Modulation of pro-inflammatory activation of monocytes and dendritic cells by aza-bis-phosphonate dendrimer as an experimental therapeutic agent

INTRODUCTION: Our objective was to assess the capacity of dendrimer aza-bis-phosphonate (ABP) to modulate phenotype of monocytes (Mo) and monocytes derived dendritic cells (MoDC) activated in response to toll-like receptor 4 (TLR4) and interferon γ (IFN- γ) stimulation. METHODS: Mo (n = 12) and MoDC (n = 11) from peripheral blood of healthy donors were prepared. Cells were preincubated or not for 1 hour with dendrimer ABP, then incubated with lipopolysaccharide (LPS; as a TLR4 ligand) and (IFN-γ) for 38 hours. Secretion of tumor necrosis factor α (TNFα), interleukin (IL) -1, IL-6, IL-12, IL-10 and IL-23 in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA) and Cytokine Bead Array. Differentiation and subsequent maturation of MoDC from nine donors in the presence of LPS were analyzed by flow cytometry using CD80, CD86, CD83 and CD1a surface expression as markers. RESULTS: Mo and MoDC were orientated to a pro-inflammatory state. In activated Mo, TNFα, IL-1β and IL-23 levels were significantly lower after prior incubation with dendrimer ABP. In activated MoDC, dendrimer ABP promoted IL-10 secretion while decreasing dramatically the level of IL-12. TNFα and IL-6 secretion were significantly lower in the presence of dendrimer ABP. LPS driven maturation of MoDC was impaired by dendrimer ABP treatment, as attested by the significantly lower expression of CD80 and CD86. CONCLUSION: Our data indicate that dendrimer ABP possesses immunomodulatory properties on human Mo and MoDC, in TLR4 + IFN-γ stimulation model, by inducing M2 alternative activation of Mo and promoting tolerogenic MoDC

Trogocytosis and killing of IL-4-polarized monocytes by autologous NK cells

International audienceCross-regulations between innate immune cells have been given more and more emphasis. Here, we address the question of bidirectional interactions between activated monocytes and autologous NK cells. Classically activated monocytes (class-monocytes), obtained by priming with IFN-gamma, drive an inflammatory immune response. On the contrary, alternatively activated monocytes (alt-monocytes), obtained by stimulation with IL-4 or IL-13, engage an anti-inflammatory immune response. We show that alt-monocytes inhibit proliferation and production of IFN-gamma by autologous, IL-2-activated NK cells, whereas class-monocytes do not inhibit these NK cell functions. Reciprocally, IL-2-activated NK cells interact and undertake intensive synaptic transfer with alt-monocytes, whereas interactions with class-monocytes are weaker. This strong trogocytosis correlates with an efficient killing of alt-monocytes, mediated by natural cytotoxicity receptors and a lowered killing of class-monocytes. These results suggest that interactions between NK cells and autologous-activated monocytes modulate inflammatory responses. This might be extended further in the elimination of tumor-associated macrophages, which actively promote solid tumor progression and metastasis

Régulation des réponses effectrices des lymphocytes T par les cellules du stroma tumoral

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

The ABP Dendrimer, a Drug-Candidate against Inflammatory Diseases That Triggers the Activation of Interleukin-10 Producing Immune Cells

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Pro-Inflammatory Versus Anti-Inflammatory effects of dendrimers: The Two Faces of Immuno-Modulatory Nanoparticles

International audienceDendrimers are soft matter, hyperbranched, and multivalent nanoparticles whose synthesistheoretically affords monodisperse compounds. They are built from a core on which one orseveral successive series of branches are engrafted in an arborescent way. At the end of thesynthesis, the tunable addition of surface groups gives birth to multivalent nano-objects whichare generally intended for a specific use. For these reasons, dendrimers have received a lot ofattention from biomedical researchers. In particular, some of us have demonstrated that dendrimerscan be intrinsically drug-candidate for the treatment of inflammatory disorders, amongst others,using relevant preclinical animal models. These anti-inflammatory dendrimers are innovativein the pharmaceutical field. More recently, it has appeared that some dendrimers (even amongthose which have been described as anti-inflammatory) can promote inflammatory responses innon-diseased animals. The main corpus of this concise review is focused on the reports whichdescribe anti-inflammatory properties of dendrimers in vivo, following which we review the fewrecent articles that show pro-inflammatory effects of our favorite molecules, to finally discuss thisduality in immuno-modulation which has to be taken into account for the preclinical and clinicaldevelopments of dendrimers

Nanoparticle-Based Strategies to Treat Neuro-Inflammation

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Anti-Inflammatory Properties of Dendrimers per se

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Utilisation d'un dendrimère phosphoré comme une nouvelle approche thérapeutique de la polyarthrite rhumatoïde

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Multivalent nanosystems: targeting monocytes/macrophages.

International audienceAmong all the cellular partners involved in inflammatory processes, monocytes and macrophages are the master regulators of inflammation. They are found in almost all the tissues and are nearly the only cells capable of performing each step of inflammation. Consequently, they stand as major relevant therapeutic targets to treat inflammatory disorders and diseases. The physiological phagocytic activity of macrophages prompts them to detect, to recognize, and eventually to engulf any nanosystem cruising in their neighborhood. Interestingly, nanosystems can be rationally engineered to afford multivalent, and multifunctional if needed, entities with multiplexed and/or reinforced biological activities. Indeed, engineered nanosystems bearing moieties specifically targeting macrophages, and loaded with or bound to drugs are promising candidates to modulate, or even eradicate, deleterious macrophages in vivo. In this review we highlight recent articles and concepts of multivalent nanosystems targeting monocytes and macrophages to treat inflammatory disorders

Multivalent nanosystems: targeting monocytes/macrophages

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