Desensitization and Cross-Desensitization During Oral Grass or Ragweed Pollen Immunotherapy

Study Overview
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Brief Summary
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The purpose of this study is to determine if sublingual allergen immunotherapy tablets work by inducing a state of desensitization in mast cells and basophils.

Detailed Description
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To induce clinical tolerance, a failure to respond to an allergen to which one was previously responsive, is an important objective for physicians, one that plays a significant role in the primary prevention of allergic reactions in the clinical practice of Allergy & Immunology. The tolerance resulting after standard subcutaneous immunotherapy to aeroallergen and insect venom allergens is long lasting and allergen-specific, and may involve antigen-specific T regulatory cells. In contrast, tolerance resulting from drug desensitization protocols is short-lived, and postulated to target mast cells and basophils. Research into the cellular and biochemical processes by which desensitization occurs has revealed that mast cells desensitized to one antigen in vitro, under certain conditions, lose the ability to degranulate to unrelated antigens or to direct FcεRI cross-linking. Preliminary data suggests that this cross-desensitization can happen in patients undergoing incremental desensitization, depending in part on the percentage of IgE targeted to the allergen used for desensitization. This proposal therefore aims to explore desensitization and cross-desensitization in human volunteers undergoing standard sublingual (SL) immunotherapy to grass or ragweed pollen. Subjects will undergo SL immunotherapy with either Timothy or Short Ragweed tablets, taking one tablet per day, or will take a placebo tablet. Titration skin testing to Timothy or Short Ragweed, to one or preferably two additional allergens to which the subject is sensitive, and to codeine as a control for mast cell activation capability through a non-IgE-dependent pathway will be performed to determine the PC3 value (see below). Skin testing, including histamine and diluent controls, will be performed prior to and at one and four weeks after initiation of immunotherapy. At each time point, blood will be obtained to measure total and antigen-specific IgE levels, tryptase and cytokine levels, and basophil activation with the relevant allergens and C5a as a non-IgE-mediated control for basophil activation.

Official Title
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Desensitization and Cross-Desensitization During Oral Grass or Ragweed Pollen Immunotherapy

Conditions
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Immunologic Desensitization

Intervention / Treatment
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* Drug: allergen extract tablet
* Drug: Placebo tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Verified allergic sensitivity to either Timothy Grass or Short Ragweed pollen (primary allergen) Verified allergic sensitivity to at least one allergen in addition to the primary allergen Exclusion Criteria: Negative skin testing to Timothy Grass or Short Ragweed pollen and at least one other environmental allergen Dermatographism Severe dermatologic condition that may interfere with skin testing Pregnancy H1 receptor antihistamine taken within 7 days of testing Systemic steroids Omalizumab taken at any time in the past Receiving or received allergen immunotherapy Desensitized to any drug within 6 months Current uncontrolled or severe asthma Eosinophilic esophagitis Significant pulmonary, cardiovascular, renal, hepatobiliary, or neurological diseases, or another disease process felt to put a subject at increased risk for adverse events Hypersensitivity to any of the inactive ingredients in the allergen extract tablets History of mental illness or drug or alcohol abuse that could interfere with the ability to comply with study requirements Inability or unwillingness to give written informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sublingual allergen tablets<br>Subjects will be administered a sublingual allergen tablet customized to their individual allergic sensitization. | Drug: allergen extract tablet<br>* 1 allergen extract tablet, placed under the tongue until dissolved, taken daily; do not swallow for 1 minute after placing tablet; do not eat or drink for 5 minutes after placing tablet<br>* Other names: Grastek;|
| Placebo Comparator: Placebo<br>Subjects will be administered placebo sublingual tablets | Drug: Placebo tablet<br>* 1 placebo tablet, placed under the tongue until dissolved, taken daily; do not swallow for 1 minute after placing tablet; do not eat or drink for 5 minutes after placing tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PC3 | Change in the dose of allergen eliciting a wheal 3 mm greater than negative control upon skin prick testing (PC3) | Assessed at 2 weeks and at the end of the study (2 months) | 
| Change in Basophil Activation | Change in the dose of allergen eliciting a 50% increase in number of basophils positive for CD63 and/or CD203c relative to negative and positive controls | Assessed at 2 weeks and at the end of the study (2 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cross-desensitization - PC3 | Change in the dose of an unrelated allergen eliciting a wheal 3 mm greater than negative control upon skin prick testing (PC3) | Assessed at 2 weeks and at the end of the study (2 months) | 
| Cross-desensitization - Basophil Activation | Change in the dose of allergen eliciting a 50% increase in number of basophils positive for CD63 and/or CD203c relative to negative and positive controls | Assessed at 2 weeks and at the end of the study (2 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allergic rhinitis, Immunotherapy, Allergen, Sublingual Immunotherapy