• Research presented at ATS 2024 highlights the critical role of thymic stromal lymphopoietin (TSLP) in severe asthma. Elevated TSLP levels are linked to more severe disease and increased type 2 inflammation, providing a potential target for new therapies.
• Thymic stromal lymphopoietin (TSLP) plays a crucial role in regulating type 2 immune responses in asthma, and targeting TSLP with therapies like tezepelumab shows promise in improving asthma control.

Asthma, a common respiratory condition, affects millions worldwide, but severe asthma, impacting up to 10% of people living with asthma, presents unique challenges. Severe asthma often resists standard treatments, resulting in significant morbidity, reduced quality of life, and increased healthcare utilization. 

The research, presented at the ATS 2024 by the University of California, San Francisco, and the SARP network, provides crucial insights into the molecular underpinnings of severe asthma, paving the way for innovative therapeutic strategies.

The Severe Asthma Research Program (SARP) is a National Institutes of Health (NIH)-sponsored initiative linking seven leading asthma clinical centers and a data coordinating center. SARP's mission is to elucidate the mechanisms of severe asthma to foster the development of more effective treatments. Now in its third phase (SARP III), the program has enrolled over 700 participants, including adults and children, for comprehensive, longitudinal studies of asthma.

Researchers from the University of California, San Francisco, and the SARP team employed a V-Plex immunoassay (Meso Scale Discovery, ACRO Biosystems Group) to measure TSLP protein levels in banked sputum samples from 414 SARP-3 participants and 104 healthy controls. 

Thymic stromal lymphopoietin (TSLP) is a pivotal molecule in regulating type 2 immune responses in asthma, also potentially influencing non-type 2 inflammation. However, detailed information on TSLP protein levels in the airways of asthma patients and their relationship with inflammation is limited.

TSLP levels in healthy controls established a normal range, defining TSLP-high and TSLP-low subsets among asthma patients. Clinical characteristics and inflammatory biomarkers associated with TSLP-high status were analyzed, including gene expression data from bulk RNA sequencing of sputum cells.

Research key findings

• Elevated Sputum TSLP in Asthma: Asthma patients exhibited significantly higher sputum TSLP levels compared to healthy controls. Using the 95th percentile TSLP value in healthy controls (1.5 pg/mL) to classify patients, 34.1% of asthma patients fell into the TSLP-high category.
• Association with Severe Disease and Type 2 Inflammation: TSLP-high asthma patients displayed more severe disease characteristics, including notably lower lung function and elevated markers of type 2 inflammation, such as increased nitric oxide in exhaled breath and higher eosinophil counts in blood and sputum.
• Lack of Association with Non-Type 2 Inflammation: Blood and sputum neutrophil levels did not differ significantly between TSLP-low and TSLP-high asthma patients, indicating no strong association with non-type 2 inflammation.
• Correlation with Type 2 Gene Network: In TSLP-high asthma, the expression of type 2 network genes in sputum cells was significantly higher than in TSLP-low asthma. While type 1 network gene expression was also elevated in TSLP-high asthma, this increase was less pronounced when excluding patients with high type 2 network gene expression.

The study concludes that airway TSLP protein levels are elevated in asthma patients, with 34% of the SARP-3 cohort classified as TSLP-high. These patients exhibit more severe asthma and a strong association with type 2 inflammation markers, underscoring TSLP’s role in type 2 immune responses. The findings highlight the potential of targeting TSLP in developing treatments for severe asthma and improving patient outcomes.

Summary: The connection between thymic stromal lymphopoietin (TSLP) and severe asthma highlights the potential for targeted therapies to manage this chronic condition more effectively. TSLP influences multiple cell types and inflammatory pathways, making it a pivotal mediator in asthma pathophysiology. Tezspire (tezepelumab), the first anti-TSLP monoclonal antibody, has shown promising results in clinical trials and has been recognized as a breakthrough therapy by the FDA. Its broad-spectrum anti-inflammatory action suggests it could offer better control of day-to-day symptoms and reduce exacerbations compared to therapies targeting individual immune mediators.

Ongoing research into various TSLP inhibitors, such as BSI-045B and other innovative approaches like fully human single-chain fragment variables and TSLP-traps, demonstrates the expanding interest in this therapeutic strategy. These developments aim to disrupt the TSLP: TSLPR interaction, thus mitigating the inflammatory signaling cascade in asthma. However, critical aspects such as long-term safety, patient subgroup identification, and the precise mechanisms of TSLP in asthma need further clarification. Addressing these will be essential to optimize the use of TSLP-targeted therapies and ensure they provide safe, effective relief for severe asthma patients.

TSLP significantly impacts airway inflammation by affecting various cell types and pathways. Consequently, targeting TSLP offers a novel approach to treating asthma-related inflammation.