T Cell Effector and Regulatory Mechanisms in Asthma

Despite advances in medications, allergic diseases, including allergic asthma, continue to
rise in prevalence. For this reason, there is a need for a better understanding of the
mechanisms of allergic diseases and novel insights into modulating allergic inflammation.
CD4+ Th2-type lymphocytes seems to be central to the pathogenesis of allergic disease, as the
levels of these cells and Th2 cytokines (IL-4, IL-5 and IL-13) are elevated in the airways of
allergic asthma patients. The unifying hypothesis of this project is that understanding the
mechanisms that determine the critical balance of effector and regulatory allergen-specific T
cell activity in asthma will lead to new approaches for inducing allergen-specific tolerance
and new therapeutic strategies for asthma.

Inclusion Criteria:

Subjects with Allergic Asthma (AA subjects):

1. All subjects will have a baseline FEV1 no less than 75 % of the predicted value after
bronchodilator administration.

2. All subjects will have both a clinical history of allergic symptoms to cat or dust
mite allergen and a positive allergen prick test (3 mm diameter greater than diluent
control)

3. Life-long absence of cigarette smoking (lifetime total of < 5 pack-years and none in 5
years).

4. Willing and able to give informed consent.

5. Expressed the desire to participate in an interview with the principal investigator.

6. Age between 18 and 50 years.

7. A methacholine PC20 < 16 mg/ml.

8. Asthma of severity defined as: requiring no more than step 3 therapy (NHLBI
Guidelines, 2007 EPR-3, http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf),
well-controlled and having a validated asthma control test (ACT) score of > 19 for one
month prior to the screening visit, and able to tolerate a 2 week stoppage of inhaled
corticosteroids prior to Visit 2.

Allergic Nonasthmatic Subjects (ANA subjects):

1. ANA subjects will have a history of at least one of the following: (a) allergic
rhinitis (with one or more of the following symptoms: nasal congestion, sneezing,
runny nose, postnasal drainage), (b) allergic conjunctivitis (ocular itching, tearing
and/or swelling) or (c) contact allergy associated with cat dander or dust mite and a
positive allergy test to the same allergen.

2. All subjects will have a baseline FEV1 and FVC determined at the characterization
visit that is no less than 90 % of the predicted value before bronchodilator
administration.

3. All subjects will have a positive allergy skin prick test to cat dander or dust mite
allergen.

4. All subjects will be in good general health.

5. Life-long absence of cigarette smoking (lifetime total of < 5 pack-years and none in 5
years).

6. Willing and able to give informed consent.

7. Expressed the desire to participate in an interview with the principal investigator.

8. Age between 18 and 50 years.

Exclusion Criteria:

Subjects with Allergic Asthma (AA subjects):

1. Women of childbearing potential who are pregnant (based on urine beta-HCG or STAT
quantitative serum hCG testing), are sexually active and not using contraception, are
seeking to become pregnant, or who are nursing.

2. The presence of spontaneous asthmatic episode or clinical evidence of upper
respiratory tract infection within the previous 6 weeks.

3. Participation in a research study involving a drug or biologic during the 30 days
prior to the study.

4. Intolerance to albuterol, atropine, lidocaine, fentanyl, or midazolam.

5. Antihistamines within 7 days of the screening visit.

6. Presence of diabetes mellitus, congestive heart failure, ventricular arrhythmias,
history of a cerebrovascular accident, renal failure, history of anaphylaxis, or
cirrhosis.

7. Use of systemic steroids, increased use of inhaled steroids, beta blockers and MAO
inhibitors or a visit for an asthma exacerbation within 1 month of the screening
visit.

8. Antibiotic use for respiratory disease within 1 month of the characterization visit or
a respiratory tract infection within 6 weeks of the bronchoscopy visits.

9. A history of asthma-related respiratory failure requiring intubation.

10. Quantitative skin-prick test positive reaction down to an allergen concentration of
0.056 BAU or AU/ml.

11. Subjects with a high possibility of poor compliance with the study.

12. Have a history of cigarette smoking within the past 5 years or > 5 pack years total.

13. Having second-hand cigarette smoke exposure or indoor furry pets except in the case of
dog, if the subject is not allergic to the dog and the subject has a negative skin
test to dog.

14. Other lung diseases, such as sarcoidosis, bronchiectasis or active lung infection.

15. Use of Xolair (omalizumab - anti-IgE monoclonal antibody) for 6 months.

16. Immunotherapy with cat or dust mite extract now or in the past.

17. Use of prophylactic aspirin for cardiovascular disease

18. Non-English speakers

Allergic Nonasthmatic Subjects (ANA subjects):

1. A history of asthma.

2. Exclusion criteria #1, 3-8 and 10- 18 from (AA) above.

3. A methacholine PC20 < 16 mg/ml.

Additional exclusion Criteria Specific to PET Imaging:

1. Anyone unable to lay flat on the scanner table for imaging.

2. We will exclude severely and morbidly obese subjects (BMI> 32) because of the poor
quality of images that can be obtained and weight restrictions on the scanner.

3. Those with a diffusing capacity < 80% predicted (if known),

4. Subjects with known exposure to agents that are associated with pulmonary disease
(i.e. asbestos, silica)

5. Subjects who have had any research related radiation exposure greater than 15 mSv
within the past year will be excluded.

6. Individuals with known allergy or hypersensitivity to FDG will be excluded.