Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies.

TIGIT is an immune checkpoint inhibitor expressed by effector CD4 and CD8 T cells, NK cells, and regulatory T cells (Tregs). Inhibition of TIGIT-ligand binding using antagonistic anti-TIGIT mAbs has shown potential to restore T-cell function and therapeutic efficacy in murine tumor models when combined with an anti-PD(L)-1 antibody. In the current work, we demonstrate broader TIGIT expression than previously reported in healthy donors and patients with cancer with expression on γδ T cells, particularly in CMV-seropositive donors, and on tumor cells from hematologic malignancies.

Characterization of the Selective Indoleamine 2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy.

Tumors use indoleamine 2,3-dioxygenase-1 (IDO1) as a major mechanism to induce an immunosuppressive microenvironment. IDO1 expression is upregulated in many cancers and considered to be a resistance mechanism to immune checkpoint therapies. IDO1 is induced in response to inflammatory stimuli such as IFNγ and promotes immune tolerance by depleting tryptophan and producing tryptophan catabolites, including kynurenine, in the tumor microenvironment.

The complex cascade of cellular events governing inflammasome activation and IL-1β processing in response to inhaled particles.

The innate immune system is the first line of defense against inhaled particles. Macrophages serve important roles in particle clearance and inflammatory reactions. Following recognition and internalization by phagocytes, particles are taken up in vesicular phagolysosomes.

Regulation of macrophage motility by the water channel aquaporin-1: crucial role of M0/M2 phenotype switch.

The water channel aquaporin-1 (AQP1) promotes migration of many cell types. Although AQP1 is expressed in macrophages, its potential role in macrophage motility, particularly in relation with phenotype polarization, remains unknown. We here addressed these issues in peritoneal macrophages isolated from AQP1-deficient mice, either undifferentiated (M0) or stimulated with LPS to orientate towards pro-inflammatory phenotype (classical macrophage activation; M1).

Why does the hemolytic activity of silica predict its pro-inflammatory activity?

Background: The hemolytic activity of inhaled particles such as silica has been widely investigated in the past and represents a usual toxicological endpoint to characterize particle reactivity despite the fact that red blood cells (RBCs) are not involved in the pathogenesis of pulmonary inflammation or fibrosis caused by some inhaled particles. The inflammatory process induced by silica starts with the activation of the inflammasome, which leads to the release of mature IL-1β. One of the upstream mechanisms causing activation of the inflammasome is the labilization of the phagolysosomal membrane after particle phagocytosis.

The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles.

Background: Inflammasome-activated IL-1β plays a major role in lung neutrophilic inflammation induced by inhaled silica. However, the exact mechanisms that contribute to the initial production of precursor IL-1β (pro-IL-1β) are still unclear. Here, we assessed the implication of alarmins (IL-1α, IL-33 and HMGB1) in the lung response to silica particles and found that IL-1α is a master cytokine that regulates IL-1β expression.

IL-1α induces CD11b(low) alveolar macrophage proliferation and maturation during granuloma formation.

Macrophages play a central role in immune and tissue responses of granulomatous lung diseases induced by pathogens and foreign bodies. Circulating monocytes are generally viewed as central precursors of these tissue effector macrophages. Here, we provide evidence that granulomas derive from alveolar macrophages serving as a local reservoir for the expansion of activated phagocytic macrophages.

Critical role of aquaporins in interleukin 1β (IL-1β)-induced inflammation.

Rapid changes in cell volume characterize macrophage activation, but the role of water channels in inflammation remains unclear. We show here that, in vitro, aquaporin (AQP) blockade or deficiency results in reduced IL-1β release by macrophages activated with a variety of NLRP3 activators. Inhibition of AQP specifically during the regulatory volume decrease process is sufficient to limit IL-1β release by macrophages through the NLRP3 inflammasome axis.

In search of the chemical basis of the hemolytic potential of silicas.

The membranolytic activity of silica particles toward red blood cells (RBCs) has been known for a long time and is sometimes associated with silica pathogenicity. However, the molecular mechanism and the reasons why hemolysis differs according to the silica form are still obscure. A panel of 15 crystalline (pure and commercial) and amorphous (pyrogenic, precipitated from aqueous solutions, vitreous) silica samples differing in size, origin, morphology, and surface chemical composition were selected and specifically prepared.

Oxidative stress induced by pure and iron-doped amorphous silica nanoparticles in subtoxic conditions.

Amorphous silica nanoparticles (SiO₂-NPs) have found broad applications in industry and are currently intensively studied for potential uses in medical and biomedical fields. Several studies have reported cytotoxic and inflammatory responses induced by SiO₂-NPs in different cell types. The present study was designed to examine the association of oxidative stress markers with SiO₂-NP induced cytotoxicity in human endothelial cells.

Model system to study the influence of aggregation on the hemolytic potential of silica nanoparticles.

A well-defined silica nanoparticle model system was developed to study the effect of the size and structure of aggregates on their membranolytic activity. The aggregates were stable and characterized using transmission electron microscopy, dynamic light scattering, nitrogen adsorption, small-angle X-ray scattering, infrared spectroscopy, and electron paramagnetic resonance. Human red blood cells were used for assessing the membranolytic activity of aggregates.

The cytotoxic activity of amorphous silica nanoparticles is mainly influenced by surface area and not by aggregation.

