Modulation of innate immunity by type 2 inflammation precision targeting therapeutics: T2 cytokines as modulators of human bronchial epithelial cells.
(2025) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Airway epithelium, formed by epithelial cells lining human airways, is a critical barrier against inhaled allergens, viruses, and pollutants. Beyond being a physical barrier, it functions as a first-line defense by secreting alarmins, inflammatory cytokines, and chemokines, thereby activating other immune cells. In respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD), the epithelial barrier's function is compromised, partly due to persistent inflammation.
This doctoral thesis primarily investigated the impact of type 2 (T2) cytokines, particularly IL-4 and IL-13, on bronchial epithelial cells (BECs) and their antiviral responses using translational in vitro air-liquid interface (ALI) cultures. These studies... (More) - Airway epithelium, formed by epithelial cells lining human airways, is a critical barrier against inhaled allergens, viruses, and pollutants. Beyond being a physical barrier, it functions as a first-line defense by secreting alarmins, inflammatory cytokines, and chemokines, thereby activating other immune cells. In respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD), the epithelial barrier's function is compromised, partly due to persistent inflammation.
This doctoral thesis primarily investigated the impact of type 2 (T2) cytokines, particularly IL-4 and IL-13, on bronchial epithelial cells (BECs) and their antiviral responses using translational in vitro air-liquid interface (ALI) cultures. These studies involved epithelial cells from healthy individuals and patients with asthma and COPD. The cytokines were introduced to BEC cultures exogenously, with and without rhinovirus (RV) infection. Additionally, we developed a co-culture system with innate lymphoid cells (ILC2) and BECs to explore the immunological interaction between these cells, given that ILC2s are potent sources of T2 cytokines.
The research further investigated the mechanisms of IL-4 receptor alpha (IL-4Rα) monoclonal antibody (mAb) treatment under T2 inflammatory conditions, focusing on its influence on viral-induced exacerbations.
Our studies indicated that BECs from individuals with asthma showed increased inflammatory responses upon acute exposure to IL-4 and IL-13. This was evidenced by increased levels of eosinophil chemoattractant (CCL26) and alarmins (TSLP) while maintaining antiviral responses. These cytokine-induced effects were attenuated by IL-4Rα mAb. In settings of chronic T2 cytokine exposure or within the BEC/ILC2 co-culture model, a reduction in TSLP over time was noted, alongside altered antiviral responses.
The findings aim to elucidate the mechanistic effects of T2 inflammation and IL-4Rα mAb inhibition specifically on airway epithelial cells, contributing to a deeper understanding of how anti-IL-4Rα treatment assists in improving lung function and reducing exacerbations in patients. Our novel data on decreased levels of CCL26 (Eotaxin-3) in both asthma and COPD may explain why asthma and COPD patients with eosinophilia respond well to IL-4Rα treatment. (Less) - Abstract (Swedish)
- Airway epithelium, formed by epithelial cells lining human airways, is a critical barrier against inhaled allergens, viruses, and pollutants. Beyond being a physical barrier, it functions as a first-line defense by secreting alarmins, inflammatory cytokines, and chemokines, thereby activating other immune cells. In respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD), the epithelial barrier's function is compromised, partly due to persistent inflammation.
This doctoral thesis primarily investigated the impact of type 2 (T2) cytokines, particularly IL-4 and IL-13, on bronchial epithelial cells (BECs) and their antiviral responses using translational in vitro air-liquid interface
(ALI) cultures. These... (More) - Airway epithelium, formed by epithelial cells lining human airways, is a critical barrier against inhaled allergens, viruses, and pollutants. Beyond being a physical barrier, it functions as a first-line defense by secreting alarmins, inflammatory cytokines, and chemokines, thereby activating other immune cells. In respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD), the epithelial barrier's function is compromised, partly due to persistent inflammation.
This doctoral thesis primarily investigated the impact of type 2 (T2) cytokines, particularly IL-4 and IL-13, on bronchial epithelial cells (BECs) and their antiviral responses using translational in vitro air-liquid interface
(ALI) cultures. These studies involved epithelial cells from healthy individuals and patients with asthma and COPD. The cytokines were introduced to BEC cultures exogenously, with and without rhinovirus (RV) infection. Additionally, we developed a co-culture system with innate lymphoid cells (ILC2) and BECs to
explore the immunological interaction between these cells, given that ILC2s are potent sources of T2 cytokines.
The research further investigated the mechanisms of IL-4 receptor alpha (IL-4Rα) monoclonal antibody (mAb) treatment under T2 inflammatory conditions, focusing on its influence on viral-induced exacerbations.
Our studies indicated that BECs from individuals with asthma showed increased inflammatory responses upon acute exposure to IL-4 and IL-13. This was evidenced by increased levels of eosinophil chemoattractant (CCL26) and alarmins (TSLP) while maintaining antiviral responses. These cytokine-induced effects were attenuated by IL-4Rα mAb. In settings of chronic T2 cytokine exposure or within the BEC/ILC2 co-culture model, a reduction in TSLP over time was noted, alongside altered antiviral responses.
