Modified Foxp3 mRNA protects against asthma through an IL-10–dependent mechanism
| Autor: | Lauren Mays, Rupert Handgretinger, Esther von Stebut, Michael S. D. Kormann, Nikolaus Rieber, Susanne Ammon-Treiber, Dominik Hartl, Mohammed Alkhaled, Melanie Grimm, Markus Mezger, Bernd Nürnberg, Jennifer Rottenberger, Eva Müller-Hermelink, Matthias Schwab, Benedikt Mothes, Sandra Beer-Hammer, Marco Idzko |
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| Rok vydání: | 2013 |
| Předmět: |
Regulatory T cell
T cell Thiouridine Gene Expression Cytidine Biology Transfection Interleukin-23 Cell Line Mice Th2 Cells medicine Interleukin 23 Animals Humans RNA Messenger Mice Knockout Mice Inbred BALB C Innate immune system Airway Resistance Interleukin-17 Pyroglyphidae FOXP3 Forkhead Transcription Factors Genetic Therapy General Medicine T helper cell Asthma Immunity Innate Interleukin-10 Interleukin 10 medicine.anatomical_structure Immunology Airway Remodeling Th17 Cells Female Interleukin 17 Inflammation Mediators Research Article |
| Zdroj: | Journal of Clinical Investigation. 123:1216-1228 |
| ISSN: | 0021-9738 |
| Popis: | Chemically modified mRNA is capable of inducing therapeutic levels of protein expression while circumventing the threat of genomic integration often associated with viral vectors. We utilized this novel therapeutic tool to express the regulatory T cell transcription factor, FOXP3, in a time- and site-specific fashion in murine lung, in order to prevent allergic asthma in vivo. We show that modified Foxp3 mRNA rebalanced pulmonary T helper cell responses and protected from allergen-induced tissue inflammation, airway hyperresponsiveness, and goblet cell metaplasia in 2 asthma models. This protection was conferred following delivery of modified mRNA either before or after the onset of allergen challenge, demonstrating its potential as both a preventive and a therapeutic agent. Mechanistically, FOXP3 induction controlled Th2 and Th17 inflammation by regulating innate immune cell recruitment through an IL-10-dependent pathway. The protective effects of FOXP3 could be reversed by depletion of IL-10 or administration of recombinant IL-17A or IL-23. Delivery of Foxp3 mRNA to sites of inflammation may offer a novel, safe therapeutic tool for the treatment of allergic asthma and other diseases driven by an imbalance in helper T cell responses. |
| Databáze: | OpenAIRE |
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