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Immunometabolism in asthma, allergy and immune tolerance.

English title Immunometabolism in asthma, allergy and immune tolerance.
Applicant Sokolowska Milena Grazyna
Number 189334
Funding scheme Project funding (Div. I-III)
Research institution Schweizerisches Institut für Allergie- und Asthmaforschung
Institution of higher education Swiss Institute of Allergy and Asthma Research - SIAF
Main discipline Immunology, Immunopathology
Start/End 01.07.2020 - 30.06.2024
Approved amount 424'009.00
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Keywords (10)

Asthma ; T cells ; Lipids ; Virus; Metabolism ; Allergen; Metabolic reprogramming; Allergen-specific immunotherapy; Immune tolerance; Epithelial cells

Lay Summary (German)

Aufgrund von Veränderungen der Umwelt und des Lebensstil während der letzten Jahrzehnte nimmt die Häufigkeit von Allergien und viralen sowie bakteriellen Atemwegsinfektionen stetig zu. Zeitgleich erleben wir eine Adipositas- und vom Stoffwechsel-Syndrom-Epidemie. Bislang besteht jedoch kein klares Verständnis über die Zusammenhänge zwischen Atemwegserkrankungen, Allergien und Stoffwechselerkrankungen. Metabolische Veränderungen verschiedener Zellen in unserem Körper, wie die Epithelzellen und T-Zellen, könnten für die Entwicklung von Allergien, Asthma und anderen Erkrankungen verantwortlich sein.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Unsere Hypothese dreht sich um die Stoffwechselveränderungen von Immunzellen während diese das Allergen als solches erkennen und zu einer Allergie statt zu einer physiologischen Verträglichkeit führen. Diese Veränderung könnte durch Atemwegsviren herbeigeführt werden. Wir werden deshalb die metabolischen Veränderungen der Epithel- und T-Zellen der Lunge während allergischen und viralen Entzündungen untersuchen. Damit wir die zugrundeliegenden Mechanismen ermitteln können, werden wir mit Zellkulturen, präklinischen Tiermodellen und menschlicher Proben aus klinischen Studien arbeiten.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Den Zusammenhang zwischen Stoffwechsel, Allergenen und Viren zu verstehen, könnte zu neuen Strategien für Prävention und Behandlung von chronischen Atemwegserkrankungen führen. Ebenso ermöglicht es, neue Einblicke in die Pathogenese von anderen weit verbreiteten Erkrankungen wie die Diabetes, Krebs oder Immunkrankheiten zu gewinnen.

Direct link to Lay Summary Last update: 13.07.2020

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Background: Chronic respiratory diseases are one of the leading causes of death and disability in the world. More than 7.4% of people suffer from asthma (300 million) and chronic obstructive pulmonary disease (214.4 million) worldwide. The epidemic of chronic inflammatory disorders of the upper and lower airways, as well as other allergic disorders has a substantial impact on both the quality of life and life expectancy. Furthermore, it results in a very high economic burden for the patients and the whole society. Alarmingly, the prevalence of chronic respiratory disorders is accelerating. Due to environmental and lifestyle changes, there is an increasing frequency of allergies and respiratory viral and bacterial infections. Simultaneously, we are witnessing obesity and metabolic syndrome epidemics throughout the developed world. To date, there is no clear understanding of the connection between respiratory diseases, allergies and metabolic disorders. Our preliminary data as well as the recent findings of others demonstrate a strong link between immune effector and immune regulatory functions with metabolic dysregulations at the single cell level. These findings suggest that functions of the immune system might be significantly influenced by systemic metabolic dysregulations coupled with environmental exposures.Immunometabolism of regulatory T cells, effector T cells and epithelial cells is a dynamically developing field of research, especially in cancer, diabetes, cardiovascular and infectious diseases. It has been suggested that reprogramming of cells in distinct metabolic pathways including glycolysis, fatty acid oxidation and oxidative phosphorylation may play a major role in determining their effector/memory responses in the direction of pro- or anti-inflammatory functions. However, there is very limited understanding on the role of immunometabolism in the field of respiratory and allergic diseases. It is not known whether allergen encounter, its processing and the subsequent outcomes such as tolerance or allergic sensitization causes or depends on metabolic reprogramming at the cellular or systemic level. Planned experiments: Our hypothesis is that metabolic reprogramming of the immune system is central in regulating immune effector or tolerance functions towards allergens. This reprogramming is affected by common environmental factors and ultimately leads to breaking peripheral tolerance and development of allergy and asthma. We will use human samples and in vivo models and apply high throughput transcriptomic, targeted proteomic, metabolomic and lipidomic methods coupled with gene editing, multi-color flow cytometry and confocal microscopy. Using such a thorough, cutting-edge methodology, we will uncover metabolic processes in T cells and airway epithelial cells upon recognition, processing and responding to allergen. We will strongly focus on human in vivo relevance of these findings and characterize metabolic reprogramming in allergen-specific T cells in patients during allergen-specific immunotherapy. Major findings will be confirmed in healthy tolerant bee keepers upon high allergen exposure and in twins discordant to allergy. Furthermore, we will analyze metabolic cross-talk between local T cell subsets and epithelial cells in the lungs of obese asthma patients and patients during viral infections to assess obesity or virus exposure as conditions of breaking immune tolerance. We will uncover the functional significance of the most interconnected transcriptional, protein and metabolic hubs in the phenotypic responses of T cells and epithelial cells by gene editing strategies and by cell specific gene-deficient mouse experiments upon allergen- or respiratory virus-induced inflammation.Impact and innovative potential: Understanding the connections between metabolism, immune tolerance to allergens and agents involved in induction or breaking immune tolerance such as viruses can lead to novel strategies in prevention and treatment of chronic respiratory diseases. This research will also impact on other areas of basic science and public health and where metabolic reprogramming, antigen-specificity and immune regulation play essential roles, such as diabetes, autoimmunity, cancer and chronic infections.