Research

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20 pages, 3741 KiB

Open AccessArticle

Complement-Opsonized Nano-Carriers Are Bound by Dendritic Cells (DC) via Complement Receptor (CR)3, and by B Cell Subpopulations via CR-1/2, and Affect the Activation of DC and B-1 Cells

by Monika Bednarczyk, Carolina Medina-Montano, Frederic Julien Fittler, Henner Stege, Meike Roskamp, Michael Kuske, Christian Langer, Marco Vahldieck, Evelyn Montermann, Ingrid Tubbe, Nadine Röhrig, Andrzej Dzionek, Stephan Grabbe and Matthias Bros

Int. J. Mol. Sci. 2021, 22(6), 2869; https://doi.org/10.3390/ijms22062869 - 11 Mar 2021

Cited by 13 | Viewed by 2866

Abstract

The development of nanocarriers (NC) for biomedical applications has gained large interest due to their potential to co-deliver drugs in a cell-type-targeting manner. However, depending on their surface characteristics, NC accumulate serum factors, termed protein corona, which may affect their cellular binding. We [...] Read more.

The development of nanocarriers (NC) for biomedical applications has gained large interest due to their potential to co-deliver drugs in a cell-type-targeting manner. However, depending on their surface characteristics, NC accumulate serum factors, termed protein corona, which may affect their cellular binding. We have previously shown that NC coated with carbohydrates to enable biocompatibility triggered the lectin-dependent complement pathway, resulting in enhanced binding to B cells via complement receptor (CR)1/2. Here we show that such NC also engaged all types of splenic leukocytes known to express CR3 at a high rate when NC were pre-incubated with native mouse serum resulting in complement opsonization. By focusing on dendritic cells (DC) as an important antigen-presenting cell type, we show that CR3 was essential for binding/uptake of complement-opsonized NC, whereas CR4, which in mouse is specifically expressed by DC, played no role. Further, a minor B cell subpopulation (B-1), which is important for first-line pathogen responses, and co-expressed CR1/2 and CR3, in general, engaged NC to a much higher extent than normal B cells. Here, we identified CR-1/2 as necessary for binding of complement-opsonized NC, whereas CR3 was dispensable. Interestingly, the binding of complement-opsonized NC to both DC and B-1 cells affected the expression of activation markers. Our findings may have important implications for the design of nano-vaccines against infectious diseases, which codeliver pathogen-specific protein antigen and adjuvant, aimed to induce a broad adaptive cellular and humoral immune response by inducing cytotoxic T lymphocytes that kill infected cells and pathogen-neutralizing antibodies, respectively. Decoration of nano-vaccines either with carbohydrates to trigger complement activation in vivo or with active complement may result in concomitant targeting of DC and B cells and thereby may strongly enhance the extent of dual cellular/humoral immune responses. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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23 pages, 2532 KiB

Open AccessArticle

A Step-by-Step Approach to Improve Clinical Translation of Liposome-Based Nanomaterials, a Focus on Innate Immune and Inflammatory Responses

by Giacomo Della Camera, Dorelia Lipsa, Dora Mehn, Paola Italiani, Diana Boraschi and Sabrina Gioria

Int. J. Mol. Sci. 2021, 22(2), 820; https://doi.org/10.3390/ijms22020820 - 15 Jan 2021

Cited by 11 | Viewed by 2453

Abstract

This study aims to provide guidelines to design and perform a robust and reliable physical-chemical characterization of liposome-based nanomaterials, and to support method development with a specific focus on their inflammation-inducing potential. Out of eight differently functionalized liposomes selected as “case-studies”, three passed [...] Read more.

