title: 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: Department of Pediatrics I-Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy, University of Tübingen, Tübingen, Germany.
authors: Lauren E
authors: LE
authors: Mays
authors: Susanne
authors: S
authors: Ammon-Treiber
authors: Benedikt
authors: B
authors: Mothes
authors: Mohammed
authors: M
authors: Alkhaled
authors: Jennifer
authors: J
authors: Rottenberger
authors: Eva Sophie
authors: ES
authors: Müller-Hermelink
authors: Melanie
authors: M
authors: Grimm
authors: Markus
authors: M
authors: Mezger
authors: Sandra
authors: S
authors: Beer-Hammer
authors: Esther
authors: E
authors: von Stebut
authors: Nikolaus
authors: N
authors: Rieber
authors: Bernd
authors: B
authors: Nürnberg
authors: Matthias
authors: M
authors: Schwab
authors: Rupert
authors: R
authors: Handgretinger
authors: Marco
authors: M
authors: Idzko
authors: Dominik
authors: D
authors: Hartl
authors: Michael S D
authors: MS
authors: Kormann
mesh_terms: D056151:Airway Remodeling; D000403:Airway Resistance; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D002460:Cell Line; D003562:Cytidine / Q000031:analogs & derivatives / Q000737:chemistry; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000494:pharmacology / Q000502:physiology; D016753:Interleukin-10 / Q000378:metabolism*; D020381:Interleukin-17 / Q000494:pharmacology / Q000502:physiology; D053759:Interleukin-23 / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D039981:Pyroglyphidae / Q000276:immunology; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013891:Thiouridine / Q000031:analogs & derivatives / Q000737:chemistry; D014162:Transfection
chemical_list: C105273:2-thiouridine; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D018836:Inflammation Mediators; D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger; D016753:Interleukin-10; D013891:Thiouridine; D003562:Cytidine; C016568:5-methylcytidine
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