Local immunomodulation in asthma

Question 1

What are the variables in asthma?

Answer 1

• Age of onset
• Gender
• Allergic sensitization
• Virus infections
• Transient/persistent wheeze
• Response to asthma medication (corticosteroids)

Question 2

What is the recent change in the approach to treating asthma?

Answer 2

Instead of treating symptoms, target the underlying cause. Focus on endotype. If you understand the underlying mechanism (endotype), you can apply the right treatment.

Question 3

What are the two phenotypes in asthma and what are their characteristics?

Answer 3

Eosinophilic and non-eosinophilic.
Eosinophilic: Th2 predominant, eosinophilia in blood and sputum, allergic sensitization and airway inflammation (FeNO)
Non-eosinophilic: neutrophilia, Th1/Th17 cells and airway inflammation (FeNO)

Question 4

What are biomarkers and treatment markers of eosinophilic asthma?

Answer 4

Biomarkers and treatment markers of eosinophilic asthma: IL-4, IL-5, IL-9, IL-13, PGD2, Cys-LTs, MBP, ECP, EPO and TGF-beta

Question 5

What are biomarkers and treatment markers of non-eosinophilic asthma?

Answer 5

Biomarkers and treatment markers of non-eosinophilic asthma: IL-8, IL-17, IL-22, MMP-9, neutrophil-elastase, LTB4, TNF-alfa, ROS and IFN-gamma

Question 6

What are clinical phenotypes of eosinophilic asthma?

Answer 6

Allergy and eosinophilic inflammation

Question 7

What are clinical phenotypes of non-eosinophilic asthma?

Answer 7

Neutrophilic inflammation and paucigranulocytic inflammation

Question 8

What clinical phenotype is present in both eosinophilic asthma and non-eosinophilic asthma?

Answer 8

Airway hyperresponsiveness and remodeling

Question 9

What cells are involved in non-eosinophilic asthma?

Answer 9

Cells involved in non-eosinophilic asthma: Epithelium, Th17, Neutrophil, ILC3, TH1, NK/NKT

Question 10

What cells are involved in eosinophilic asthma?

Answer 10

Cells involved in eosinophilic asthma: Epithelium, eosinophil, Th2, mast cell and ILC2

Question 11

Is eosinophilic early onset or late onset?

Answer 11

Eosinophilic is early onset

Question 12

Is non-eosinophilic early onset or late onset?

Answer 12

Non-eosinophilic is late onset

Question 13

What are treatments of asthma?

Answer 13

• Antihistamines
• Bronchodilators: β2 receptor agonists
• (Inhaled) corticosteroids
• Leukotriene inhibitors (LABA)
• New kids on the block: (expensive) biologicals!

Question 14

Asthma can be subdivided in T2/Th2 and non-T2/Th2 asthma. What are essential elements of T2 asthma?

Answer 14

Eosinophilia, Th2 cells and ILC2 cells

Question 15

What are the effector cytokines that can be found in T2/Th2-asthma?

Answer 15

TSLP, IL-33, IL-25,(T2 innate cytokines produced by the epithelial cells) IL-4, IL-5, IL-9, IL-13 (produced by Th2 and ILC2 cells).

Question 16

What happened with the therapeutic application of the monoclonal anti-IgE antibody Omaluzimab?

Answer 16

With this treatment, there was still a seasonal effect, but the amount of excerbations was significantly less than the control group.

Question 17

What is the effect of therapeutic anti-IgE?

Answer 17

The effect of therapeutic anti-IgE: anti-IgE prevents mast cells from acquiring cell-surface IgE. Mast cell cannot be activated through Fc-epsilon-RI and downregulates its cell-surface expression

Question 18

What is the effect of experimental anti-IgE?

Answer 18

The effect of experimental anti-IgE: anti-IgE cross-links IgE bound to Fc-epsilon-RI and activates mast-cell deregulation. Inflammatory response

Question 19

In what group of asthma patients were T2 applied?

Answer 19

A small group of severe (uncontrolled) asthma

Question 20

What types of biologicals are there?

Answer 20

Anti-IgE, anti-IL-4 receptor, anti-IL-5, IL-5 receptor antagonist, anti-TSLP, anti-IL-33/ST2 and DP2 receptor antagonist (acts on ILC2).

Question 21

What types of biologicals are FDA approved?

Answer 21

Anti-IgE , anti-IL-5, anti-IL-5R and anti-IL-4R

Question 22

How effective are biologicals as treatment for asthma?

Answer 22

• All reduced annual exacerbation rate and hospitalization
• Benralizumab (anti-IL-5R), dupilumab (anti-IL-4R) and reslizumab (anti-IL-5) reduce daily dose of oral corticosteroids
• All effect asthma control, Quality of Life and FEV1 slightly to moderately

However, the cost-effectiveness per quality adjusted life year is above willingness to pay threshold

Question 23

Why is asthma more prevelant in Western countries and urban centres of developing countries?

Answer 23

Because of the change in lifestyle:
•Rural –> Urban (Economic drive)
•Slow food –> Fast Food
•Physical labor –> sitting professions
•Outdoors –> Indoors Housing: isolation, central heating, less humid
•Health care: prevent/treat infections diseases
(improved sanitation)

Huge differences between urban and rural in the immune system detected by mass cytometry (based on 40 markers).

Question 24

What is Strachan’s hygiene hypothesis?

Answer 24

Strachan’s hygiene hypothesis: children have less hay fever because they are exposed to germs from older siblings.

Question 25

What is the Old friends hypothesis?

Answer 25

Old friends hypothesis: Microorganisms (‘Old Friends’) that were once abundant trained our immune system: they were tolerated at dispense of excessive tissue damage to eradicate them. Our immune system has evolved in their continuous presence.

Question 26

What is the influence of diet on cells in broncho-alveolar lavage?

Answer 26

Short Chain Fatty Acids are produced by the gut microbiota from fermentation of dietary fibers. Most common are acetate, butyrate & propionate.
A high fiber diet causes less eosinophils in broncho-alveolar lavage compared to a regular diet.
A low fiber diet causes more eosinophils and lymphocytes in broncho-alveolar lavage compared to a regular diet.

Question 27

Can asthma patients be treated by allergen-immunotherapy?

Answer 27

Yes, but only for those that are allergic and it may only affect the allergic symptoms. This is because the therapy really focuses on the allergen-specific immune response and deviation in those immune responses.

Question 28

How is it going with therapeutic exploitation of gut microbiota?

Answer 28

How is it going with therapeutic exploitation of gut microbiota?

Clinical trials:
•Pre/probiotics (disappointing)
•Bacterial lysates (lung pathogens)

Issues:
•Duration of intervention
•Single vs multiple species

New Opportunities (mouse models):
•Metabolites
•Immunomodulatory molecules