This study aims to provide guidelines to design and perform a robust and reliable physical-chemical characterization of liposome-based nanomaterials, and to support method development with a specific focus on their inflammation-inducing potential. Out of eight differently functionalized liposomes selected as “case-studies”, three passed the physical-chemical characterization (in terms of size-distribution, homogeneity and stability) and the screening for bacterial contamination (sterility and apyrogenicity). Although all three were non-cytotoxic when tested in vitro, they showed a different capacity to activate human blood cells. HSPC/CHOL-coated liposomes elicited the production of several inflammation-related cytokines, while DPPC/CHOL- or DSPC/CHOL-functionalized liposomes did not. This work underlines the need for accurate characterization at multiple levels and the use of reliable in vitro methods, in order to obtain a realistic assessment of liposome-induced human inflammatory response, as a fundamental requirement of nanosafety regulations. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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21 pages, 3704 KiB

Open AccessArticle

Characterization of Urine Stem Cell-Derived Extracellular Vesicles Reveals B Cell Stimulating Cargo

by Asmaa A. Zidan, Mohammed Al-Hawwas, Griffith B. Perkins, Ghada M. Mourad, Catherine J. M. Stapledon, Larisa Bobrovskaya, Xin-Fu Zhou and Plinio R. Hurtado

Int. J. Mol. Sci. 2021, 22(1), 459; https://doi.org/10.3390/ijms22010459 - 05 Jan 2021

Cited by 16 | Viewed by 4296

Abstract

Elucidation of the biological functions of extracellular vesicles (EVs) and their potential roles in physiological and pathological processes is an expanding field of research. In this study, we characterized USC–derived EVs and studied their capacity to modulate the human immune response in vitro. [...] Read more.

Elucidation of the biological functions of extracellular vesicles (EVs) and their potential roles in physiological and pathological processes is an expanding field of research. In this study, we characterized USC–derived EVs and studied their capacity to modulate the human immune response in vitro. We found that the USC–derived EVs are a heterogeneous population, ranging in size from that of micro–vesicles (150 nm–1 μm) down to that of exosomes (60–150 nm). Regarding their immunomodulatory functions, we found that upon isolation, the EVs (60–150 nm) induced B cell proliferation and IgM antibody secretion. Analysis of the EV contents unexpectedly revealed the presence of BAFF, APRIL, IL–6, and CD40L, all known to play a central role in B cell stimulation, differentiation, and humoral immunity. In regard to their effect on T cell functions, they resembled the function of mesenchymal stem cell (MSC)–derived EVs previously described, suppressing T cell response to activation. The finding that USC–derived EVs transport a potent bioactive cargo opens the door to a novel therapeutic avenue for boosting B cell responses in immunodeficiency or cancer. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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15 pages, 3064 KiB

Open AccessArticle

Human Intestinal Tissue Explant Exposure to Silver Nanoparticles Reveals Sex Dependent Alterations in Inflammatory Responses and Epithelial Cell Permeability

by Kuppan Gokulan, Katherine Williams, Sarah Orr and Sangeeta Khare

Int. J. Mol. Sci. 2021, 22(1), 9; https://doi.org/10.3390/ijms22010009 - 22 Dec 2020

Cited by 14 | Viewed by 2339

Abstract

Consumer products manufactured with antimicrobial silver nanoparticles (AgNPs) may affect the gastrointestinal (GI) system. The human GI-tract is complex and there are physiological and anatomical differences between human and animal models that limit comparisons between species. Thus, assessment of AgNP toxicity on the [...] Read more.

Consumer products manufactured with antimicrobial silver nanoparticles (AgNPs) may affect the gastrointestinal (GI) system. The human GI-tract is complex and there are physiological and anatomical differences between human and animal models that limit comparisons between species. Thus, assessment of AgNP toxicity on the human GI-tract may require tools that allow for the examination of subtle changes in inflammatory markers and indicators of epithelial perturbation. Fresh tissues were excised from the GI-tract of human male and female subjects to evaluate the effects of AgNPs on the GI-system. The purpose of this study was to perform an assessment on the ability of the ex vivo model to evaluate changes in levels of pro-/anti-inflammatory cytokines/chemokines and mRNA expression of intestinal permeability related genes induced by AgNPs in ileal tissues. The ex vivo model preserved the structural and biological functions of the in-situ organ. Analysis of cytokine expression data indicated that intestinal tissue of male and female subjects responded differently to AgNP treatment, with male samples showing significantly elevated Granulocyte-macrophage colony-stimulating factor (GM-CSF) after treatment with 10 nm and 20 nm AgNPs for 2 h and significantly elevated RANTES after treatment with 20 nm AgNPs for 24 h. In contrast, tissues of female showed no significant effects of AgNP treatment at 2 h and significantly decreased RANTES (20 nm), TNF-α (10 nm), and IFN-γ (10 nm) at 24 h. Smaller size AgNPs (10 nm) perturbed more permeability-related genes in samples of male subjects, than in samples from female subjects. In contrast, exposure to 20 nm AgNPs resulted in upregulation of a greater number of genes in female-derived samples (36 genes) than in male-derived samples (8 genes). The ex vivo tissue model can distinguish sex dependent effects of AgNP and could serve as a translational non-animal model to assess the impacts of xenobiotics on human intestinal mucosa. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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16 pages, 5046 KiB

