NCT03455959

Lung-Resident Memory Th2 Cells in Asthma

• Status: Active Not Recruiting
• Phase: N/A
• Study type: Interventional
• Enrollment: 37 (actual)
• Sponsor: Andrew D. Luster, M.D.,Ph.D. · Academic / Other
• Sex: All
• Age: 18 Years – 55 Years
• Healthy volunteers: Accepted

Summary

Determining how memory T helper type 2 (Th2) initiate recall responses to aeroallergens has the potential to change the therapeutic approach to allergic asthma, the most common asthma subtype. \~5-10% of effector Th2 cells recruited into the lung give rise to long-lived tissue resident memory cells that are poised to respond upon allergen re-exposure.Consequently, targeting memory Th2 cell activation is an attractive therapeutic strategy. However, it is not well understood how allergen inhalation initiates a memory Th2 cell response in the lung. The focus of this new study on the role of lung-resident memory Th2 cells in orchestrating the recall response to allergen in the lung, including the recruitment and activation of circulating Th2 cells, is a natural, timely and exciting extension of the investigators' ongoing Allergen Challenge Protocol.

Detailed description

The objective of this study is to define the mechanisms whereby Th2-Trm persisting in the lung orchestrates a recall response to inhaled allergens. The investigators' central hypothesis is that Th2-Trm ignite allergic airway inflammation via a rapid and enhanced response to cognate antigen in the airway and the ability to recruit circulating Th2 cells (Th2-Tcr) to the sites of antigen presentation in the lung. Mechanistically, the investigators hypothesize that Th2-Trm co-localize with DCs expressing the Th2 cell-attracting chemokine CCL17 and after allergen re-challenge rapidly produce type 2 cytokines that initiate allergic inflammation and markedly enhance DC expression of CCL17. This increased CCL17 expression recruits Th2-Tcr cells from the blood to sites of antigen presentation where Th2-Tcr receive a "second touch" from cognate antigen loaded and activated DCs and become fully competent to amplify allergic inflammation. The investigators propose to use innovative experimental systems to define the function of Th2-Trm, including single cell RNA-seq analysis of human airway mucosal CD4+ T cells obtained via bronchial brushing. Specifically, the investigators propose to define the transcriptional phenotype of human lung Th2-Trm and Th2-Tcr. Defining the mechanisms regulating Th2-Trm function in the asthmatic airway has the potential to yield new therapeutic approaches for allergic asthma. Memory CD4+ T helper type 2 (Th2) cells are critical in promoting allergic asthma, the most common asthma endotype. The investigators propose to define the function of newly described lung-resident memory Th2 cells in driving recurrent allergic airway inflammation. The successful completion of the proposed study has the potential to focus new asthma therapies on specifically targeting the biology of lung-resident memory Th2 cells.

Conditions

• Asthma, Allergic

Interventions

Type	Name	Description
PROCEDURE	Bronchoscopy/BAL	Participants may receive 3 inhalations (90 ug ea) of albuterol to minimize bronchoconstriction. Medication includes midazolam by intravenous injection, and fentanyl by intravenous injection as judged necessary. 2% lidocaine is delivered via atomizer spray to the oral pharynx for local anesthesia. 1% lidocaine is delivered through the bronchoscope to the vocal cords and lung segments for local anesthesia. The bronchoscope is then passed through the vocal cords into the trachea. Throughout the procedure, all participants will have continuous blood pressure, heart rate, and oxygen saturation monitoring. Participants will be instructed to relate any discomfort or problems through a series of standardized hand signals. Once in the lung, aliquots of sterile saline are instilled into two subsegments of the right middle lobe (preferred and if not possible then the right upper lobe) and withdrawn into a trap by gentle suction.
PROCEDURE	Airway Brushing	After completion of the BALs, endobronchial brushing of the airways will be performed using the airway brushings with a Conmed Harrell™ 4 mm unsheathed cytology brush. Upon completing the brushing the investigators remove the bronchoscope with the brush in place to avoid shearing off isolated cells. The brush will be gently glided back and forth on the airway epithelium 10 times in 2 different locations within the same airway. The brush is then placed in media and flicked to remove the cells. A second brush will then be introduced into an adjacent airway of the same lobe and gently glided back and forth on the airway epithelium 10 times in 2 different locations as was done with the first brush. The second brush will also be placed in media and flicked to remove the cells. There is some airway bleeding caused by the procedure, and participants are made aware that they may cough up small amounts of blood for 24-48 hours following the procedure.

Timeline

• Start date: 2019-05-23
• Primary completion: 2024-11-15
• Completion: 2027-12-15
• First posted: 2018-03-07
• Last updated: 2026-04-17

Locations

1 site across 1 country: United States