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

Pro-Inflammatory Versus Anti-Inflammatory Effects of Dendrimers: The Two Faces of Immuno-Modulatory Nanoparticles

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

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

The ABP dendrimer, which is built on a phosphorus-based scaffold and bears twelve azabisphosphonate groups at its surface, is one of the dendrimers that has been shown to display immuno-modulatory and anti-inflammatory effects towards the human immune system. Its anti-inflammatory properties have been successfully challenged in animal models of inflammatory disorders. In this review, we trace the discovery and the evaluation of the therapeutic effects of the ABP dendrimer in three different animal models of both acute and chronic inflammatory diseases. We emphasize that its therapeutic effects rely on the enhancement of the production of Interleukin-10, the paradigm of anti-inflammatory cytokines, by different subsets of immune cells, such as monocytes/macrophages and CD4+ T lymphocytes

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

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

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Nanoparticle-Based Strategies to Treat Neuro-Inflammation

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Multivalent nanosystems: targeting monocytes/macrophages

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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

Modulation de la surcharge en fer dans un modèle murin d'hémochromatose (mise en évidence de facteurs génétiques et études d'expression génique)

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