Open AccessArticle

Gingival Response to Dental Implant: Comparison Study on the Effects of New Nanopored Laser-Treated vs. Traditional Healing Abutments

by Barbara Ghinassi, Angela Di Baldassarre, Gianmaria D’Addazio, Tonino Traini, Mauro Andrisani, Giorgio Di Vincenzo, Giulia Gaggi, Maurizio Piattelli, Sergio Caputi and Bruna Sinjari

Int. J. Mol. Sci. 2020, 21(17), 6056; https://doi.org/10.3390/ijms21176056 - 22 Aug 2020

Cited by 11 | Viewed by 2685

Abstract

The health of peri-implant soft tissues is important for the long-term success rate of dental implants and the surface topography is pivotal in influencing it. Thus, the aim of this study was to evaluate, in human patients, the inflammatory mucosal microenvironment in the [...] Read more.

The health of peri-implant soft tissues is important for the long-term success rate of dental implants and the surface topography is pivotal in influencing it. Thus, the aim of this study was to evaluate, in human patients, the inflammatory mucosal microenvironment in the tissue surrounding a new, nanoscale, laser-treated healing abutment characterized by engineered nanopores versus a standard machined-surface. Analyses of anti- and pro-inflammatory markers, cytokeratins, desmosomal proteins and scanning electron microscopy were performed in 30 soft-tissue biopsies retrieved during second-stage surgery. The results demonstrate that the soft tissue surrounding the laser-treated surface was characterized by a lower grade of inflammation than the one facing the machined-surface, which, in turn, showed a disrupted epithelium and altered desmosomes. Moreover, higher adhesion of the epithelial cells on the laser-treated surface was detected compared to the machined one. In conclusion, the laser-treated surface topography seems to play an important role not only in cell adhesion, but also on the inflammatory makers’ expression of the soft tissue microenvironment. Thus, from a clinical point of view, the use of this kind of topography may be of crucial importance not only on healing abutments but also on prosthetic ones. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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16 pages, 1901 KiB

Open AccessArticle

In Vitro Determination of the Immunogenic Impact of Nanomaterials on Primary Peripheral Blood Mononuclear Cells

by Christopher A. W. David, Michael Barrow, Patricia Murray, Matthew J. Rosseinsky, Andrew Owen and Neill J. Liptrott

Int. J. Mol. Sci. 2020, 21(16), 5610; https://doi.org/10.3390/ijms21165610 - 05 Aug 2020

Cited by 7 | Viewed by 2666

Abstract

Investigation of the potential for nanomaterials to generate immunogenic effects is a key aspect of a robust preclinical evaluation. In combination with physicochemical characterization, such assessments also provide context for how material attributes influence biological outcomes. Furthermore, appropriate models for these assessments allow [...] Read more.

