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Effet d'un contexte inflammatoire sur le transfert de gènes dans les cellules trachéales glandulaires mucoviscidosiques

Abstract : Cystic Fibrosis (CF), a lethal monogenic disease, is caused by mutations in the cftr gene, and is characterized by chronic infection and inflammation in the lung. cftr is strongly expressed in tracheal glands. Clinical trials in wllich the hunlan CFTR cDNA was delivered to the lung of CF patients have only resulted in weak and transient gene expression. We herein hypothesized that the non specific immune response may be partly responsible for failure of gene therapy in CF. We tested the action of two cytokines, involved in the ThllTh2 inflammatory response, TNFq and Interleukin 4 (IL-4), on IgA transcytosis and gene transfer efficacy in a model of human CF tracheal gland cells (CF-KM4). Gene transfer was efficient using non viral trailsfection reagents and as judged by luciferase expression and by correction of CF cell secretory defects. The two cytokines, TNFa and IL-4, did not inhibit gene transfer efficiency, but inhibited transgene expression probably acting through their respective receptors. Study of signalling pathways involved by these two cytokines showed that inhibition of transgene expression was preveilted by glucocorticoïds but not by NSAI agents. Furthermore, we showed that IgA transcytosis was functional and efficient in this cell model, and that afier gene transfer, cells increased expression of IgA receptor gene. We suggest that the inflammatory context found in CF lung may be a stocking block for CF gene transfer and should be taken into account for developing new strategies of CF gene therapy.
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Submitted on : Thursday, March 29, 2018 - 10:48:44 AM
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  • HAL Id : tel-01746968, version 1


Sonia Bastonero. Effet d'un contexte inflammatoire sur le transfert de gènes dans les cellules trachéales glandulaires mucoviscidosiques. Biologie cellulaire. Université Henri Poincaré - Nancy 1, 2005. Français. ⟨NNT : 2005NAN11316⟩. ⟨tel-01746968⟩



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