cationic proteins (eosinophil cationic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, and major basic protein), cytokines/chemokines, and lipid mediators – the capacity to adhere to activated blood endothelial cells, to leave the blood stream, and to concentrate at the site of allergic inflammation [5]. These cells and their mediators were found in airway tissue and sputum of patients with asthma. Other findings have added the identification of interleukin-5 (IL-5) as the most important growth, differentiation, and activating factors for human eosinophils [4,5]. In addition, there is compelling evidence that human eosinophils modulate the functions of a plethora of cells of the innate and adaptive immune system including subsets of lymphocytes, neutrophils, macrophages, mast cells, basophils, dendritic, and plasma cells. There is now clear evidence that eosinophils and their mediators are critical effectors to eosinophilic respiratory disorders including asthma and eosinophilic granulomatosis with polyangiitis (EGPA) [6,7].

Human eosinophils develop in the bone marrow from pluripotent progenitors under the control of IL-5, IL-3, and granulocyte-monocyte colony-stimulating factor (GM-CSF) that activate the IL-5 receptor (IL-5R). This receptor is composed of a specific receptor subunit, IL-5Rα, and a separate motif for binding to the signaling unit, βc, of the receptor [8]. The IL-5Rα subunit is specific only to IL-5 binding whereas the βc chain also binds IL-3 and GM-CSF. Eosinophils highly express the IL-5Rα on their surface; for example, these cells express about a threefold higher levels of IL-5Rα compared with basophils [9]. Th2 cells, mast cells, group 2 innate lymphoid cells (ILC 2), CD34⁺ progenitor cells, invariant natural killer (NK) T cells, and eosinophils themselves are major cellular source of IL-5 [10].

During the last decades, it has been recognized that the eosinophil and its mediators are prominent components of severe allergic asthma [7,11]. Therefore, targeting IL-5 or IL-5Rα appeared an interesting approach to the treatment of patients with severe eosinophilic asthma. Two different anti-IL-5 monoclonal antibodies (mepolizumab and reslizumab) bind to distinct epitopes of IL-5 interfering with its binding to IL-5R expressed on eosinophil membrane [7,8]. Mepolizumab, a humanized monoclonal antibody, has been investigated for the treatment of asthma, atopic dermatitis, hypereosinophilic syndromes, and EGPA [7,12]. Initial studies on small groups of patients with eosinophilic asthma demonstrated that mepolizumab intravenously (i.v.) every 4 weeks decreased blood and sputum eosinophils without improving asthma control questionnaire (ACQ) score and lung functions [13–15]. These preliminary studies demonstrated that i.v. administration of mepolizumab was safe and reduced asthma exacerbations by approximately 40%, findings that were extended in a larger study [16]. Two recent studies have clearly shown that mepolizumab administered subcutaneously (s.c.) every 4 weeks reduced exacerbations, improved ACQ scores and pulmonary functions, and had a glucocorticoid sparing effect [17,18]. The difference between the initial and the latter studies was probably due to a better selection of patients with blood eosinophilia (at least 300–400 eosinophils/mm³), a larger number of patients, and the s.c. administration of the anti-IL-5 monoclonal antibody. The latter observation is probably relevant, because the possibility exists that mepolizumab, like human polyclonal immunoglobulins [19], diffuses relatively slowly to block IL-5 compared to i.v. administration. Mepolizumab has been approved in 2015 by the US FDA and European Medicine Agency as an add-on treatment for adult patients with severe eosinophilic asthma.

Reslizumab, another humanized anti-IL-5 monoclonal antibody, has been shown to be effective in patients with asthma [20]. Based on these clinical studies, reslizumab has been recently recommended by FDA for approval for treatment of adult patients with severe eosinophilic asthma.

Benralizumab is a humanized monoclonal antibody directed against the α-chain of the IL-5Rα present on eosinophils and basophils [9]. Benralizumab is not fucosylated and binds to FcγRIIIa, leading to antibody-dependent cell-mediated cytotoxicity. In adult patients with eosinophilic asthma receiving benralizumab, there were fewer exacerbations [21]. This study provided useful information to design studies underway in patients with severe asthma with peripheral eosinophil count of at least 300 cells/μl and it demonstrated that benralizumab induced a rapid decrease of blood eosinophils presumably due to its different mechanisms of action (including the cytotoxic effect on these cells). Interestingly, a single dose of benralizumab administered to adult patients with severe asthma resulting in emergency department visit reduced blood eosinophils and exacerbations during the following 3 months [22]. Additional studies are needed to assess the disease-modifying effects of IL-5/IL-Rα inhibitors after their suspension.

