Induced Tolerogenic Dendritic Cells as Modulators of Allergic Asthma (MGH-002)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Andrew D. Luster, M.D.,Ph.D., Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT01711593
First received: June 28, 2012
Last updated: May 22, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention
Asthma
Allergies
Biological: Bronchoscopy, Segmental Allergen Challenge and Bronchoalveolar Lavage
Procedure: Phlebotomy

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Induced Tolerogenic Dendritic Cells as Modulators of Allergic Asthma

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • Effect of it-DC on the phenotype, function, proliferation and survival of allergen-specific effector T cells. [ Time Frame: 24 hours ] [ Designated as safety issue: No ]

    We will generate induced tolerogenic dendritic cells (it-DCs) in vitro from peripheral blood monocytes and dendritic cells isolated from each allergic asthmatic subject and assess their capacity to (a) attenuate effector CD4+ T cell (Teff) responses and/or (b) induce T regulatory (Treg) cells from Teff cells as well as CD4+ naïve and memory T cells. Attenuation of T cell responses (a) will be assessed by proliferation assays and cytokine production. Moreover, in order to evaluate the functionality of the it-DC induced Tregs (b), co-culture suppression assays using cat or house dust-mite allergen-specific Teff cells isolated from BAL following segmental allergen challenge (SAC) as responder cells, will be examined. The percent suppression of responding Teff cells will be assessed by examining Teff cell proliferation and survival/apoptosis, and by cytokine production.

    (Note: SAC samples from healthy controls are not involved in the primary analysis.)



Secondary Outcome Measures:
  • Percent distribution of peripheral blood DC subsets [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    We will determine the frequency of each peripheral blood DC subset from allergic asthmatic subjects at 0 and 8 weeks using cell surface staining/flow cytometry analysis. Results will be expressed in terms of percent distribution of each DC subset within the total DC pool.

  • Percent suppression of naïve T cells (Tn) and memory T cells (Tmem) proliferation by it-DC-induced Tregs from each subject. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    The ability of it-DC-induced Tregs from each allergic asthmatic to suppress proliferation of autologous CD4+ Tn and Tmem cells in response to anti-CD3 will be assessed and expressed as a percent suppression of proliferation using an in vitro proliferation assay.

  • Differences in proliferation by allergen-specific Teff cells from BAL and blood. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    We will measure the proliferative responses in it-DC co-culture assays by allergen-specific CD4+ Teff cells obtained from the BAL of allergic asthmatic subjects as compared to those of blood-derived CD4+ Tmem cells from the same subjects and from 5 healthy controls.


Estimated Enrollment: 15
Study Start Date: January 2013
Estimated Study Completion Date: January 2021
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Allergic Asthmatic, Non-allergic non-asthmatics(HC)
Adult subjects who are allergic asthmatics will receive segmental allergen challenge to the lung and have their blood drawn at 2 time points. Adult subjects who are non-allergic non-asthmatics(Healthy Controls) will not receive segmental allergen challenge to the lung but will have their blood drawn at 2 time points.
Biological: Bronchoscopy, Segmental Allergen Challenge and Bronchoalveolar Lavage
On the day of the first bronchoscopy, BAL will first be performed in the lingual without instillation of diluent or allergen.Then, a 2-ml aliquot of isotonic diluent is instilled into the right upper lobe.Then, the procedure will be repeated in the right middle lobe with instillation of 2-ml 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 the threshold concentration.If on visual inspection through the bronchoscope there is no evidence of mucosal inflammation, a second segmental allergen challenge will be done in the right middle lobe using 2-ml of full-dose allergen at the threshold concentration. 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.
Other Names:
  • One of 3 Standardized allergen extracts will be used:
  • 1)Cat hair allergen extract
  • 2)Mite Dermatophagoides farinae
  • 3)Mite Dermatophagoides pteronyssinus
  • Phenolized saline diluent will also be used in this study.
  • All will be purchased from Greer Laboratories Lenoir,NC.
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 subjects 8 weeks later for isolation of T lymphocytes for functional studies.
Other Name: Blood Draw
Biological: Bronchoscopy, Segmental Allergen Challenge and Bronchoalveolar Lavage
On the day of the first bronchoscopy, BAL will first be performed in the lingual without instillation of diluent or allergen.Then, a 2-ml aliquot of isotonic diluent is instilled into the right upper lobe.Then, the procedure will be repeated in the right middle lobe with instillation of 2-ml 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 the threshold concentration.If on visual inspection through the bronchoscope there is no evidence of mucosal inflammation, a second segmental allergen challenge will be done in the right middle lobe using 2-ml of full-dose allergen at the threshold concentration. 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.
Other Names:
  • One of 3 Standardized allergen extracts will be used:
  • 1)Cat hair allergen extract
  • 2)Mite Dermatophagoides farinae
  • 3)Mite Dermatophagoides pteronyssinus
  • Phenolized saline diluent will also be used in this study.
  • All will be purchased from Greer Laboratories Lenoir,NC.

