Eosinophil Lineage-Committed Progenitors as a Therapeutic Target for Asthma

Abstract

Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5–10%) remain uncontrolled with significant therapy-related side effects. This indicates the need for a consideration of alternative treatment strategies that target airway eosinophilia with corticosteroid-sparing benefits. A growing body of evidence shows that a balance between systemic differentiation and local tissue eosinophilopoietic processes driven by traffic and lung homing of bone marrow-derived hemopoietic progenitor cells (HPCs) are important components for the development of airway eosinophilia in asthma. Interleukin (IL)-5 is considered a critical and selective driver of terminal differentiation of eosinophils. Studies targeting IL-5 or IL-5R show that although mature and immature eosinophils are decreased within the airways, there is incomplete ablation, particularly within the bronchial tissue. Eotaxin is a chemoattractant for mature eosinophils and eosinophil-lineage committed progenitor cells (EoP), yet anti-CCR3 studies did not yield meaningful clinical outcomes. Recent studies highlight the role of epithelial cell-derived alarmin cytokines, IL-33 and TSLP, (Thymic stromal lymphopoietin) in progenitor cell traffic and local differentiative processes. This review provides an overview of the role of EoP in asthma and discusses findings from clinical trials with various therapeutic targets. We will show that targeting single mediators downstream of the inflammatory cascade may not fully attenuate tissue eosinophilia due to the multiplicity of factors that can promote tissue eosinophilia. Blocking lung homing and local eosinophilopoiesis through mediators upstream of this cascade may yield greater improvement in clinical outcomes.

Comparative Efficacy and Safety of Tezepelumab and Other Biologics in Patients with Inadequately Controlled Asthma According to Thresholds of Type 2 Inflammatory Biomarkers: A Systematic Review and Network Meta-Analysis

“…However, the inhibitory effects of dupilumab, benralizumab, and mepolizumab on non-type 2 inflammation are very limited [ 5 ]. These differences in the effects of tezepelumab and conventional biologics (dupilumab, benralizumab, and mepolizumab) on non-type 2 inflammation may explain our findings ( Figure 7 ) [ 2 , 3 , 4 , 66 , 67 ].…”

Potent CCR3 Receptor Antagonist, SB328437, Suppresses Colonic Eosinophil Chemotaxis and Inflammation in the Winnie Murine Model of Spontaneous Chronic Colitis

“…Furthermore, these CD34 + progenitor cells had an increase in mRNA expression for CCR3 receptors, potentially leading to the differentiation of eosinophil lineage [ 127 ]. As EPoCs differentiate into mature eosinophil lineages, CD34 + expression diminishes, due to activation by factors inducing eosinopoiesis, inclusive of IL-3, IL-5, and GM-CSF [ 128 ]. In our study, the lack of effects of SB3 treatment on the number of EPoCs in the bone marrow of mice with chronic colitis coincided with elevated IL-5 levels in their serum after treatment.…”

Strategies Targeting Type 2 Inflammation: From Monoclonal Antibodies to JAK-Inhibitors

“…Mepolizumab, reslizumab and benralizumab are three mAbs that reduce eosinophilic inflammation and are recommended as add-on therapies for the treatment of patients with severe, uncontrolled asthma who exhibit an eosinophilic phenotype [65][66][67]. These biological agents have been designed taking into account the central role of IL-5 in the differentiation, maturation and survival of eosinophils [67][68][69]. While the effect of the anti-IL-5 mAbs has been related to their ability to indirectly target eosinophils, benralizumab, a humanized afucosylated mAb recognizing the α-subunit of the IL-5 receptor, exerts its effect directly by depleting eosinophils through antibody-dependent cell-mediated cytotoxicity (ADCC) [70,71].…”