Investigation of the potential for nanomaterials to generate immunogenic effects is a key aspect of a robust preclinical evaluation. In combination with physicochemical characterization, such assessments also provide context for how material attributes influence biological outcomes. Furthermore, appropriate models for these assessments allow accurate in vitro to in vivo extrapolation, which is vital for the mechanistic understanding of nanomaterial action. Here we have assessed the immunogenic impact of a small panel of commercially available and in-house prepared nanomaterials on primary human peripheral blood mononuclear cells (PBMCs). A diethylaminoethyl-dextran (DEAE-dex) functionalized superparamagnetic iron oxide nanoparticle (SPION) generated detectable quantities of tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and IL-10, the only tested material to do so. The human leukemia monocytic cell line THP-1 was used to assess the potential for the nanomaterial panel to affect cellular oxidation-reduction (REDOX) via measurement of reactive oxygen species and reduced glutathione. Negatively charged sulfonate-functionalized polystyrene nanoparticles demonstrated a size-related trend for the inhibition of caspase-1, which was not observed for amine-functionalized polystyrene of similar sizes. Silica nanoparticles (310 nm) resulted in a 93% increase in proliferation compared to the untreated control (p < 0.01). No other nanomaterial treatments resulted in significant change from that of unstimulated PBMCs. Responses to the nanomaterials in the assays described demonstrate the utility of primary cells as ex vivo models for nanomaterial biological impact. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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20 pages, 3544 KiB

Open AccessArticle

An In Vitro Lung System to Assess the Proinflammatory Hazard of Carbon Nanotube Aerosols

by Hana Barosova, Bedia Begum Karakocak, Dedy Septiadi, Alke Petri-Fink, Vicki Stone and Barbara Rothen-Rutishauser

Int. J. Mol. Sci. 2020, 21(15), 5335; https://doi.org/10.3390/ijms21155335 - 27 Jul 2020

Cited by 33 | Viewed by 3874

Abstract

In vitro three-dimensional (3D) lung cell models have been thoroughly investigated in recent years and provide a reliable tool to assess the hazard associated with nanomaterials (NMs) released into the air. In this study, a 3D lung co-culture model was optimized to assess [...] Read more.

In vitro three-dimensional (3D) lung cell models have been thoroughly investigated in recent years and provide a reliable tool to assess the hazard associated with nanomaterials (NMs) released into the air. In this study, a 3D lung co-culture model was optimized to assess the hazard potential of multiwalled carbon nanotubes (MWCNTs), which is known to provoke inflammation and fibrosis, critical adverse outcomes linked to acute and prolonged NM exposure. The lung co-cultures were exposed to MWCNTs at the air-liquid interface (ALI) using the VITROCELL^® Cloud system while considering realistic occupational exposure doses. The co-culture model was composed of three human cell lines: alveolar epithelial cells (A549), fibroblasts (MRC-5), and macrophages (differentiated THP-1). The model was exposed to two types of MWCNTs (Mitsui-7 and Nanocyl) at different concentrations (2–10 μg/cm²) to assess the proinflammatory as well as the profibrotic responses after acute (24 h, one exposure) and prolonged (96 h, repeated exposures) exposure cycles. The results showed that acute or prolonged exposure to different concentrations of the tested MWCNTs did not induce cytotoxicity or apparent profibrotic response; however, suggested the onset of proinflammatory response. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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15 pages, 3672 KiB

Open AccessArticle

Modulation of the In Vivo Inflammatory Response by Pro- Versus Anti-Inflammatory Intervertebral Disc Treatments

by Carla Cunha, Graciosa Q. Teixeira, Cláudia Ribeiro-Machado, Catarina L. Pereira, Joana R. Ferreira, Maria Molinos, Susana G. Santos, Mário A. Barbosa and Raquel M. Goncalves

Int. J. Mol. Sci. 2020, 21(5), 1730; https://doi.org/10.3390/ijms21051730 - 03 Mar 2020

Cited by 16 | Viewed by 3336

Abstract

Inflammation is central in intervertebral disc (IVD) degeneration/regeneration mechanisms, and its balance is crucial to maintain tissue homeostasis. This work investigates the modulation of local and systemic inflammatory response associated with IVD degeneration/herniation by administration of PRO- versus ANTI-inflammatory treatments. Chitosan/poly-γ-glutamic acid nanocomplexes, [...] Read more.

