Allergic Diseases and Hypersensitivity Mechanisms

Targeted Therapies in Allergogy

• Overview of targeted therapies in the field of allergology
• Types of hypersensitivity identified:
  • Type I hypersensitivity
• Diagnostics & testing
  • Current methods for allergy diagnosis
  • Prerequisite for allergen immunotherapy (AIT)
• Therapeutic management techniques
  • Classic treatments
  • Biological treatments
  • Allergen immunotherapy (AIT)

Atopy and Allergy Definitions

• Atopy: A predisposition to an exaggerated immune response to various antigens, leading to the production of immunoglobulin E (IgE). Includes conditions like atopic dermatitis, allergic rhinitis, asthma, and food allergies
• Allergy: An exaggerated immune response against a harmless foreign substance (allergen) involving an allergen-specific adaptive response.

Burden of Allergic Diseases in Europe

• Epidemiology (2016) data:
  • 150 million Europeans live with allergies today
  • 1 in 2 Europeans will suffer from an allergy by 2025
  • Over 20% of Europeans suffer from allergies .
  • 100 million experience allergic rhinitis,
  • 70 million experience asthma.
  • 17 million have food allergies, risk of acute anaphylaxis
  • 90% have allergy as a contributing factor to asthma.
  • Huge financial burden (€17.7 billion, €9.8 billion, and €55-151 billion/year) due to costs of treatment, lost productivity and indirect costs from untreated allergies.
  • Opportunities for savings with proper diagnosis and treatment (€142 billion).

Type I Hypersensitivity

• Immediate hypersensitivity response to an antigen
• Antigen exposure triggers rapid onset of symptoms
• Mediated by allergen-specific IgE antibodies
• Involves mast cells and basophils, releasing histamine
• Occurs in genetically predisposed individuals ("atopic")
• Potential severe life-threatening reactions (anaphylaxis)

Immediate Hypersensitivity (IgE-mediated)

• Sensitization phase: First exposure to allergen
  • Antigen presentation by dendritic cells to lymphocytes
  • Production and release of specific IgE antibodies for this allergen
• Elicitation phase (subsequent allergen exposure)
  • Immediate elicitation phase: Mast cell degranulation (release of histamine)
  • Symptomatic phase: Inflammatory responses
• Late elicitation phase:
  • Cytokines and chemokines are primarily involved.
    • Neutrophils, Eosinophils, Mast cells, Basophils, other inflammatory mediators involved.
    • Neosynthesized lipid mediators, including prostaglandins, leukotrienes, and platelet-activating factor

Etiological Diagnosis of Type I Allergy

• Clinical history and examination
• Prick test
• Quantification of circulating specific IgE
• Basophil activation test

Quantification of Circulating Specific IgE

• Total IgE assays are not helpful
• Immunochemical methods do exist
• The importance of confirming results with clinical history

Molecular Allergology - Component Resolved Diagnosis

• Precise and individual sensitization profile for each patient
• Document profile according to allergen categories/families
• Assess clinical risk (systemic/local reaction risk)
• Explain symptoms from cross-reactivity reactions
• Indication and guidance, or even performance of AIT

Clinical Risk Assessment

• Clinical risk assessment by molecular families :
• Categorization of protein types by risk of causing allergic reactions.
• Different risk assessment profiles exist

Targeted Therapies in Allergogy (Part 3: Therapeutic Management of Allergies)

• Classic Treatments
• Biologicals (Monoclonal Antibodies)
• Allergen immunotherapy (AIT)

Therapeutic Principles in Allergogy

• Allergen avoidance. Includes avoiding exposure to allergens such as domestic pets, food, and certain medications.
• Classic treatments. Including non-allergen specific treatments for symptoms.
• Innovative treatments. Include treatments not specific to the allergen.
• Biological therapies (allergen-specific treatments) .
• Allergen immunotherapy (AIT) (allergen-specific treatments) .

Biologicals in the Treatment of Allergies

• Typically prescribed for chronic, severe allergies with significant quality-of-life decline.
• Not used for immediate symptoms (e.g., acute urticaria, anaphylaxis).
• Specific molecular targets: Target soluble mediators, cell surface molecules, and/or alarmins.

Atopic Dermatitis

• Chronic, relapsing, inflammatory disorder affecting skin
• Typically presents as recurrent eczema, intense itching, and risk of skin infection.
• Often associated with other allergic conditions (e.g., food allergy, asthma).
• Genetic predisposition and epidermal dysfunction are significant factors.
• Primarily T-cell driven inflammation, with type 2 immune mechanisms playing a dominant role.

Asthma

• Chronic inflammatory disease of the lower airways characterized by inflammation, obstruction, and hyperresponsiveness.
• Respiratory distress, chest tightness, wheezing, coughing, and exercise intolerance.
• Bronchial hyperresponsiveness and airway inflammation characterized by mucus plugs and airway remodeling.
• Airway wall remodeling occurs. Uncontrolled asthma leads to reduced quality of life.
• Different asthma subtypes (Type 2 Asthma, Non-allergic asthma).

