The Role of Thymic Stromal Lymphopoietin in the Pathogenesis and Treatment of Severe Uncontrolled Asthma

The Role of Thymic Stromal Lymphopoietin in the Pathogenesis and Treatment of Severe Uncontrolled Asthma

Nightingale Syabbalo*

Department of Physiology and Medicine, Nabanji Medical Centre, Lusaka, Zambia

*Corresponding author: Nightingale Syabbalo, Department of Physiology and Medicine, Nabanji Medical Centre, Lusaka, Zambia, Tel No: +260 966 486117; E-mail: nightsyab@gmail.com

Received date: December 19, 2020; Accepted date: August 16, 2021; Published date: August 26, 2021

Citation: Nightingale S (2021) The Role of Thymic Stromal Lymphopoietin in the Pathogenesis and Treatment of Severe Uncontrolled Asthma. J Lung Vol: 2 No: 3.

Visit for more related articles at Journal of Lung

Abstract

Asthma is a highly prevalent chronic airway disease, affecting more than 358 million individuals globally [1], and it is the most common chronic inflammatory respiratory disease in children [2]. Asthma has been classified cytological depending on the predominant leucocyte count in induced sputum, and biomarkers of airway inflammation into eosinophilia, neutrophil, mixed granulocytic, and paucigranulocytic phenotypes [3, 4].

Approximately 40-60% of patients with severe asthma have eosinophilic phenotype [5-9], which is uncontrolled on high-dose inhaled corticosteroids (ICS), and long-acting β2-agonists (LABA), and leukotriene receptor antagonists (LTRA) [10,11].

Key words: Severe asthma, Interleukin, Thymic stromal lympopoietin, Tezepelumab.

A proportion of patients with eosinophilia asthma respond favorably to monoclonal antibody (mAb), targeted at T helper lymphocytes (Th2) cytokines, such as interleukin-4 (IL-4), IL-5, IL-13, IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). Th2 cytokines play a pivotal role in the pathogenesis of eosinophilia asthma. Pharmacological blockade of IgE, IL-4, Il-5, TSLP, and their receptors has led to the development of very efficacious biologics for the treatment of eosinophilic asthma. The approved biologics for the treatment of eosinophilic asthma include omalizumab (anti-IgE) [12,13], mepolizumab and reslizumab (anti-IL-5) [14], benralizumab (anti-IL-5R) [15], dupilumab (anti-IL-4R), which block the actions of IL-4 and IL-13 [16]. Eosinophilic biologics have been demonstrated to significantly reduce exacerbation rates, emergency medical visits, improve asthma control, quality of life, and lung functions [12-17].

Several clinical trials have shown that eosinophilic targeted biologics only reduce exacerbation rates in about 48-59% of the patients [12-17]. Furthermore, some patients with eosinophilic asthma do not achieve significant symptoms control, and improvement in lung functions [18-20]. Additionally, some of the biologics may be inadequate to control sputum eosinophilia, and airway eosinophilic inflammation. Therefore, they may not have corticosteroid-sparing effects, particularly in patients with severe oral steroid-dependent asthma [12,21].

Currently, there are no biologics which have been approved for the treatment of patients with neutrophilic, paucigranulocytic, and other phenotypes of asthma [22]. There is unmet need to develop novel biologists which target different Th2 cytokine-driven pathways of asthma [23]. Epithelial “alarmin” cytokines, IL-25, IL-33, and TSLP seem attractive to inhibit, because they are upstream, and initiator cytokines [24].

TSLP plays a central role in the pathophysiology of eosinonophilic asthma, and participates in orchestrating neutrophil asthma, and airway remodeling [25]. Targeting TSLP seems to be an attractive approach for the development of novel biotherapeutics for the treatment of alarming-driven severe uncontrolled asthma [26].

Thyme stromal lymphopoietin is an epithelial derived cytokine that belongs to type 1 cytokine group, which is part of the interleukin-2 cytokine family, comprising of IL-2, IL-4, IL-5. IL-7, IL-9, IL-13, and IL-21 [27]. TSLP is released from airway epithelial cells, following environmental insults, such as allergen proteases, respiratory viral and bacterial infections, chemical irritants, pollutants, and trauma [28-34].

TSLP signaling pathway is mediated through its complex heterodimer receptor formed by a TSLP-specific TSLPR subunit (CRLF2), and the IL-7α signaling chain [35,36]. Signal transduction of the TSLP receptor is via activation of signal transducer and activator of transcription (STAT)1, 3, 4, 5 and 6, as well as Janus Kinase (JAK)1 [37-39]. Upon binding to its receptor, TSLP activates several immune pathways leading to the production of cytokines, chemokine’s, growth factors, and enzymes by immune and structural cells. The aforementioned pro-inflammatory mediators orchestrate eosinophilia airway inflammation, and participate also in airway neutrophil, hyper responsiveness (AHR), and remodeling [26].

TSLP seems attractive to target in therapeutic interventions to treat asthma because it is an upstream cytokine at epithelial barrier. It plays a central role in the pathophysiology of both severe eosinophilia and Europhilic asthma, and paucigranulocytic asthma through its effects on AHR, and airway remodeling.

Tezepelumab is a first-in-class fully human IgGÊ?2 me that bind to TSLP, and prevents it to interact with its receptor TSLPR, thus inhibiting multiple downstream immune pathways, and production of cytokines, and chemokine’s [40]. Tezepelumab has been shown to attenuate both the early and late asthmatic responses, reduce exacerbation rates by 62-71% depending on the dosage [41,42], and to decrease biomarkers of Eosinophilic inflammation (blood eosinophil counts, IgE, and fractional exhaled nitric oxide, FeNO) [43]. The improvements were observed in all the phenotypes of asthma, and independent of baseline blood eosinophil counts, IgE levels, and FeNO concentration [43]. Recently, Tezepelumab has also been shown to decrease serum IL-5, and IL-13 by 30% at 1 year, FeNO by 25%, and total serum IgE by 20% [44]. Therefore, Tezepelumab may be an effective add-on biologics for the treatment of severe uncontrolled Eosinophilic asthma. Additionally, Tezepelumab may ameliorate airway remodeling in other phenotypes of asthma.

Most recently, CSJ117, a fully human neutralizing antibody antigen-binding fragment (Fab) that belongs to IgG1 isotope subclass attenuated both the early asthmatic response (EAR), and late asthmatic response (LAR) in 28 patients with mild, atopic asthma [45]. CSJ117 will probably be the first inhaler biologic for the treatment of asthma.

In summary, asthma is a prevalent chronic airway disease affecting both adults and children, and impacts a incommensurate socio-economic impact of health care systems in many countries. Add-on biologics targeting Th2 cytokines are very effective therapeutic options for the treatment of severe Eosinophilic asthma. However, they do not reduce exacerbation rates, improve asthma control, and lung functions in most patients with different phenotypes of asthma. Tezepelumab is an effective biologics which has been shown to reduce exacerbations in patients regardless of biomarkers of inflammation, and phenotypes of asthma. An inhaler topical anti-TSLP offers an advantage in the management patients with asthma, particularly when added to single maintenance and reliever therapy (SMART) with low-dose ICS-formoterol therapy.