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

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.

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