Modeling Bronchial Epithelium in Severe Asthma With Human Induced Pluripotent Stem Cells (iPSC)
Condition: Severe Asthma; Allergic Bronchopulmonary Aspergillosis (ABPA)
MeSH terms: Aspergillosis; Pulmonary Aspergillosis; Aspergillosis, Allergic Bronchopulmonary; Asthma
Study type: Interventional

Summary: 
      Asthma is severe when it cannot be controlled with maximum-dose inhaled therapies while
      management of comorbidities and other precipitating or aggravating factors has been
      optimized. Allergic bronchopulmonary aspergillosis (ABPA) is a complex bronchopulmonary
      disease resulting from immunological reactions against Aspergillus Fumigatus.

      The development of a model of bronchial epithelium generated from patients with chronic lung
      disease will allow the modeling of bronchial tissue to understand the formation of these
      mucus plugs. This study aims to validate this model

      The investigators propose to verify the feasibility of obtaining and comparing two epithelia
      in two populations based on the following experiments:

      Differentiation of an Induced Pluripotent Stem cell (iPSC) clone derived from blood sample
      (Peripheral Blood Mononuclear Cells) of Type 2 inflammation (T2) severe asthma and Allergic
      Bronchopulmonary Aspergillosis (ABPA) in order to obtain differentiated bronchial epithelia
      in vitro.
    

Detailed description: 
      Asthma is severe when it cannot be controlled with maximum-dose inhaled therapies while
      management of comorbidities and other precipitating or aggravating factors has been
      optimized. Allergic bronchopulmonary aspergillosis (ABPA) is a complex bronchopulmonary
      disease resulting from immunological reactions against Aspergillus Fumigatus.

      At the cellular and molecular level, severe asthma and ABPA are chronic bronchial diseases
      characterized by type 2 (T2) airway inflammation, bronchial smooth muscle hyperplasia,
      excessive mucus production by mucus cell metaplasia and epithelial remodeling. Type 2
      inflammation in asthma is predominant and is characterized by the accumulation of immune
      cells, such as eosinophils, mast cells, T-helper 2 (Th2) cells, innate lymphoid cells type 2
      (ILC2s) and dendritic cells.

      Persistent airway obstruction despite maximal therapy is currently considered the greatest
      unmet medical need in asthma treatment. Fahy and colleagues published a key paper in 2018
      that may explain airway obstruction. Using chest CT scans, they demonstrated the presence of
      mucus plugs that completely occlude segments of the airways of severe asthmatics. These mucus
      plugs are associated with a high number of circulating eosinophils in the blood.

      There is no large-scale model to model severe asthma and ABPA. The investigators propose to
      develop a bronchial epithelium with pluripotent stem cells (iPSC) in air-liquid interface
      called iALI generated from these patients in aim to model severe asthma and ABPA and in
      particular the epithelium.

      The secondary objectives aims to answer are:

        -  Comparison of the iPSC derived airway epithelium with nasal epithelial cells isolated
           from the same patient (nasal brush).

        -  To characterize the phenotype of the iPSC derived airway epithelium from ABPA and T2
           severe asthma patient, in comparison to a healthy control.

        -  Differentiation of iPSC into mature eosinophils

        -  Co culture of the epithelia with iPSC derived eosinophils

        -  Culture of iPSC derived airway epithelium with Charcot-Leyden crystal

        -  Demonstrate the feasibility of obtaining iPSC from peripheral blood sampling.
    

Intervention name(s): Blood sample
Intervention type(s): Other
Intervention description(s): A blood sample and a nasal brush for each participant. The nasal brushing will allow the isolation of epithelial cells that will serve as a comparison for the bronchial tissue produced from blood-derived iPS.
A blood sample of approximately 14 ml will be taken for isolation and freezing of the blood mononuclear cells allowing the generation of iPS.
Other intervention name(s): nasal brush
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Severe asthma; ABPA; Pluripotent stem cells; Airway epithelium; Eosinophils; Crystal