Inflammation is central in intervertebral disc (IVD) degeneration/regeneration mechanisms, and its balance is crucial to maintain tissue homeostasis. This work investigates the modulation of local and systemic inflammatory response associated with IVD degeneration/herniation by administration of PRO- versus ANTI-inflammatory treatments. Chitosan/poly-γ-glutamic acid nanocomplexes, known as pro-inflammatory (PRO), and soluble diclofenac, a non-steroidal anti-inflammatory drug (ANTI), were intradiscally administered in a rat IVD injury model, 24 h after lesion. Two weeks after administration, a reduction of disc height accompanied by hernia formation was observed. In the PRO-inflammatory treated group, IL-1β, IL-6 and COX-2 IVD gene expression were upregulated, and loss of nucleus pulposus (NP) structure and composition was observed. Systemically, lower T-cell frequency was observed in the lymph nodes (LN) and spleen (SP) of the PRO group, together with an increase in CD4+ T cells subset in the blood (BL) and LN. In contrast, the ANTI-group had higher proteoglycans/collagen ratio and collagen type 2 content in the NP, while an increase in the frequency of myeloid cells, M1 macrophages and activated macrophages (MHCII+) was observed at the systemic level. Overall, this study illustrates the dynamics of local and systemic inflammatory and immune cell responses associated with intradiscal therapies, which will contribute to designing more successful immunomodulatory treatments for IVD degeneration. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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Review

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15 pages, 3566 KiB

Open AccessReview

Nanomaterials and the Serosal Immune System in the Thoracic and Peritoneal Cavities

by C. Frieke Kuper, Raymond H. H. Pieters and Jolanda H. M. van Bilsen

Int. J. Mol. Sci. 2021, 22(5), 2610; https://doi.org/10.3390/ijms22052610 - 05 Mar 2021

Cited by 2 | Viewed by 4346

Abstract

The thoracic and peritoneal cavities are lined by serous membranes and are home of the serosal immune system. This immune system fuses innate and adaptive immunity, to maintain local homeostasis and repair local tissue damage, and to cooperate closely with the mucosal immune [...] Read more.

The thoracic and peritoneal cavities are lined by serous membranes and are home of the serosal immune system. This immune system fuses innate and adaptive immunity, to maintain local homeostasis and repair local tissue damage, and to cooperate closely with the mucosal immune system. Innate lymphoid cells (ILCs) are found abundantly in the thoracic and peritoneal cavities, and they are crucial in first defense against pathogenic viruses and bacteria. Nanomaterials (NMs) can enter the cavities intentionally for medical purposes, or unintentionally following environmental exposure; subsequent serosal inflammation and cancer (mesothelioma) has gained significant interest. However, reports on adverse effects of NM on ILCs and other components of the serosal immune system are scarce or even lacking. As ILCs are crucial in the first defense against pathogenic viruses and bacteria, it is possible that serosal exposure to NM may lead to a reduced resistance against pathogens. Additionally, affected serosal lymphoid tissues and cells may disturb adipose tissue homeostasis. This review aims to provide insight into key effects of NM on the serosal immune system. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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35 pages, 999 KiB

Open AccessReview

Possible Adverse Effects of Food Additive E171 (Titanium Dioxide) Related to Particle Specific Human Toxicity, Including the Immune System

by Nicolaj S. Bischoff, Theo M. de Kok, Dick T.H.M. Sijm, Simone G. van Breda, Jacco J. Briedé, Jacqueline J.M. Castenmiller, Antoon Opperhuizen, Yolanda I. Chirino, Hubert Dirven, David Gott, Eric Houdeau, Agnes G. Oomen, Morten Poulsen, Gerhard Rogler and Henk van Loveren

Int. J. Mol. Sci. 2021, 22(1), 207; https://doi.org/10.3390/ijms22010207 - 28 Dec 2020

Cited by 48 | Viewed by 8142

Abstract

Titanium dioxide (TiO₂) is used as a food additive (E171) and can be found in sauces, icings, and chewing gums, as well as in personal care products such as toothpaste and pharmaceutical tablets. Along with the ubiquitous presence of TiO₂ [...] Read more.

