Dupilumab to Treat Type 2 Inflammatory Diseases in Children and Adolescents

Type-2 inflammatory mediators as targets for precision medicine in children

“…The prevalence, heterogeneity and severity of in type 2 inflammatory diseases, including asthma and atopic dermatitis (AD), continue to rise, especially in children and adolescents, who are bearing the highest burden in terms of morbidity and health care expenditure. 1 Although allergen immunotherapy has disease-modifying properties and confers long-term clinical benefit after cessation of treatment, its indication is still limited to patients with clinically significant immunoglobulin E (IgE)-mediated respiratory allergies. 2 Most treatments available today merely provide long-term relief of symptoms, making it increasingly clear that new targeted approaches for the management of allergic diseases are required.…”

“…Type 2 inflammation is sustained by a specific subset of cytokines, such as interleukin (IL)-4, IL-5, IL-13, and IgE, resulting in the recruitment of cells such as eosinophils, basophils, and mast cells into the affected tissues. 1 Type 2 responses are initiated with the disruption of the respiratory and, to a minor extent, epidermal epithelial barrier by exposures to allergens, viruses, bacteria, and other environmental triggers. Epithelial cells release IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), which stimulate Th2 cells, type 2 innate lymphoid cells (ILC2), and invariant natural killer T cells (NKT cells) to secrete Th2 cytokines and to activate dendritic cells (DCs).…”

“…Epithelial cells release IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), which stimulate Th2 cells, type 2 innate lymphoid cells (ILC2), and invariant natural killer T cells (NKT cells) to secrete Th2 cytokines and to activate dendritic cells (DCs). 1 This results in further differentiation and clonal expansion of Th2 cells and activation of ILC2 cells, as well as tissue eosinophilia. Activated Th2 cells and ILC2 cells mainly release IL-4 and IL-13, which both have a central role in many of the pathobiological tissue changes, including airway inflammation and remodeling in asthma and epidermal barrier dysfunction in AD.…”

“…Their biological functions are exerted through the binding of two receptor (IL-4R) subtypes, both sharing the common IL-4Rα. 1 IL-4R plays a key role in the IgE class-switch in B cells and the production of allergen specific IgE antibodies and in the activation of other immune cells, such as mast cells, basophils, and macrophages. IL-13 and, to a lesser extent, IL-4 stimulate globet cell hyperplasia, increase mucus production and proliferation of smooth muscle cells in the airways; in the skin, IL-4 and IL-13 promote barrier dysfunction on epidermis by downregulating expression of filaggrin in normal keratinocytes, as well as increasing susceptibility to infections by inhibiting production of antimicrobial peptides.…”

“…IL-13 and, to a lesser extent, IL-4 stimulate globet cell hyperplasia, increase mucus production and proliferation of smooth muscle cells in the airways; in the skin, IL-4 and IL-13 promote barrier dysfunction on epidermis by downregulating expression of filaggrin in normal keratinocytes, as well as increasing susceptibility to infections by inhibiting production of antimicrobial peptides. 1 In addition, it has been demonstrated that the chronic activation of the IL-4R pathway alters immunotolerance by promoting the complete subversion of Treg cells into Th2 cells, thus expanding and maintaining the type 2 inflammation.…”