The aggregation state of NP has been a significant source of difficulty for assessing their toxic activity and great efforts have been done to reduce aggregation of and/or to disperse NP in experimental systems. The exact impact of aggregation on toxicity has, however, not been adequately assessed. Here we compared in vitro the cytotoxic activity of stable monodisperse and aggregated silicon-based nanoparticles (SNP) without introducing a dispersing agent that may affect NP properties.

Lung fibrosis induced by crystalline silica particles is uncoupled from lung inflammation in NMRI mice.

Previous studies in rats have suggested a causal relationship between progressive pulmonary inflammation and lung fibrosis induced by crystalline silica particles. We report here that, in NMRI mice, the lung response to silica particles is accompanied by a mild and non progressive pulmonary inflammation which is dispensable for the development of lung fibrosis. We found that glucocorticoid (dexamethasone) dramatically reduced lung injury, cellular inflammation and pro-inflammatory cytokine expression (TNF-α, IL-1β and KC) but had no significant effect on silica-induced lung fibrosis and expression of the fibrogenic and suppressive cytokines TGF-β and IL-10 in mice.

Exploring the aneugenic and clastogenic potential in the nanosize range: A549 human lung carcinoma cells and amorphous monodisperse silica nanoparticles as models.

We explored how to assess the genotoxic potential of nanosize particles with a well validated assay, the in vitro cytochalasin-B micronucleus assay, detecting both clastogens and aneugens. Monodisperse Stöber amorphous silica nanoparticles (SNPs) of three different sizes (16, 60 and 104 nm) and A549 lung carcinoma cells were selected as models. Cellular uptake of silica was monitored by ICP-MS.

Influence of size, surface area and microporosity on the in vitro cytotoxic activity of amorphous silica nanoparticles in different cell types.

Identifying the physico-chemical characteristics of nanoparticles (NPs) that drive their toxic activity is the key to conducting hazard assessment and guiding the design of safer nanomaterials. Here we used a set of 17 stable suspensions of monodisperse amorphous silica nanoparticles (SNPs) with selected variations in size (diameter, 2-335 nm), surface area (BET, 16-422 m(2)/g) and microporosity (micropore volume, 0-71 microl/g) to assess with multiple regression analysis the physico-chemical determinants of the cytotoxic activity in four different cell types (J774 macrophages, EAHY926 endothelial cells, 3T3 fibroblasts and human erythrocytes). We found that the response to these SNPs is governed by different physico-chemical parameters which vary with cell type: In J774 macrophages, the cytotoxic activity (WST1 assay) increased with external surface area (alphas method) and decreased with micropore volume (r(2) of the model, 0.

Synthesis and characterization of stable monodisperse silica nanoparticle sols for in vitro cytotoxicity testing.

For the investigation of the interaction of nanoparticles with biomolecules, cells, organs, and animal models there is a need for well-characterized nanoparticle suspensions. In this paper we report the preparation of monodisperse dense amorphous silica nanoparticles (SNP) suspended in physiological media that are sterile and sufficiently stable against aggregation. SNP sols with various particle sizes (2-335 nm) were prepared via base-catalyzed hydrolysis and polymerization of tetraethyl orthosilicate under sterile conditions using either ammonia (Stober process (1) ) or lysine catalyst (Lys-Sil process (2) ).

Absence of carcinogenic response to multiwall carbon nanotubes in a 2-year bioassay in the peritoneal cavity of the rat.

Toxicological investigations of carbon nanotubes have shown that they can induce pulmonary toxicity, and similarities with asbestos fibers have been suggested. We previously reported that multiwall carbon nanotubes (MWCNT) induced lung inflammation, granulomas and fibrotic reactions. The same MWCNT also caused mutations in epithelial cells in vitro and in vivo.

Size-dependent cytotoxicity of monodisperse silica nanoparticles in human endothelial cells.

The effect that monodisperse amorphous spherical silica particles of different sizes have on the viability of endothelial cells (EAHY926 cell line) is investigated. The results indicate that exposure to silica nanoparticles causes cytotoxic damage (as indicated by lactate dehydrogenase (LDH) release) and a decrease in cell survival (as determined by the tetrazolium reduction, MTT, assay) in the EAHY926 cell line in a dose-related manner. Concentrations leading to a 50% reduction in cell viability (TC(50)) for the smallest particles tested (14-, 15-, and 16-nm diameter) ranging from 33 to 47 microg cm(-2) of cell culture differ significantly from values assessed for the bigger nanoparticles: 89 and 254 microg cm(-2) (diameter of 19 and 60 nm, respectively).

Sintered indium-tin-oxide (ITO) particles: a new pneumotoxic entity.

Indium-Tin-Oxide (ITO) is a sintered mixture of indium- (In(2)O(3)) and tin-oxide (SnO(2)) in a ratio of 90:10 (wt:wt) that is used for the manufacture of LCD screens and related high technology applications. Interstitial pulmonary diseases have recently been reported in workers from ITO producing plants. The present study was conducted to identify experimentally the exact chemical component responsible for this toxicity and to address possible mechanisms of action.

Nominal and effective dosimetry of silica nanoparticles in cytotoxicity assays.

Because of their small size and large specific surface area (SA), insoluble nanoparticles are almost not affected by the gravitational force and are generally formulated in stable suspensions or sols. This raises, however, a potential difficulty in in vitro assay systems in which cells adhering to the bottom of a culture vessel may not be exposed to the majority of nanoparticles in suspension. J.