Targeting interleukin-33 and thymic stromal lymphopoietin pathways for novel pulmonary therapeutics in asthma and COPD

Abstract

Interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) are alarmins that are released upon airway epithelial injury from insults such as viruses and cigarette smoke, and play critical roles in the activation of immune cell populations such as mast cells, eosinophils and group 2 innate lymphoid cells. Both cytokines were previously understood to primarily drive type 2 (T2) inflammation, but there is emerging evidence for a role for these alarmins to additionally mediate non-T2 inflammation, with recent clinical trial data in asthma and COPD cohorts with non-T2 inflammation providing support. Currently available treatments for both COPD and asthma provide symptomatic relief with disease control, improving lung function and reducing exacerbation rates; however, there still remains an unmet need for further improving lung function and reducing exacerbations, particularly for those not responsive to currently available treatments. The epithelial cytokines/alarmins are involved in exacerbations; biologics targeting TSLP and IL-33 have been shown to reduce exacerbations in moderate-to-severe asthma, either in a broad population or in specific subgroups, respectively. For COPD, while there is clinical evidence for IL-33 blockade impacting exacerbations in COPD, clinical data from anti-TSLP therapies is awaited. Clinical data to date support an acceptable safety profile for patients with airway diseases for both anti-IL-33 and anti-TSLP antibodies in development. We examine the roles of IL-33 and TSLP, their potential use as drug targets, and the evidence for target patient populations for COPD and asthma, together with ongoing and future trials focused on these targets.

A conversation on allergy: recognizing the past and looking to the future

“…[69][70][71] However, over the past decade, a new wave of biologics targeting the cytokines IL-4, IL-13, IL-5, IL-33, thymic stromal lymphopoietin (TSLP), IL-31 and/or their receptors have heralded a new age in the treatment of diseases including asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis and other diseases. 6,72,73 In line with the efficacy of several new biologics, we have come to a greater appreciation of endotypes of allergy, which greatly inform patient treatment options. Patients are no longer stratified only on the basis of IgE, but on the expression type 2 cytokines, levels of eosinophils, presence of airway inflammation (fractional exhaled nitric oxide) and on specific allergen reactivities.…”

“…Omalizumab (a monoclonal targeting IgE) was first approved for use in 2003 and demonstrated efficacy in moderate–severe asthmatics 69–71 . However, over the past decade, a new wave of biologics targeting the cytokines IL‐4, IL‐13, IL‐5, IL‐33, thymic stromal lymphopoietin (TSLP), IL‐31 and/or their receptors have heralded a new age in the treatment of diseases including asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis and other diseases 6,72,73 . In line with the efficacy of several new biologics, we have come to a greater appreciation of endotypes of allergy, which greatly inform patient treatment options.…”

Ferroptosis triggers airway inflammation in asthma

“…31 The molecular pathways that can be targeted include T2 cytokines, IgE, thymic stromal lymphopoietin (TSLP), and IL-33 etc. [32][33][34] The latest research shows that ferroptosis may be an emerging target in inflammatory diseases. 10 Authors identified that ferroptosis inhibitor alleviates bronchial epithelial cell injury in asthma.…”

Integrating TREC/KREC assay and some cytokines in the evaluation of the immune status of patients with DiGeorge Syndrome

“…It is found in multiple organs and is mainly localized to barrier epithelial cells and endothelial cells. Fibroblasts, myo broblasts, and airway smooth muscle cells were also found to express Il-33 [19,20]. (Byers et al, 2013Calderon et al, 2023.…”

“…Fibroblasts, myo broblasts, and airway smooth muscle cells were also found to express Il-33 [19,20]. (Byers et al, 2013Calderon et al, 2023.…”