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COMPLETED

NCT01711593

PHASE1

Induced Tolerogenic Dendritic Cells as Modulators of Allergic Asthma

Sponsor: Andrew D. Luster, M.D.,Ph.D.

View on ClinicalTrials.gov

Summary

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. The investigators hypothesize that much remains to be learned about the behavior of T effector and T regulatory cells in allergic disease. Furthermore, the investigators hypothesize that novel mechanisms of allergic tolerance may exist, and elucidation of these mechanisms may provide insights into novel therapeutic strategies to control allergic diseases. The investigators will investigate the capacity for T cell tolerance induction in allergic subjects by a novel type of immune tolerizing dendritic cell (it-DC). The investigators will assess whether in vitro generated it-DCs have the capacity to induce antigen-specific T regulatory cells and suppress allergen-specific T effector cell function in vitro. Standardized Cat Allergen extract and Dust Mite Allergens will be used to generate changes in the airways that occur during exposure to allergen. For this investigation, the route of administration will be topical application of the titrated allergen to a bronchoscopically isolated subsegment of one lobe of one lung. The dose of biologic will be determined from prior skin-prick testing.

Key Details

Gender

All

Age Range

18 Years - 50 Years

Study Type

INTERVENTIONAL

Enrollment

Start Date

2013-01

Completion Date

2016-09

Last Updated

2026-09-28

Healthy Volunteers

Yes

Conditions

Asthma Allergies

Interventions

BIOLOGICAL

Bronchoscopy, Segmental Allergen Challenge and Bronchoalveolar Lavage

On the first bronchoscopy day,BAL will first be performed in the lingual without instillation of diluent or allergen. A 2ml aliquot of isotonic diluent is instilled into the right upper lobe.The procedure is repeated in the right middle lobe with instillation of 2ml of standardized cat or mite allergen solution. A test dose concentration of allergen is administered first consisting of 2 ml of allergen at 1/10th(Cat,D.farinae)or 1/30th(D.pteronyssinus)the threshold concentration.If on visual inspection through the bronchoscope there is no evidence of mucosal inflammation after 2 minutes a second segmental allergen challenge will be done in the right middle lobe using 2ml of full-dose allergen at the threshold concentration(Cat,D.farinae)or 1/3 the threshold concentration(D.pteronyssinus). This dose will be predetermined by quantitative skin prick testing.A second bronchoscopy is performed 24 hours after delivery of allergen extract and diluent to obtain BAL fluid from the RUL and RML.

PROCEDURE

Phlebotomy

200 (40 teaspoons) ml of blood will be obtained from the subjects to collect different leukocyte populations. A second 200 ml of blood will be obtained from the Track 2 subjects 4 weeks later for isolation of T lymphocytes for functional studies.

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), 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. Healthy Control Subjects (HC subjects): Normal control subjects will be individuals who are in good overall health, age and sex matched to the asthmatic group, age 18 - 50 and nonallergic, i.e. entirely negative on the panel of prick skin tests with no history of allergic rhinitis or asthma, no history of allergic symptoms caused by cats or dust mite allergen exposure, life-long nonsmokers of cigarettes (defined as a lifetime total of less than 5 pack-years and none in 5 years), normal spirometry (i.e. FEV1 and FVC of at least 90% of predicted) and with a methacholine PC20 of \> 16 mg/ml. Exclusion Criteria: Subjects with Allergic Asthma (AA subjects): 1. Women of childbearing potential who are pregnant (based on urine beta-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. 19. Weight less than 110 pounds 20. Hematocrit \< 0.36 for females, \<0.38 for males. Healthy Normal Control Subjects (HC subjects): 1. A history of allergy, asthma, nasal or sinus disease. 2. Exclusion criteria #1, 3-8 and 10-20 from (A.) above.

Locations (1)

Massachusetts General Hospital

Boston, Massachusetts, United States