T Cell Effector and Regulatory Mechanisms in Asthma

T Cell Effector and Regulatory Mechanisms in Asthma

The specific hypothesis for this study is that there are fundamental differences in T effector and T regulatory cell responses in the lung to allergens in allergic asthma (AA) when compared to allergic nonasthmatics (ANA) that account for the difference in clinical responses. We will address this by comparing T cell responses in AA versus ANA subjects. These experiments will correlate T cell responses with measures of airway physiology using state-of-the art lung imaging and examine mechanisms controlling T cell activation in the airways of AA and the function of airway T regulatory cells during AA.

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.