Treatment of severe persistent asthma with IL-6 receptor blockade

Abstract

The use of tocilizumab in two children with severe persistent, steroid-resistant asthma resulted in immunological improvement and suggestive of clinical improvement.

A regulatory T cell Notch4–GDF15 axis licenses tissue inflammation in asthma

“…Analysis of peripheral blood cells of a severe asthmatic subject treated with the anti-IL-6R mAb Tocilizumab revealed decreased Notch4 expression on the patient T reg cells post initiation of therapy, consistent with the requirement for IL-6R signaling to upregulate Notch4 expression ( Fig. 8i ) 25 . These results, which mirror those obtained in the mouse system, indicate that Notch4 expression may similarly serve as an immune regulatory switch that licenses allergic inflammation in human asthmatics.…”

“…Remarkably, this pathway thus integrates several genetic loci, including NOTCH4 , IL6 and IL33 , identified to impart susceptibility to asthma incidence and/or disease severity 26 , 27 , 28 , 29 , 30 . T reg cell-specific deletion of Il6ra or Stat3 substantially attenuated Notch4 expression in T reg cells in allergic airway inflammation, as did treatment of a severe asthmatic subject with the anti-IL-6Rα chain mAb tocilizumab 25 . STAT3 was demonstrated to bind to the Notch4 promoter, consistent with direct upregulation of Notch4 expression by IL-6-STAT3 signaling.…”

Serum Concentrations of Interleukin 6 in the General Adult Population: Possible Implications for Anti–IL-6 Therapy in SARS-Cov-2 Infection and IL-6–Related Diseases

“…Serum IL-6 is a wellknown inflammatory marker [2]. Moreover, IL-6-neutralizing therapies are used in a variety of inflammatory diseases, including rheumatoid arthritis, polyarticular and systemic juvenile idiopathic arthritis, giant cell arteritis, Castleman's disease and, chimeric antigen receptor T cell therapy (CAR-T)-induced cytokine release syndrome [3], and some forms of severe asthma [4].…”

“…Serum IL-6 concentrations are slightly higher in males than in females and they significantly increase with age. The latter is particularly important for diseases that are either more frequent or clinically more severe in older patients, such as some systemic inflammatory diseases, some forms of asthma, or SARS-Cov-2-induced disease [3][4][5]15] c Alcohol consumption was calculated by the sum of units regularly consumed per week (1 glass of wine or 1 beer are approximately equivalent to 10 g of alcohol or 1 unit; 1 cup of spirits is approximately equivalent to 20 g of alcohol or 2 units). d Body mass index was calculated as the weight (in kg) divided by the square of the height (in meters).…”

Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections

“…In this setting, Notch4 acts via downstream pathways, including Hippo and Wnt, to disrupt Treg cell regulation of the T helper type 2 (Th2) and Th17 adaptive immune responses. In case studies, treatment of individuals with severe asthma with the anti-IL-6R mAb tocilizumab decreased Notch4 expression on circulating Treg cells and improved disease outcomes ( Esty et al., 2019 ).…”