Funktion des T-regulatorischen Zellen in Notch Signalling in allergischen Entzündung
Zusammenfassung der Projektergebnisse
In this study, we were able to identify Notch4 as a hub molecule that regulate immune tolerance in airway inflammation. In that regard, two main pathways were identified. Hippo pathway, through its main regulators YAP1 and WWTR1 were found to regulate Treg subversion into Th17-like cells and their suppressive activity toward Teff cells. Wnt pathway on the other hand, was found to regulate Th2 inflammation and the suppressive activity on ILC2 in airway inflammation. These two distinct pathways with distinct mechanism of action, that are both tightly controlled by Notch4, opens new possibilities on how Notch receptors act to license tissue tolerance/inflammation in different organ. Furthermore, the identification of GDF15 as an important biomarker on one side and a regulator of ILC2 inflammation in the lung on the other will open new venues for further research on the role of this newly identified cytokine on regulating ILC2 in the lung and its role in regulation ILC activity in other organs. One interesting finding was our ability to treat one very sick asthmatic patient, who was unresponsiveness to other asthma medications, with IL-6R monoclonal antibody (Tocilizumab) successfully as per their identifying their genetic background for IL-4R (IL-4R576R) and their Notch4 expression on their Treg cells. This project has the potential to push the asthma research into a new venue and thus toward a new therapeutic possibility that drives this field from treating effector mechanisms toward restoring tolerance in the lung. To our knowledge, this study is the first of its kind that investigates the role of Treg cells in Asthma showing a very important pathway in tolerance breakdown and thus the possibility in restoring it and thus curing asthma in a more sustainable way.
Projektbezogene Publikationen (Auswahl)
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A Jagged1-Notch4 molecular switch mediates airway inflammation induced by ultrafine particles. J Allergy Clin Immunol. 2018 Oct;142(4):1243-1256.e17
Xia M, Harb H, Saffari A, Sioutas C, Chatila TA
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Functional reprogramming of regulatory T cells in the absence of Foxp3. Nat Immunol. 2019 Sep;20(9):1208-1219
Charbonnier LM, Cui Y, Stephen-Victor E, Harb H, Lopez D, Bleesing JJ, Garcia-Lloret MI, Chen K, Ozen A, Carmeliet P, Li MO, Pellegrini M, Chatila TA
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Microbiota therapy acts via a regulatory T cell MyD88/RORγt pathway to suppress food allergy. Nat Med. 2019 Jul;25(7):1164-1174. Erratum in: Nat Med. 2019 Sep;25(9):1458
Abdel-Gadir A, Stephen-Victor E, Gerber GK, Noval Rivas M, Wang S, Harb H, Wang L, Li N, Crestani E, Spielman S, Secor W, Biehl H, DiBenedetto N, Dong X, Umetsu DT, Bry L, Rachid R, Chatila TA
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Treatment of severe persistent asthma with IL-6 receptor blockade. J Allergy Clin Immunol Pract. 2019 May - Jun;7(5):1639-1642.e4
Esty B, Harb H, Bartnikas LM, Charbonnier LM, Massoud AH, Leon-Astudillo C, Visner G, Subramaniam M, Phipatanakul W, Chatila TA
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Mechanisms of Dupilumab. Clin Exp Allergy. 2020 Jan;50(1):5-14
Harb H, Chatila TA
