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Asthma, Eosinophilic Granulomatosis with Polyangiitis, and Eosinophilic Chronic Rhinosinusitis

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Asthma, Eosinophilic Granulomatosis with Polyangiitis, and Eosinophilic Chronic Rhinosinusitis Allergology International 69 (2020) 178e186 Contents lists available at ScienceDirect Allergology International journal homepage: http://www.elsevier.com/locate/alit Invited Review Article The roles of IL-5 and anti-IL-5 treatment in eosinophilic diseases: Asthma, eosinophilic granulomatosis with polyangiitis, and eosinophilic chronic rhinosinusitis * ** *** Hiroyuki Nagase a, , 1, Shigeharu Ueki b, , 1, Shigeharu Fujieda c, , 1 a Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan b Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan c Division of Otorhinolaryngology - Head & Neck Surgery, Department of Sensory and Locomotor Medicine, Faculty of Medical Science, University of Fukui, Fukui, Japan article info abstract Article history: IL-5 is the most potent activator of eosinophils and is produced by Th2 cells and ILC2s. A role for IL-5 in Received 8 February 2020 eosinophil extracellular trap cell death, i.e., a proinflammatory cell death, has also been reported. Available online 2 March 2020 Mepolizumab and benralizumab are humanized mAbs that target IL-5 and the IL-5 receptor a, respec- tively, and their therapeutic efficacy for severe asthma has been established. Although consistent dif- Keywords: ferences in the efficacies of those drugs have not been proven, benralizumab extensively depleted Benralizumab eosinophils via Ab-dependent cell-mediated cytotoxicity. Blood eosinophil count, but not FeNO or IgE, is Chronic rhinosinusitis with nasal polyps the best-established predictive biomarker of the efficacy of anti-IL-5 treatment. Regarding the choice of Eosinophils IL-5 biologics, the balance between blood eosinophil count and FeNO, indication of comorbidities, longitu- Mepolizumab dinal safety, and interval of injection should be considered. Mepolizumab was also effective in main- taining the remission of refractory eosinophilic granulomatous polyangiitis. Moreover, mepolizumab decreased the proportion of patients who required surgery and lowered the nasal polyp score in patients with chronic rhinosinusitis with nasal polyps; a further extensive trial is currently under way. In a phase II benralizumab study performed in Japan, no significant effect on nasal polyp score at week 12 was observed, suggesting a requirement for longer treatment. In this review, the role of IL-5 in eosinophil biology and the current status of anti-IL-5 therapy are discussed. The longitudinal safety of anti-IL-5 therapy has been increasingly established, and this strategy will be continuously indicated for eosino- philic diseases as a specific treatment for eosinophilic inflammation. Copyright © 2020, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Basic aspects of IL-5 and eosinophilic inflammation homeostatic conditions, the half-life of blood eosinophils is approximately 25 h.1 The majority of senescent (or apoptotic) eo- For more than 100 years, eosinophils have been linked to sinophils are cleared in the liver and spleen, where they are taken- allergic and parasitic diseases. Eosinophils are terminally differ- up by macrophages of the reticuloendothelial system. The þ entiated myeloid cells derived from CD34 hematopoietic stem remaining eosinophils are distributed across the gastrointestinal cells in the bone marrow. The process is regulated by transcription tract, thymus, lung, uterus, and adipose tissue, indicating physio- factors, including the GATA-binding factor 1. Once eosinophils logical function in each organ2 (reviewed in Ref. 3). In response to reach maturity, they are released into the blood stream. In normal type 2 reactions, eosinophils are markedly mobilized from the bone * Corresponding author. Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan. ** Corresponding author. Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010- 8543, Japan. *** Corresponding author. Division of Otorhinolaryngology - Head & Neck Surgery, Department of Sensory and Locomotor Medicine, Faculty of Medical Science, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan. E-mail addresses: [email protected] (H. Nagase), [email protected] (S. Ueki), [email protected] (S. Fujieda). Peer review under responsibility of Japanese Society of Allergology. 