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Nouvelles immunothérapies dans le traitement du syndrome de Sjögren et autres maladies interféron-dépendantes

Abstract : My PhD thesis focused on the link between autoimmune diseases and the interferons’ (IFN) system. These cytokines are well known for their antiviral effects, but their role goes far beyond this, with a growing body of evidence concerning their implication in many autoimmune diseases, such as systemic lupus erythematosus (SLE), Sjögren’s syndrome (SjS), myositis and systemic sclerosis (SSc), especially concerning type 1 IFNs. Hence, we mainly focused on IFNα, which is the main representative of type 1 IFNs. After an in-depth thinking on the choice and current use of mouse models in SjS, especially about the concept of primary and secondary SjS, the first part of my work was dedicated to the conduct of a preclinical trial evaluating IFN-Kinoid (IFN-K) in a systemic SjS mouse model, MRL/MpJ-Faslpr/lpr (MRL/lpr) mice. We obtained good results, in terms of immunogenicity and tolerance, and improved the glandular manifestations, peripheral neuropathy and IFN signature in these mice, which paves the way towards IFN-K’s future clinical development in SjS, as it is already the case for SLE. These results allowed us to conduct another preclinical trial with IFN-K in a SjS model developing B lymphomas: the human interleukin 14α transgenic mouse model.In the second part of my PhD thesis, I studied some of the mechanisms leading to the activation of the IFN pathways in SjS, especially the effects of anti-Ro60/SSA immunoglobulin E autoantibodies, and we conducted a regional clinical trial to evaluate this new biomarker in the disease. Finally, I have reported here the first human case of a patient with systemic SjS (including autoimmune myelofibrosis), successfully treated with the JAK inhibitor, ruxolitinib.The set of data produced in this PhD thesis clarifies some aspects about the role of IFNs (especially IFNα) in SjS, and paves the way towards new therapeutic leads.
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Martin Killian. Nouvelles immunothérapies dans le traitement du syndrome de Sjögren et autres maladies interféron-dépendantes. Médecine humaine et pathologie. Université de Lyon, 2019. Français. ⟨NNT : 2019LYSES051⟩. ⟨tel-02895179⟩

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