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Mode of Action of Biologicals Targeting Th2 Immunity

• Various biologicals target different aspects of the Th2 immune response to moderate or prevent allergic reactions..

Mechanism of Action of Omalizumab

• Binds to free IgE, decreasing cellular IgE
• Reduces expression of high-affinity IgE receptors and prevents mediator release.
• Decreases eosinophil survival, inducing eosinophil apoptosis
• Inhibits allergen presentation to T cells.

Indications of Omalizumab

• Moderate-to-severe persistent allergic asthma, Nasal Polyps, Chronic Spontaneous Urticaria
• Off-label use in food allergy, as an adjuvant in other treatments for drug and food allergies .

Omalizumab in Food Allergies (OUTMATCH trial)

• Trial involving 177 children and adolescents with multiple food allergies.
• Omalizumab showed improved oral challenge thresholds for peanuts and other common food allergens, compared to a placebo.

Omalizumab in Food Allergies: Summary of Results

• Significantly increase reaction thresholds in participants receiving omalizumab vs. placebo
• Data suggests improved reaction thresholds for different allergens, including peanut.

Indications for Four Representative Biologicals (MoAb)

• Details on indications of specific monoclonal antibodies for the treatment of allergy conditions.

Immune Mechanisms of TSLP in Asthma

• Summary of the role of TSLP (Thymic stromal lymphopoietin), an inflammatory cytokine and its immune interplay with various cells in the context of asthma.

General Tolerance and Side Effects of Biological MoAb

• Biologics are generally well tolerated but some side effects may occur, common side effects are local reactions at the injection site, Pseudo-allergic reactions, and general symptoms like headaches, abdominal pain.
• Anti-drug antibodies can form and cause therapeutic failure over time.

AIT: Principles and Definitions

• Regular administration of allergens to induce allergen tolerance and reduce symptom severity through multiple treatment phases: initial build-up and prolonged maintenance .
• Seasonal or Perannual treatments
• Different treatment modalities exist.

AIT Indications

• Criteria for considering AIT for certain allergy conditions like moderate/severe intermittent allergic rhinitis . Allergic asthma excluding severe or uncontrolled asthma and several other complex conditions.
• Allergic manifestations of allergies to hymenoptera, some food allergies (peanut, egg, cow's milk). Atopic dermatitis with pneumallergenic sensitization

AIT Contraindications

• Uncontrolled asthma, active autoimmune disease, active neoplasia, cardiovascular pathology, ongoing pregnancy (unless started before), children under 2 years of age are ineligible.

Effects of 2 Years of Grasses Pollen Subcutaneous Immunotherapy (SCIT)

• Results on seasonal changes to nasal mucosa from SCIT

Persistence of Allergen-Specific IgG

• Persistence of allergen-specific IgG after AIT discontinuation in the long term.

Clinical Efficacy of Grass Pollen Tablets

• Summary of study demonstrating clinical efficacy of sublingual immunotherapy (SLIT) for grass pollen allergy in adults, demonstrates significant reduction in nasal and ocular allergy symptoms, and fewer rescue medication requirements.

Clinical Benefits of SLIT in Respiratory Allergy

• Details on a five-year sublingual immunotherapy (SLIT) trial for grass pollen allergy , demonstrated positive responses in children with asthma.

Mechanisms of Action of AIT

• Summary of the complex mechanisms of action involving multiple cell types and mediators that occur during AIT , involving switching Th2 to Th1, induction of regulatory T cells, increase in IL-10, decrease in release of inflammatory cytokines

AIT: Current Routes of Administration

• List of available administration techniques. Includes: subcuntaneous, sublingual,oral

AIT: New Routes of Administration

• Summary of new approaches to allergen immunotherapy (AIT), including intranasal and epicutaneous routes, and discussion of potential advantages and challenges.

AIT market in France

• Summary market figures (patients on treatment) and prevalent allergen types in France, includes: sublingual, Oral, injection types of therapies .

Source of Allergens for IAT

• Sources of allergens for immunotherapy (IAT) .
• Method of preparation and standardization for both raw and standardized extracts.

Modified/Recombinant Allergens

• Summary of chemically modified or recombinant allergen types (hypallagenic).
• Advantages of using modified allergens, including safer administration and potential for improved tolerance, including improvements for safety, efficacy, better treatment, and greater tolerance

Strategies for the Development of a Safer and More Reliable AIT Vaccine

• Key strategies for improving the safety and efficacy of AIT treatments, including strategies for developing new and safer methods of allergen delivery, including reduced side-effects, improved adjuvants, new routes of administration

Future ITA Route

• Future avenues for IT treatment considering injection and non-injection routes including, intranasal, epicutaneous, sublingual, and oral routes. Includes considerations of modified chemical and recombinant allergens, and the use of TLR-9 agonists, and omalizumab.

Thank You

• Thank you for attention.