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Etude de l’efficacité des stratégies d’immunothérapies actives anti-cytokine et évaluation des conséquences de la vaccination anti-TNF dans des modèles infectieux

Abstract : Rheumatoid arthritis (RA) is the most frequent inflammatory rheumatism. This disease is accompanied by hyperplasia of the synovial membrane surrounding the joint. Pannus formation is controlled by pro-inflammatory and pro-angiogenic cytokines. Anti-TNF immunotherapies used in the treatment of RA presents many drawbacks (loss of efficacy, infections), which leaves some place for the development of an anti-TNF immunization strategy. In the first part of my work, we developed an anti-VEGF vaccine to study the links between angiogenesis and inflammation in collagen-induced arthritis (CIA) model. In the second part, we developed a mouse anti-TNF vaccine to assess the consequences of the neutralization of TNF-α by vaccination in infectious models. Inhibition of VEGF with a vaccine consisting of whole VEGF or VEGF peptide coupled to KLH, showed a clinical and histological protection in the CIA model. In the second part of my work, we developed a mouse anti-TNF vaccine (TNF-KLH). This vaccine is as effective as etanercept in CIA, but does not increase the risk of infection in Mycobacterium tuberculosis model. In Listeria monocytogenes model, unlike etanercept, immunization with TNF-KLH does not increase the bacterial burden and mortality. My work contributed to the development of active anti-VEGF vaccine and our results show a partial protection with this strategy. Also, we demonstrate that targeting TNF by active immunotherapy does not alter the immune response in our models of infections.
Keywords : Anti-VEGF vaccine
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Nadia Belmellat-Bouadi. Etude de l’efficacité des stratégies d’immunothérapies actives anti-cytokine et évaluation des conséquences de la vaccination anti-TNF dans des modèles infectieux. Biologie moléculaire. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCD028⟩. ⟨tel-01818519⟩

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