L7 - pathogenesis of asthma 2

• chronic asthma is a long term exposure to allergen that drives repeated inflammatory episodes leading to chronic inflammation and serious long term illness
• airways of asthmatics shows characteristics of chronic wounding with evidence ongoing epithelial injury and repair
• type 2 cytokines in pathogenesis of asthma act on innate and adaptive immune cells

  • IL-5 and IL-4
• type 2 cytokines also act on non-immune cells that drive many salient features of asthma
• IL-13 - increases ICAM1 and VCAM1 on epithelium

  • inflammatory cells bind and transmigrate through endothelial walls into tissue
• inhaled corticosteroids as frontline treatment


  suppresses Th2 response - dampens inflammation in airways

  not effective during viral-induced exacerbation, smokers, or Th17-dominated asthma endotypes
• inhaled b2-adrenoceptor agonists


  short acting = salbutamol

  long-acting = formaterol
• salbutamol is short acting and causes bronchodilation, induces smooth muscle relaxation
• formaterol is long acting and causes bronchodilation for 12hours dor endotypes not controlled by corticosteroids
• can use a combination inhaled
• omalizumab - targets IgE in moderate to severe allergic asthma
• omalizumab is a humanised anti-IgE antibody


  binds epitope IgE overlaps site antibody that bind FCeR1 receptor

  • blocks IgE from binding to receptor on mast cells
  • prevents degranulation
  • decreases soluble mediators
  • prolonged treatment causes a reduction in Th2 cytokines in lung tissue
• Dupilumab - targets Th2 cytokines in severe asthma with type 2 inflammation
• Dipilumab is a human anti-IL-Ra antibody that target 2 cytokines with 1 antibody


  IL-4 receptor and IL-13 receptor, both have a subunit IL-4 receptor

  • can block downstream signalling via receptors IL-4 and IL-13
  • improves lung function
  • decreases frequency exacerbation in patients with moderate and severe asthma with high eosinophil levels
• Mepolizumab - IL-5 inhibition, blocks eosinophils in severe eosinophilic asthma
• Mepolizumab is humanised monoclonal anti-IL-5


  decreases eosinophil numbers in blood

  IL-5 get eosinophils out bone marrow into lung, so inhibiting decreases frequency exacerbations

  • decreases ECM components
• Benralizumab - blocks eosinophils by targeting IL-4 inhibtion
• Benralizumab is used in severe eosinophilic asthma


  depletes eosinophils for months post single injection by antibody dependent cellular cytotoxicity
• Lebrikizumab blocks IL-13 in asthma, isnt yet licenced
• Lebrikizumab is humanised anti-IL-13


  there have been 2 identical phase 3 trials for severe asthma in 2016

  • successful - asthmatics with high blood eosinophil levels or high periostin levels experienced: significant reduction exacerbation and improvement in lung function
  • other trial endpoints not met, not sufficient improvements
• Brodalumab - blocks IL-17 signalling - not licenced
• Brodalumab is human anti-IL-17RA monoclonal antibody


  blocks activity IL-17A , IL-17F, IL-25 in certain endotypes

  did not control mild moderate in phase 2 trial

  sub-groups of patients with higher neutrophil counts may respond more favourably
• Tezepelumab - target endothelial cell derived cytokines - thymic stromal lymphopoietin
• Tezepelumab is human anti-TSLP antibody

  TSLP contributes to airway remodelling produced by epithelial cells

  so blocks late asthmatic responses and bronchoconstriction

  • reduces eosinophil counts
  • trials underway to investigate targeting IL-33