Is Treatment for Type 2 Inflammation With Mepolizumab Beneficial?

A recent study aimed to understand the precise impact of mepolizumab, an anti-IL5 medication, on inflammatory pathways associated with asthma exacerbations in urban children. 

The researchers utilized nasal transcriptomics to identify gene co-expression modules related to exacerbations despite mepolizumab treatment. They employed a method called "differential co-expression network analysis" to assess gene co-expression and loss of correlation, known as "decoherence."

The study involved 290 urban children between the ages of 6 and 17 who had exacerbation-prone asthma and high blood eosinophil levels (≥150/µL). Participants were randomly assigned to receive either placebo or mepolizumab injections every 4 weeks, in addition to guideline-based care for 52 weeks. Nasal lavage samples were collected before and during treatment for RNA-sequencing, allowing researchers to analyze gene networks and their interactions related to type 2 and eosinophilic airway inflammation.

The results showed mepolizumab, but not placebo, significantly reduced the overall expression of a gene co-expression module associated with type 2 inflammation. This module was enriched for genes related to eosinophils, mast cells, and epithelial IL-13 responses. Mepolizumab treatment disrupted the co-expression of genes within this pathway. 

During mepolizumab treatment, there was a significant loss of correlation among eosinophil-specific genes, such as RNASE2 (EDN), RNASE3 (ECP), CLC, SIGLEC8, and IL5RA. In contrast, there was an increase in correlation among mast cell-specific genes (TPSAB1, CPA3, FCER1A), T2 cytokines (IL4, IL5, and IL13), and POSTN.

The findings suggest mepolizumab disrupts the regulatory interactions among airway eosinophils, mast cells, and the epithelium by interrupting transcription regulation, specifically in eosinophils. This disruption leads to an enhancement of mast cell and epithelial inflammation, which may contribute to an incomplete reduction of asthma exacerbations. The study highlights how differential co-expression network analysis can be used to identify potential targets for more precise therapies, researchers said.

Mepolizumab has a paradoxical effect on gene co-expression within the airway, with an impact on eosinophils, mast cells, and the epithelium. These findings shed light on the complex mechanisms involved in asthma exacerbations and provide insights for the development of targeted therapies to improve asthma management in urban children, according to the researchers.

Reference:
Gaberino C, Segnitz RM, Cox M, et al. Mepolizumab alters regulation of airway type-2 inflammation in urban children with asthma by disrupting eosinophil gene expression but enhancing mast cell and epithelial pathways. J Allergy Clin Immunol. 2023;151(2):AB125. doi:10.1016/j.jaci.2022.12.396