Strategies Targeting Type 2 Inflammation: From Monoclonal Antibodies to JAK-Inhibitors

Abstract

Bronchial asthma and its frequent comorbidity chronic rhinosinusitis (CRS), are characterized by an inflammatory process at lower and upper respiratory tract, with a variability in terms of clinical presentations (phenotypes) and distinct underpin pathophysiological mechanisms (endotypes). Based on the characteristics of inflammation, bronchial asthma can be distinguished into type 2 (eosinophilic) or nontype 2 (noneosinophilic) endotypes. In type 2 asthma endotype, the pathogenic mechanism is sustained by an inflammatory process driven by Th2 cells, type 2 innate lymphoid cells (ILC2) and type 2 cytokines, which include interleukin (IL)-4, IL-5, IL-9 and IL-13. The definition of asthma and chronic rhinusinusitis phenotype/endotype is crucial, taking into account the availability of novel biologic agents, such as monoclonal antibodies targeting the classical type 2 cytokines. Recently, new therapeutic strategies have been proposed and analyzed in preliminary clinical trials. Among them Janus kinase (JAK) inhibitors, now largely used for the treatment of other chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases, is receiving great relevance. The rationale of this strategy derives from the data that JAK is a tyrosine kinase involved in the signaling of T cell receptor and of several cytokines that play a role in allergic respiratory disease, such as IL-2, IL-4 and IL-9. In this review, we discuss whether treatment with biological agents and JAK inhibitors may be equally effective in controlling type 2 inflammatory process in both asthma and CRS.

Identifying key genes and functionally enriched pathways in Th2-high asthma by weighted gene co-expression network analysis

“…Based on the characteristics of inflammation, bronchial asthma can be identified into two endotypes, type 2 asthma and nontype 2 asthma [ 14 – 16 ]. Th2 cells and cytokines (an imbalance of Th1/Th2) play a major role in type 2 inflammation, which is considered a major pathophysiological mechanism of asthma [ 2 , 4 ]. Several reports have identified a typical Th2 feature characterized by elevated Th2-type inflammation in the lower airway [ 7 , 17 ].…”

“…The CD4 T-helper cell type 2 (Th2)-mediated pathway in the airway epithelium is critical in allergic asthma [ 2 ]. Drugs targeting Th2 cytokines (IL-4, IL-5, and IL-13) have been developed and shown efficacy in recent studies [ 3 , 4 ]. However, the etiology and progression of asthma are still under investigation.…”

“…Although multiple studies have shown differences in cytokine expression between Th2-high and Th2-low asthma [ 4 , 5 ], it is not known whether the gene signature of bronchial airway epithelium can identify Th2-high and Th2-low endotypes. Weighted gene coexpression network analysis (WGCNA) is a useful tool to identify functional pathways and candidate biomarkers and has recently been used to explore the complex relationships between gene network signatures and complicated phenotypes [ 6 ].…”

Drug Targeting and Nanomedicine: Lessons Learned from Liver Targeting and Opportunities for Drug Innovation

“…This is particularly relevant for the treatment of chronic diseases. These studies may therefore provide important information for the chronic use of kinase inhibitors which play a pivotal role in current therapies against cancers and chronic inflammatory diseases [84][85][86].…”

A Comparative and Comprehensive Review of Antibody Applications in the Treatment of Lung Disease

“…Four commonly used mAbs in treating T2 asthma by reducing eosinophilic inflammation are mepolizumab, dupilumab, reslizumab, and benralizumab [55].…”