Induced Tolerogenic Dendritic Cells as Modulators of Allergic Asthma
| Status: | Completed |
|---|---|
| Conditions: | Allergy, Asthma |
| Therapuetic Areas: | Otolaryngology, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - 50 |
| Updated: | 9/16/2017 |
| Start Date: | January 2013 |
| End Date: | September 2016 |
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.
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.
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 20 AA subjects (10 in Track 1 & 10 in Track 2) and 10 HC
subjects (Track 1). 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 and HC subjects in Track 1 will undergo
preliminary screening tests and provide 200 ml of blood for DC and T cell studies on one
occasion. Track 1 subjects will not undergo bronchoscopy, bronchoalveolar lavage, or
segmental allergen challenge. The 10 allergic asthmatic (AA) subjects in Track 2 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 4 weeks and not more than 12 weeks.
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 20 AA subjects (10 in Track 1 & 10 in Track 2) and 10 HC
subjects (Track 1). 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 and HC subjects in Track 1 will undergo
preliminary screening tests and provide 200 ml of blood for DC and T cell studies on one
occasion. Track 1 subjects will not undergo bronchoscopy, bronchoalveolar lavage, or
segmental allergen challenge. The 10 allergic asthmatic (AA) subjects in Track 2 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 4 weeks and not more than 12 weeks.
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.
We found this trial at
1
site
185 Cambridge Street
Boston, Massachusetts 02114
Boston, Massachusetts 02114
617-724-5200
Phone: 617-724-8256
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