Induced Tolerogenic Dendritic Cells as Modulators of Allergic Asthma
Condition: Asthma; Allergies
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 1

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.
    

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 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.
    

Intervention name(s): Bronchoscopy, Segmental Allergen Challenge and Bronchoalveolar Lavage; Phlebotomy
Intervention type(s): Biological; Procedure
Intervention description(s): 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.; 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.
Other intervention name(s): One of 3 Standardized allergen extracts will be used:; 1)Cat hair; 2)Dust Mite Dermatophagoides farinae; 3)Dust Mite Dermatophagoides pteronyssinus; Phenolized saline diluent will also be used in this study.; All will be purchased from Greer Laboratories Lenoir,NC.; Blood Draw
Intervention MeSH terms: Dimercaprol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Asthma; Allergic; Inflammation; Airway; Challenge; Chemokines; Tolerization