The findings aim to elucidate the mechanistic effects of T2 inflammation and IL-4Rα mAb inhibition specifically on airway epithelial cells, contributing to a deeper understanding of how anti-IL-4Rα treatment assists in improving lung function and reducing exacerbations in patients. Our novel data on decreased levels of CCL26 (Eotaxin-3) in both asthma and COPD may explain why asthma and COPD patients with eosinophilia respond well to IL-4Rα treatment. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/ec8166ce-0fc4-481e-a9c3-7a76c4d621e6
- author
- Pesic, Jelena LU
- supervisor
- organization
- publishing date
- 2025
- type
- Thesis
- publication status
- published
- subject
- keywords
- ASTHMA, COPD, Epithelial cell, IL-4, IL-13, Rhinovirus, Alarmins, Interferon, ILC2s, dupilumab
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2025:69
- pages
- 83 pages
- publisher
- Lund University, Faculty of Medicine
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-722-4
- language
- English
- LU publication?
- yes
- additional info
- Date: 2025-06-12 Time: 09:00 Place: Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Teams: https://teams.microsoft.com/l/meetup-join/19%3ameeting_Y2VmZDRkNmItZjdlNy00OTFkLTg5ZWItOTc5YzU5ZDNiNjcz%40thread.v2/0?context=%7b%22Tid%22%3a%22af8e89a3-d9ac-422f-ad06-cc4eb4214314%22%2c%22Oid%22%3a%227915cd56-22a3-44fe-b8da-259d44624c6e%22%7d External reviewer(s) Name: Bossios Apostolos Title: Associate Professor, MD Affiliation: Karolinska University Hospital, Institute of Environmental Medicine, Unit of Lung and Airway Research, Stockholm
- id
- ec8166ce-0fc4-481e-a9c3-7a76c4d621e6
- date added to LUP
- 2025-05-19 09:06:03
- date last changed
- 2025-05-26 09:34:35
@phdthesis{ec8166ce-0fc4-481e-a9c3-7a76c4d621e6,
abstract = {{Airway epithelium, formed by epithelial cells lining human airways, is a critical barrier against inhaled allergens, viruses, and pollutants. Beyond being a physical barrier, it functions as a first-line defense by secreting alarmins, inflammatory cytokines, and chemokines, thereby activating other immune cells. In respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD), the epithelial barrier's function is compromised, partly due to persistent inflammation.<br/>This doctoral thesis primarily investigated the impact of type 2 (T2) cytokines, particularly IL-4 and IL-13, on bronchial epithelial cells (BECs) and their antiviral responses using translational in vitro air-liquid interface (ALI) cultures. These studies involved epithelial cells from healthy individuals and patients with asthma and COPD. The cytokines were introduced to BEC cultures exogenously, with and without rhinovirus (RV) infection. Additionally, we developed a co-culture system with innate lymphoid cells (ILC2) and BECs to explore the immunological interaction between these cells, given that ILC2s are potent sources of T2 cytokines.<br/>The research further investigated the mechanisms of IL-4 receptor alpha (IL-4Rα) monoclonal antibody (mAb) treatment under T2 inflammatory conditions, focusing on its influence on viral-induced exacerbations.<br/>Our studies indicated that BECs from individuals with asthma showed increased inflammatory responses upon acute exposure to IL-4 and IL-13. This was evidenced by increased levels of eosinophil chemoattractant (CCL26) and alarmins (TSLP) while maintaining antiviral responses. These cytokine-induced effects were attenuated by IL-4Rα mAb. In settings of chronic T2 cytokine exposure or within the BEC/ILC2 co-culture model, a reduction in TSLP over time was noted, alongside altered antiviral responses. <br/>The findings aim to elucidate the mechanistic effects of T2 inflammation and IL-4Rα mAb inhibition specifically on airway epithelial cells, contributing to a deeper understanding of how anti-IL-4Rα treatment assists in improving lung function and reducing exacerbations in patients. Our novel data on decreased levels of CCL26 (Eotaxin-3) in both asthma and COPD may explain why asthma and COPD patients with eosinophilia respond well to IL-4Rα treatment.}},
author = {{Pesic, Jelena}},
isbn = {{978-91-8021-722-4}},
issn = {{1652-8220}},
keywords = {{ASTHMA; COPD; Epithelial cell; IL-4; IL-13; Rhinovirus; Alarmins; Interferon; ILC2s; dupilumab}},
language = {{eng}},
number = {{2025:69}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Modulation of innate immunity by type 2 inflammation precision targeting therapeutics: T2 cytokines as modulators of human bronchial epithelial cells.}},
url = {{https://lup.lub.lu.se/search/files/219485422/Avhandling_Jelena_Pesic_LUCRIS.pdf}},
year = {{2025}},
}