Allergen immunotherapy Flashcards
What is allergen immunotherapy?
Treatment for IgE mediated allergies (type 1 allergies) such as hay fever (allergic rhino-conjunctivitis), venom allergy, allergic asthma and immediate-type food allergy.
What are immunological hallmarks of type I allergy?
Immunological hallmarks of type I allergy: Allergen specific IgE antibodies Allergen-specific Th2 cells ILC2 (Innate Lymphoid Cells type 2) cells IL-4, IL-5, IL-13 Effector cells of allergic response o Mast cells/basophils o Eosinophils
What are treatment options for allergies?
- Allergen avoidance
- “Traditional” symptom medications such as anti-histamines, corticosteroids, adrenaline, etc.
- “New generation” symptom medications: biologicals, e.g. anti-IgE (Omalizumab), anti-IL4/IL13 receptor (Dupilumab)
- Allergen Immunotherapy
What is allergen immunotherapy treatment?
- Exposing the allergic patient to the allergen source they are allergic to, starting at a very low dose and slowly increasing it to a high maintenance dose
- Originally, all AIT was administered via monthly subcutaneous injections (SCIT), but later also via daily sublingual drops or tablets (SLIT).
- For good efficacy, at least 3 years of treatment are needed. After that in majority of patients tolerance remains intact, even if AIT is discontinued (big advantage compared to symptomatic treatment).
What is the mechanism of IgE-mediated allergy?
Sensitization:
- A DC phagocytoses the allergen. The epithelium cells secrete TSLP, IL25, IL33, CCL2 and CCL20. ILC2s and basophils secrete IL-13 and IL-4
- When there is a lack of IFN-gamma, DCs present the antigen to basophils and Th0 cells.
- Th0 cells differentiate into Th2 cells and Tfh cells.
- These Th2 and Tfh cells secrete IL-4/IL-5 and IL-13/IL-21
- This stimulates B-cells that start synthesize IgE.
- This also stimules Th2 and Tfh and Th2A
Subsequent allergen exposure:
1. B-cells recognize allergens using the allergen-specific IgE. They then activate Th2 cells. DCs phagocytose the allergen with and without the allergen specific IgE. The DCs then activate Th2, Tfh and Th2A cells.
2. The Th2, Tfh and Th2A cells secrete: IL-5: this activates the eosinophils IL-4 and IL-13: this makes the B-cells differentiate into plasma cells and start producing allergen-specific IgE. IL-9: This activates mast cells. CCL 17 and CCL22
- The allergen-specific IgE lets the mast cells and basophils recognize the allergens.
- The mast cells secrete PDG2, Histamine and Tryptase. This stimulates the Th2, Th2A and Tfh cells.
- Mast cells stimulate allergen presentation of ILC2 to Th2
What is the mechanism of AIT?
To inhibit the immune response to allergens at several points in the reaction.
What parts of the immune response to allergens can blocking antibodies modulate?
Blocking Abs can block many different aspects of the allergic response. These 4 functions of blocking Abs are at the basis of immunotherapy, they can:
• Block IgG antibodies
• Block allergens from reaching mast cells and basophils: block induction of release of mediators
• Block allergen reaching memory B-cells: block further expansion of IgE producing plasma cells
• Block facilitated antigen presentation through CD23 (the B-cells that were acting as antigen presenting cells to enhance the Th2 response)
What are potential biomarkers for allergy/allergen immunotherapy?
Local/systemic immunoglobulins: decreased IgE, increased IgG4, IgA.
Basophils: increased CD63, CD203c. Histamine release (DAO)
Molecular markers:
DC2: GATA-3, CD141, RIPK4.
DCreg: C1qA, Fc-epsilon-RI
B-cells: IL-10+ B-cells, CD24 highCD38high, CD73-CD25+CD71+
T-cells: IL10+ T-cells, increased Th1, decreased Th2
What medication do patients use for their allergy?
AIT is the only available allergy treatment that is disease modifying, yet <10% of patients is treated with it. Most patients are using symptom medication like anti-histamines, corticosteroids and also more and more biologicals.
Why is allergen immunotherapy used so little if it has the potential to get so close to a cure?
• AIT means exposure to high dose allergen which can induce potentially severe side-effects
• AIT needs to be given for at least 3 years, which is a burden for the patient, requiring monthly visits to the doctor in case of SCIT or daily self-administration for SLIT
o Adherence to therapy is poor because of this burden. Therapy adherence is also often poor in symptom medication, but most of these treatments give rapid relief when started. AIT really requires treatment discipline to work
What is in allergen immunotherapy?
All AIT on the market is based on extracts of the relevant allergen source, such as grass pollen/tree pollen/house dust mite. Extracts are biological and contain variable quantities of the relevant major allergens and non-allergenic proteins.
For a few decades, attempts were made to replace extracts by purified recombinant versions of major allergens (only the disease causing proteins)
o The idea was that this would allow more accurate/effective dosing and offer the possibility to modify recombinants into safer hypo-allergenic versions (mutagenisis)
o Clinical studies (up to Phase II) demonstrated efficacy and safety, but recombinant products did not perform better than extracts. This development track has therefore largely been abandoned.
Can adjuvants improve allergen immunotherapy?
Most AIT products use aluminium hydroxide as an adjuvant. Attempts to improve AIT by the use of alternative adjuvants that may more effectively induce the desired mixed Th1/Treg/Breg response have so far not been very succesful o CpG (TLR agonist) was tested as adjuvant, but failed in phase III
One product with mono-phosphoryl lipid A (safer version of LPS) (MPL/TLR4) is on the market, but added value is still disputed and it is certainly not a “game changer”
What are the effects of co-administration of vitamin D3 on the efficacy of suboptimal allergen immunotherapy?
In mice: eosinophils and Th2 cytokines go down, IL-10 goes up : looks good
Clinical trial in birch pollen allergic patients
o Randomized controlled trial with registered AIT product with either vitamin D3 or placebo
o Antibody responses (IgG4): no significant differences between placebo and vitamin D3
o Cellular responses still under investigation
What are other approaches to improve allergen immunotherapy?
Other approaches that are or have been under investigation:
• Alternative peptide (to make it safer) approaches: so far disappointing:
o Short peptides representing B-cell epitopes conjugated to hepatitis antigen: discontinued/disappointing results
o Large overlapping peptides representing B-cell and T-cell epitopes: disappointing results so far
• Various nano-particle approaches:
o Virus-like particles surface expressing allergen
o Plant-derived bio-particles surface expressing allergen
o Liposomes packaged with allergen and adjuvant
• Other:
o Sialylated allergens (should drive regulatory responses): works in mice
What is the ultimate goal for improving allergen immunotherapy?
AIT that is safe and effective with only a few shots (per year) instead of 3-5 years of monthly injections. –> more like a vaccine for infectious diseases.
