Modified Foxp3 mRNA protects against asthma through an IL-10–dependent mechanism
Lauren E. Mays, … , Dominik Hartl, Michael S.D. Kormann
Lauren E. Mays, … , Dominik Hartl, Michael S.D. Kormann
Published February 8, 2013
Citation Information: J Clin Invest. 2013;123(3):1216-1228. https://doi.org/10.1172/JCI65351.
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Research Article Pulmonology

Modified Foxp3 mRNA protects against asthma through an IL-10–dependent mechanism

Abstract

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.

Authors

Lauren E. Mays, Susanne Ammon-Treiber, Benedikt Mothes, Mohammed Alkhaled, Jennifer Rottenberger, Eva Sophie Müller-Hermelink, Melanie Grimm, Markus Mezger, Sandra Beer-Hammer, Esther von Stebut, Nikolaus Rieber, Bernd Nürnberg, Matthias Schwab, Rupert Handgretinger, Marco Idzko, Dominik Hartl, Michael S.D. Kormann

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Figure 8

Helper T cell responses are no longer rebalanced in the presence of recombinant IL-17A/IL-23 or depletion of IL-10.

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Helper T cell responses are no longer rebalanced in the presence of reco...
Mice were sensitized and challenged with OVA or PBS. During challenge, mice received modified Foxp3 mRNA either alone or in combination with recombinant IL-17A or IL-23. Some groups received an IL-10–depleting antibody before the onset of OVA challenge. (A) Fold change increase in Foxp3, Gata3, and Rorγt mRNA levels relative to PBS controls as detected by RT-PCR and normalized to ß-actin. (B) Expression of Th2 cytokines (IL-4, IL-5, and IL-13), Th17 cytokines (IL-17A and IL-23), and Treg cytokine (IL-10) in BAL by ELISA. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 (mean ± SD). (A and B), n = 8 mice per group. “PBS,” “OVA,” and “OVA + Foxp3” groups were also repeated in a total of 3 independent studies.