Detailed Description:

This is a single-center, open-label, controlled mechanistic study before-and-after allergen instillation study that uses each subject as his/her own control. Reliability of study measurements of expression is accomplished by comparing repeated measurements. Additional controls are provided by measuring the expression of markers known to have stable expression, including cell structural proteins and chemokine markers that the investigators know are induced in this experimental paradigm from our previous studies. This is an investigational study. Subjects will receive an investigational product, either Standardized Cat Allergen Extract or Standardized Dust Mite Allergen (Dermatophagoides farinae or D. pteronyssinus). No subject will be given a placebo. There are 2 cohorts, allergic asthmatics (AA) and healthy controls (HC). The main comparisons will be measurement of primary and secondary outcome measures in: (1) diluent versus allergen-challenged segments of the lung in each asthmatic subject and (2) comparison of these responses in allergic asthmatics (AA) and healthy controls (HC).

The investigators will enroll 10 AA subjects and 5 HC subjects. There will be no randomization. The choice of allergen will be determined by allergy skin testing. When a subject is allergic to both cat and dust mite, one will be selected with a goal of having a representative sample of cat and dust mite challenges in each cohort. The 10 allergic asthmatic (AA) subjects will undergo SAC with either standardized cat or mite allergen. These subjects will also donate 200 ml of blood on two occasions separated by a minimum of 8 weeks and not more than 12 weeks. The HC subjects will undergo preliminary screening tests and provide 200 ml of blood for DC and T cell studies on two occasions separated by a minimum of 8 weeks and not more than 12 weeks. The HC subjects will not undergo bronchoscopy, bronchoalveolar lavage, or segmental allergen challenge.

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Subjects with Allergic Asthma (AA subjects):

  1. All subjects will have a baseline FEV1 no less than 75 % of the predicted value.
  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. Have indoor animal or second-hand cigarette smoke exposure
  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

Healthy Normal Control Subjects (NC subjects):

  1. A history of allergy, asthma, nasal or sinus disease.
  2. Exclusion criteria #1, 3-8 and 10-17from (A.) above.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01711593

Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Andrew D. Luster, M.D.,Ph.D.
Investigators
Principal Investigator: Andrew D Luster, M.D., Ph.D. Massachusetts General Hospital
  More Information

No publications provided

Responsible Party: Andrew D. Luster, M.D.,Ph.D., Chief, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT01711593     History of Changes
Other Study ID Numbers: 2012P0001076, 1U19AI095261-01
Study First Received: June 28, 2012
Last Updated: May 22, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Massachusetts General Hospital:
Asthma
Allergic
Inflammation
Airway
Challenge
Chemokines
Tolerization

Additional relevant MeSH terms:
Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases

ClinicalTrials.gov processed this record on August 20, 2014