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Impact d'une exposition aux nanoparticules sur les fonctions des cellules présentatrices d'antigènes

Abstract : Nanoparticles (NP) have been introduced in medicine to develop intelligent drugs or imaging agents. Due to their small size (<200 nm), NPs allow the development of targeted therapies, increase drug diffusion and effectiveness while facilitating modes of administration and decreasing public health costs. Nevertheless, the potential risks for human health associated to NP exposure remain poorly documented; especially about their effects on the immune system. Antigen-presenting cells (APC) (including macrophages and dendritic cells) are recruited at the site of pathogen-induced inflammation and constitute to the maintenance of body integrity, engulfing pathogens and delivering signals to other components of the immune system. Due to their internalization abilities, APC accumulate NP in their cytoplasm. Thus, these cells will be among the most affected by exposure to NP and constitute a relevant experimental model for the study of the cellular fate of NP and their effects on the host.In this study, we investigated whether the functions of these cells could be modified by an exposure to NP. As models of NP, we selected gold (AuNP) and gadolinium-polysiloxane (GdSi) used as contrast agent for therapeutic and diagnostic applications, and poly lactic-co-glycolic acid (PLGA) and lipid nano emulsion (LNP) developed as a platform for the delivery of antigens or drugs.First, using fluorescent microspheres as probe, we have shown that all of the tested NP did not alter the phagocytosis capacity of the J774 macrophage cell line. Then, cell activation was analyzed by flow cytometry, based on the expression of the surface markers CD-86 and MHC-II. We have established that NP exposure did not activate bone marrow derived dendritic cells (BMDC). In this way, none of these NP induced cytokine secretions by the BMDC. Furthermore, activation of these cells by known activators, such as bacterial lipopolysaccharide (LPS) was not modified by NP.However, in this case, the cytokine response was altered by AuNP exposure, showing reduced inflammatory cytokine production such as IL-6, IL-12 and IL-23. Interestingly, these cytokines are involved in the polarization of CD4 + T lymphocytes to the appropriate T helper phenotype (Th). In a model of antigen presentation in vitro, this cytokine profile resulted into an altered development of specific immune responses. AuNP exposure increased T cell specific cytokines: IL-13 and IL-4 (indicating a shift of classical Th1/Th2 balance towards Th2) and IL-17 (standing for an alteration of T-cell fate towards Th17). The exposure of BMDC to the other NP of the study only very slightly altered their inflammatory cytokine secretions and therefore did not affect the fate of T lymphocytes after antigen presentation.All together, these results demonstrate that GdSi, PLGA and LNP do not modify phagocytosis, DC activation and antigen presentation. However, exposure to AuNP alters the DC induced inflammatory responses and polarizes the T cell fate towards Th2 and Th17 phenotypes. These changes could impair the physiology of the immune system and contribute to chronic diseases or autoimmunity.
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  • HAL Id : tel-01726627, version 1

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Alexis Gonon. Impact d'une exposition aux nanoparticules sur les fonctions des cellules présentatrices d'antigènes. Virologie. Université Grenoble Alpes, 2017. Français. ⟨NNT : 2017GREAV078⟩. ⟨tel-01726627⟩

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