T2 asthma and T2-associated diseases: a consolidated approach to biological therapy

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Abstract

This article is dedicated to the main characteristics of severe bronchial asthma (SBA) and its heterogeneity. In particular, it describes T2 asthma and the role of the main cytokines involved in T2 inflammation. It focuses on the role of IL-4 and IL-13 in the pathogenesis of asthma and other T2-associated diseases, as key cytokines in the initiation and maintenance of T2 inflammation. The article presents the results of experimental studies proving that the activation of IL-4/IL-13 can cause significant hyperresponsiveness of the human airway smooth muscles and the combined blockade of the activity of these cytokines using a human monoclonal antibody against the common IL-4/13 receptor á-subunit-dupilumab-determines the clinical efficacy not only in relation to exacerbations and control of asthma symptoms, but also an improvement of the lung function and a reduction in bronchial hyperresponsiveness. When type 2 helper cells (Th2) interact with antigen-presenting cells, IL-4 and IL-13 are simultaneously released, therefore, blocking IL-4Rá is more effective than blocking each of the ligands separately, which explains the high efficacy of dupilumab not only in T2 asthma, but also other T2-associated diseases: atopic dermatitis and chronic rhinosinusitis with nasal polyps. In addition to asthma and atopic dermatitis, a new indication for dupilumab, chronic rhinosinusitis with nasal polyps, has recently been approved.

According to the recommendations of the European Academy of Allergy and Clinical Immunology (EAACI) for the biological therapy of SBA 2020, dupilumab is recommended as an add-on maintenance therapy in adults and children aged 12–17 years old with uncontrolled severe T2 asthma, including asthma with the allergic and eosinophilic phenotype, as well as mixed (when there are signs of both phenotypes) and steroid-dependent asthma. At the same time, dupilumab is well tolerated.

About the authors

Natalya M. Nenasheva

Federal State Budgetary Educational Institution of Additional Professional Education Russian Medical Academy of Continuous Professional Education

Author for correspondence.
Email: 1444031@gmail.com
ORCID iD: 0000-0002-3162-2510

Head of Allergology and Immunology Department of Russian Medical Academy of Continuing Professional Education of the Ministry of Health of the Russian Federation, PhD, professor

Russian Federation, Moscow

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2. Fig. 1. IL-4 and IL-13 are the main and central type 2 cytokines that determine the pathophysiological mechanisms of the development of T2 inflammation (adapted from Gandhi NA et al., 2017 [16])

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3. Fig. 2. Dual inhibition of IL-4/IL-13 prevents HDMA-induced impairment of the lung function (c – genetically modified mice were challenged with HDMA or saline for 4 weeks. Two groups of mice exposed to HDMA were subsequently injected with hIgGcontr or anti-IL-4Rα antibodies; d–f – 72–100 h after the last exposure to HDMA, pulmonary function and airway hyperresponsiveness in mice were assessed using negative pressure-driven forced expiratory maneuvers (NPFE) and the forced oscillation technique (FOT) on the FlexiVent platform. After registration of the baseline parameters (d), the mice received increasing doses of methacholine via a nebulizer, for 10 seconds each (0; 2; 4; 6; 10 and 14 mg/mL), after which the functional parameters were measured again (e, f). For each dose of methacholine, FEV0,1 is presented in absolute figures (e) and in relation to the baseline (f) (n≥5 mice in the group); d – * p<0.01 compared with mice that were not exposed to HDMA; e, f – # p<0.1; ## – p<0.01; ### – p<0.001 for mice not exposed to HDMA, compared to mice exposed to HDMA; * – p<0.01; ** – p<0.001 for anti-IL-4Rα antibodies compared to groups treated with IgG control (other significant comparisons not shown), adapted from [29]

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4. Fig. 3. Effect of dupilumab on BH stimulated by IL-13 and IL-4. Cumulative concentration-response curves were obtained for histamine in human bronchial rings treated for 2 days with IL-13 (a) and IL-4 (b) with and without dupilumab (1 μmol). Statistical comparison of the cytokine pEC50 in human bronchial rings treated with dupilumab and in bronchial segments treated with IL-13 and IL-4 was performed using the paired t-test; a – p<0.01; b – p<0.05. Maximum induction of intracellular calcium by histamine in human airway smooth muscles treated with IL-13 (c) or IL-4 (d) for 24 h with or without dupilumab. Data are presented as mean ± standard error of the mean [32]

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5. Fig. 4. The main mechanism of action of dupilumab (adapted from Gandhi NA et al., 2016 [33]; JAK1,2,3 – Janus kinases; TYK2 – tyrosine kinase; STAT – transcription factors)

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6. Fig. 5. Dupilumab significantly reduced the frequency of severe exacerbations in patients with uncontrolled persistent bronchial asthma (adapted from [30])

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7. Fig. 6. The study of a steroid-sparing effect (VENTURE): a statistically significant decrease in the need for OCS compared to placebo at week 24 in the general population while using dupilumab (adapted from [31])

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8. Fig. 7. A reduction in the frequency of exacerbations and improvement of the lung function (adapted from [34])

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