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Agrégation et immunisation contre les protéines thérapeutiques : étude de la maturation des cellules dendritiques et de la réponse lymphocytaire

Abstract : Immunogenicity of biotherapeutic proteins is a major drawback in the treatment of patients with chronic diseases characterized by the production of anti-drug antibodies (ADA). The detection of ADA with high affinity and of various isotypes suggests a CD4 T cell-dependent adaptive immune response with a pivotal role for dendritic cells. Among other factors, the presence of protein aggregates in the administered products can promote immunogenicity, as aggregates seem to act as danger signals.The aim of our work is to better understand the interactions of protein aggregates with dendritic cells and T cells, leading to the establishment of a specific adaptive immune response needed for the production of ADA.We first showed that aggregation of infliximab, a monoclonal anti-TNFa; antibody, induced the maturation of human monocyte-derived dendritic cells (moDC) via an increase in the expression of activation and costimulatory surface markers and the secretion of pro-inflammatory cytokines and chemokines. Moreover, we showed that these phenotypic changes induced by aggregates promote CD4 T-cell proliferation and cytokine production. Subsequently, we described the early events involved in moDC and T-cell response by showing that the neutralization of the FcgRIIa receptor and the tyrosine kinase Syk inhibited moDC maturation and CD4 T-cell activation.Furthermore, we evaluated the involvement of infliximab aggregates in the generation of neo-epitopes by identifying a naïve CD4 T-cell repertoire recognizing infliximab aggregates in healthy subjects. By testing well characterized aggregate preparations and using an autologous co-culture model of naïve CD4 T cells and moDC loaded with aggregates, we showed that the frequency of naïve CD4 T cells specific for infliximab aggregates was higher than the one found for the native antibody. These results suggested an increased presentation of epitopes and neo-epitopes derived from infliximab aggregates.In resume, our work contributes to a better understanding of the biological consequences of therapeutic protein aggregation on the onset of the specific adaptive immune response by focusing on the adjuvant and antigenic role of protein aggregates.
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Submitted on : Tuesday, June 15, 2021 - 1:01:23 AM
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Myriam Nabhan. Agrégation et immunisation contre les protéines thérapeutiques : étude de la maturation des cellules dendritiques et de la réponse lymphocytaire. Immunologie. Université Paris Saclay (COmUE), 2019. Français. ⟨NNT : 2019SACLS576⟩. ⟨tel-03260428⟩

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