1 These authors equally contributed to this article. https://doi.org/10.1016/j.alit.2020.02.002 1323-8930/Copyright © 2020, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). H. Nagase et al. / Allergology International 69 (2020) 178e186 179 marrow and blood pool to local sites, creating a tissue eosinophilia. pathological conditions of asthma, such as airway hypersensitiv- The excessive accumulation and activation of eosinophils can have ity.11 In addition, nasal appreciation of recombinant IL-5 induced a deleterious effect and contribute to tissue damage. selective recruitment of eosinophils in the mucosa.12,13 Eosinophil differentiation is mediated by IL-5, IL-3, and the In a variety of allergic diseases, circulating blood eosinophils are granulocyte macrophage colony-stimulating factor (GM-CSF). in a resting state and do not degranulate until they have reached These cytokines are called b common cytokines, because of their their target tissue.14 The proinflammatory chemokines, especially shared b receptor structure. The b common cytokine receptor eotaxins (CCL11, CCL24, and CCL26), that are produced by structural comprises a cytokine-specific a chain and a common b chain that is cells (including bronchial epithelial cells and fibroblasts) primarily essential for receptor signaling and assembly.4 Among them, IL-5 regulate the accumulation of eosinophils in the airways.15 The ca- has been considered to be a therapeutic target for allergic/eosino- pacity to generate reactive oxygen species and the secretory func- philic diseases because of the presence of exclusive IL-5 receptor tion of eosinophils are important features of their role as tissue- (IL-5R) expression in eosinophils and basophils (in humans) and its damaging cells. Eosinophil pack approximately 200 granules that critical role in eosinophilopoiesis.5 contain not only cytotoxic proteins (i.e., major basic protein, In the allergen-induced adaptive immunity process, IL-5 is pri- eosinophil peroxidase, eosinophil cationic protein (ECP), and mary produced by Th2 cells. In addition, ILC2s produce abundant eosinophil-derived neurotoxin), but also over 30 cytokines.16 This IL-5 in response to IL-33 and other alarmins, thus playing a critical cargo is an efficient system for short-lived eosinophils, as de novo role in innate immunity settings.6 A previous study indicated that protein synthesis is time consuming.17,18 Eosinophils can rapidly IL-5-deficient mice exhibit a slight reduction in circulating eosin- release selected cytokines from granular storage through piecemeal ophils under baseline conditions, but completely fail to induce degranulation and possibly exocytosis. Moreover, eosinophils also parasite-induced eosinophilia.7 In contrast, IL-5 transgenic mice release their total cellular content through cytolytic degranulation showed high-level eosinophilia at the baseline.8 Familial eosino- (cytolysis). Cytolytic degranulation in inflamed tissues has been e philia is a rare autosomal dominant inherited disorder that is shown to occur in 30%e80% of eosinophils.19 21 Recent evidence characterized by prolonged peripheral eosinophilia likely second- revealed that cytolysis is an active cell death program, i.e., extra- ary to IL-5 overproduction in peripheral blood mononuclear cells.9 cellular trap cell death (ETosis).22 Unlike apoptosis, eosinophil To date, a considerable amount of evidence indicates that the sys- ETosis (EETosis) releases the total cellular content of these cells, temic increase of IL-5 is important for promoting eosinophilia. including damage-associated molecular patterns. Thus, EETosis is It is noteworthy that the systemic increase of IL-5 is not always considered to be a potentially proinflammatory type of cell death. sufficient to cause an eosinophil-mediated pathological condition. In tissues, the presence of multiple inflammatory signals (e.g., IL-5 transgenic mice remain physically normal, with the exception adhesion molecules, complements, lipid mediators, cytokines, and of the development of splenomegaly.8 In patients with familial pathogens) that work synergistically with IL-5 are required for the eosinophilia, clinical manifestations related to the eosinophilia are “full” activation of eosinophils.23 In in vitro systems, isolated human uncommon.9 At a mechanistic level, IL-5 signaling in mature eo- eosinophils spontaneously undergo apoptosis within 48 h; how- sinophils activates several signaling molecules, such as the JAK- ever, the survival of eosinophils is significantly prolonged in the STAT and MAPK pathways, inducing priming (augmentation of presence of a low concentration of IL-5.17 Of interest, the stimula- effector functions), chemokinesis/chemotaxis,
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