In 1951, J. Churg and L. Strauss first described a systemic vasculitis occurring exclusively in patients with asthma and eosinophilia [6]. This condition, called ‘Churg–Strauss syndrome’ for many years, has now been recognized as EGPA [6]. IL-5 appears to be upregulated and eosinophils are increased in peripheral blood and tissue lesions in active EGPA [23]. There is no consensus regarding the remission induction and remission maintenance therapy in patients with EGPA. However, asthma is a prominent clinical hallmark in the vast majority of EGPA patients [24]. A pilot study in a small group of patients with EGPA tested the safety and efficacy of mepolizumab [25]. Although this preliminary study demonstrated the efficacy of mepolizumab in reducing blood eosinophils, the pulmonary functions did not change. Several clinical trials have or are exploring the efficacy of mepolizumab in EGPA patients (NCT00716651, NCT02020889, EUDRA CT2014-003162-25). IgE concentrations are increased in the majority of EGPA patients. Interestingly, omalizumab (anti-IgE) s.c. administration for 36 months in patients with EGPA resulted in clinical improvement of asthma, reduction of eosinophils, and prednisone administration [26].

In conclusion, several studies have demonstrated that the i.v. and s.c. administration of anti-IL-5 (mepolizumab and reslizumab) and anti-IL-5Rα (benralizumab) monoclonal antibodies are well tolerated in adult patients with eosinophilic asthma. The success of these biological agents in severe asthma largely depends on the selection of the appropriate patients. The blood and/or sputum eosinophil count appears to be closely associated with a clinical response to IL-5 pathway inhibition in adult patients with eosinophilic asthma. We would like to suggest that other biomarkers in eosinophilic asthma might include activated eosinophil surface phenotype detected by flow cytometry, elevated levels of blood, and/or sputum IL-5, soluble IL-5Rα, soluble Siglec-8, and EMR1, a specific surface receptor of eosinophils [7,12]. Perhaps, the combined use of multiple biomarkers might be a better strategy to identify patients responsive to IL-5 pathway inhibitors. Supervised cluster analysis can also help to select patients responsive to IL-5 pathway inhibition [27].

We anticipate that in the near future, biological samples from patients with eosinophilic respiratory disorders could be analyzed (biomarkers, transcriptome, genes, microRNA, and others) for phenotyping patients to tailor their treatment.

Recent evidence suggests that eosinophils and their mediators play a major role in cancer rejection [28] and several cancers can be associated with eosinophilia [29]. Although eosinophil deficiency is not associated with clinical abnormalities [30], long-term studies should evaluate the safety of targeted anti-eosinophilic strategies such as has been shown in severe asthmatics treated with omalizumab [31].

Severe eosinophilic asthma can occur in children and pharmacologic and biologic treatment of asthma can differ in children when compared to adults [32]. Studies are underway to characterize the effects of mepolizumab administered s.c. in children from 6 to 11 years of age with severe eosinophilic asthma (NCT02377427). The results of these studies will provide useful information whether eosinophilia is a useful biomarker also in children with eosinophilic asthma. Lastly, the cost-effectiveness of these anti-IL-5/IL-5R treatments will also be carefully evaluated [33]; in fact, the regulatory authorities will consider the innovative features of the single products and their cost-effectiveness.

In conclusion, targeted therapies with anti-IL-5 or anti-IL-5Rα are safe and efficacious in a short- and medium-term treatment of adult patients with severe eosinophilic asthma. The long-term safety of these agents needs to be addressed. Identification of novel biomarkers, in addition to blood eosinophilia, will allow a better selection of patients responsive to these treatments. Ongoing studies will provide information whether inhibition of IL-5/IL-5R pathways is safe and efficacious in children with eosinophilic asthma and in patients with EGPA.

Declaration of interest

GW Canonica has consultancies and honoraria with AstraZeneca, GSK and Teva. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgments

We apologize to the many authors who have contributed importantly to this field and whose work has not been cited due to space limitations.

Additional information

Funding

This work was supported in part by grants from Regione Campania CISI-Lab Project, CRèME Project, TIMING Project and ARMIA (Associazione Ricerca Malattie Allergiche e Immunologiche).