Titanium dioxide (TiO₂) is used as a food additive (E171) and can be found in sauces, icings, and chewing gums, as well as in personal care products such as toothpaste and pharmaceutical tablets. Along with the ubiquitous presence of TiO₂ and recent insights into its potentially hazardous properties, there are concerns about its application in commercially available products. Especially the nano-sized particle fraction (<100 nm) of TiO₂ warrants a more detailed evaluation of potential adverse health effects after ingestion. A workshop organized by the Dutch Office for Risk Assessment and Research (BuRO) identified uncertainties and knowledge gaps regarding the gastrointestinal absorption of TiO₂, its distribution, the potential for accumulation, and induction of adverse health effects such as inflammation, DNA damage, and tumor promotion. This review aims to identify and evaluate recent toxicological studies on food-grade TiO₂ and nano-sized TiO₂ in ex-vivo, in-vitro, and in-vivo experiments along the gastrointestinal route, and to postulate an Adverse Outcome Pathway (AOP) following ingestion. Additionally, this review summarizes recommendations and outcomes of the expert meeting held by the BuRO in 2018, in order to contribute to the hazard identification and risk assessment process of ingested TiO₂. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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23 pages, 1191 KiB

Open AccessReview

The Impact of Nanoparticles on Innate Immune Activation by Live Bacteria

by Benjamin J. Swartzwelter, Alexandra C. Fux, Litty Johnson, Elmer Swart, Sabine Hofer, Norbert Hofstätter, Mark Geppert, Paola Italiani, Diana Boraschi, Albert Duschl and Martin Himly

Int. J. Mol. Sci. 2020, 21(24), 9695; https://doi.org/10.3390/ijms21249695 - 18 Dec 2020

Cited by 19 | Viewed by 4649

Abstract

The innate immune system evolved to detect and react against potential dangers such as bacteria, viruses, and environmental particles. The advent of modern technology has exposed innate immune cells, such as monocytes, macrophages, and dendritic cells, to a relatively novel type of particulate [...] Read more.

The innate immune system evolved to detect and react against potential dangers such as bacteria, viruses, and environmental particles. The advent of modern technology has exposed innate immune cells, such as monocytes, macrophages, and dendritic cells, to a relatively novel type of particulate matter, i.e., engineered nanoparticles. Nanoparticles are not inherently pathogenic, and yet cases have been described in which specific nanoparticle types can either induce innate/inflammatory responses or modulate the activity of activated innate cells. Many of these studies rely upon activation by agonists of toll-like receptors, such as lipopolysaccharide or peptidoglycan, instead of the more realistic stimulation by whole live organisms. In this review we examine and discuss the effects of nanoparticles on innate immune cells activated by live bacteria. We focus in particular on how nanoparticles may interfere with bacterial processes in the context of innate activation, and confine our scope to the effects due to particles themselves, rather than to molecules adsorbed on the particle surface. Finally, we examine the long-lasting consequences of coexposure to nanoparticles and bacteria, in terms of potential microbiome alterations and innate immune memory, and address nanoparticle-based vaccine strategies against bacterial infection. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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29 pages, 731 KiB

Open AccessReview

Susceptibility Factors in Chronic Lung Inflammatory Responses to Engineered Nanomaterials

by Dorothy J. You and James C. Bonner

Int. J. Mol. Sci. 2020, 21(19), 7310; https://doi.org/10.3390/ijms21197310 - 03 Oct 2020

Cited by 12 | Viewed by 4861

Abstract

Engineered nanomaterials (ENMs) are products of the emerging nanotechnology industry and many different types of ENMs have been shown to cause chronic inflammation in the lungs of rodents after inhalation exposure, suggesting a risk to human health. Due to the increasing demand and [...] Read more.

Engineered nanomaterials (ENMs) are products of the emerging nanotechnology industry and many different types of ENMs have been shown to cause chronic inflammation in the lungs of rodents after inhalation exposure, suggesting a risk to human health. Due to the increasing demand and use of ENMs in a variety of products, a careful evaluation of the risks to human health is urgently needed. An assessment of the immunotoxicity of ENMs should consider susceptibility factors including sex, pre-existing diseases, deficiency of specific genes encoding proteins involved in the innate or adaptive immune response, and co-exposures to other chemicals. This review will address evidence from experimental animal models that highlights some important issues of susceptibility to chronic lung inflammation and systemic immune dysfunction after pulmonary exposure to ENMs. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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