Regulation of Eosinophilia in Asthma—New Therapeutic Approaches for Asthma Treatment

Abstract

Asthma is a complex and chronic inflammatory disease of the airways, characterized by variable and recurring symptoms, reversible airflow obstruction, bronchospasm, and airway eosinophilia. As the pathophysiology of asthma is becoming clearer, the identification of new valuable drug targets is emerging. IL-5 is one of these such targets because it is the major cytokine supporting eosinophilia and is responsible for terminal differentiation of human eosinophils, regulating eosinophil proliferation, differentiation, maturation, migration, and prevention of cellular apoptosis. Blockade of the IL-5 pathway has been shown to be efficacious for the treatment of eosinophilic asthma. However, several other inflammatory pathways have been shown to support eosinophilia, including IL-13, the alarmin cytokines TSLP and IL-33, and the IL-3/5/GM-CSF axis. These and other alternate pathways leading to airway eosinophilia will be described, and the efficacy of therapeutics that have been developed to block these pathways will be evaluated.

B-Cell-Depleting Therapy Improves Myocarditis in Seronegative Eosinophilic Granulomatosis with Polyangiitis

“…In addition, in human immunodeficiency virus-associated multicentric Castleman disease with systemic manifestations attributed to disarranged cytokine profiles, there were decreased plasma levels of inflammatory cytokines, including IL-5 after the RTX treatment [ 50 ]. Since B cells are involved in the pathogenesis by inducing the release of IL-5 from Th2 cells [ 6 , 7 , 8 , 9 , 10 ], an action mechanism of B-cell-depleting therapy in seronegative EGPA myocarditis might include the suppression of IL-5-mediated eosinophilia.…”

“…Eosinophils play a central role in the EGPA pathophysiology with blood and tissue eosinophilia as the disease hallmark; IL-5 is recognized as the key mediator in the development and maintenance of this pathogenic finding [ 8 , 9 ]. Through the presentation of autoantigens and costimulatory signaling to Th2 cells, B cells can participate in the pathogenesis by inducing the release of IL-5, resulting in the activation, maturation, survival and recruitment of eosinophils [ 6 , 7 , 8 , 9 , 10 ]. Therapeutic indications of rituximab (RTX), a B-cell-depleting anti-CD20 monoclonal antibody (mAb), have been approved for induction therapy in AAV-related diseases, not including EGPA [ 1 , 8 ].…”

Eosinophils, beyond IL-5

“…They also comment on evidence of eosinophilopoeisis occurring locally in airway tissue. In the same vein, Cusack et al [17] detail the therapies that are used or are evaluated for treatment of eosinophilic asthma, including corticosteroids, the IL-3/5/GM-CSF axis, CCR3, type-2 cytokines and CRTH2, as well as Siglec-8, which is the focus of the article by Youngblood et al [18]. That article relates to the history leading to the development of the humanized therapeutic antibody directed against Siglec-8 to deplete eosinophils.…”

Eosinophilic inflammation: An Appealing Target for Pharmacologic Treatments in Severe Asthma

“…Corticosteroids (CSs) are the most common and powerful anti-inflammatory agents used for the treatment of eosinophilic asthma [ 100 , 101 ]. The therapeutic effects of CSs depend on their binding to cytoplasmic glucocorticoid (GR) receptors, which are mainly represented by the functional isoform GRa, largely more expressed than the GRb variant, which is alternately spliced and dysfunctional [ 102 , 103 ].…”