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Current Insights into Immunotoxicology
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Current Insights into Immunotoxicology

A special issue of International Journal of Environmental Research and Public Health (ISSN 1660-4601). This special issue belongs to the section "Toxicology and Public Health".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 51446

Special Issue Editors

Dr. Jörg Lehmann

E-Mail Website
Guest Editor
Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
Interests: immunotoxicology; aryl hydrocarbon receptor (AhR) ligands in toxicology and therapy; chronic-inflammatory bowel disease (IBD); immunity to infection; immune oncology; cancer immunotherapy; food allergy; therapeutic antibodies; good laboratory practice (GLP); efficacy and safety studies for ATMPs; biopharmaceuticals; small molecules; medical devices
Special Issues, Collections and Topics in MDPI journals
Dr. Robert Landsiedel

E-Mail Website
Guest Editor
BASF SE, Experimental Toxicology and Ecology-Z470-RB/TB, 67056 Ludwigshafen am Rhein, Germany
Interests: immunotoxicology; xenobiotic/drug-metabolizing enzymes; risk assessment of nanomaterials; endocrine disrupters; in vitro to in vivo extrapolation; physiologically based pharmacokinetic (PBPK) modeling; physiologically based toxicokinetic (PBTK) modeling

Special Issue Information

Dear Colleagues,

This Special Issue will comprehensively address cutting-edge scientific topics in the field of immunotoxicology. This interdisciplinary research area includes basic as well as applied research but also regulatory issues in preclinical and clinical drug development.

Topic 1: Basic Research

  •  AhR-related research
  •  Immunotoxic aspects of new pharmaceuticals (i.e., small molecules, phytopharmaceuticals, biopharmaceuticals, advanced therapy medicinal products)
  •  Immunotoxic aspects of nanomaterials (i.e., quantum dots)
  •  Immunotoxic aspects of heavy metals (i.e., cadmium)
  •  Immunotoxic aspects of organic compounds (i.e., benzo[a]pyrene)
  •  Immunotoxic aspects of pesticides (i.e., glyphosate)
  •  Multi-omics approaches in immunotoxicology
  •  Systems immunotoxicology

Topic 2: Applied Research

  •  Development and validation of immunotoxicological testing strategies
  •  Reports on preclinical immunotoxicological proof-of-concept studies
  •  Studies on the mode of action in terms of immunotoxic effects of drug candidates under development or approved drugs
  •  Methodological studies on in vitro models for immunotoxicological objectives
  •  Methodological studies on in vivo models for immunotoxicological objectives
  •  Physiologically based toxicokinetic modeling

Topic 3: Regulatory Issues

  •  Implementation of regulatory guidelines (i.e., EMA, FDA)
  •  Testing strategies – in vitro, in vivo
  •  Reports on preclinical immunotoxicological GLP studies
  •  Reports on immunotoxicological endpoints from clinical trials

Dr. Jörg Lehmann
Dr. Robert Landsiedel
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Environmental Research and Public Health is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2500 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • immunotoxicology
  • aryl hydrocarbon receptor ligands
  • glyphosate
  • heavy metals
  • multi-omics approaches in immunotoxicology
  • systems immunotoxicology
  • immunotoxic aspects of nanomaterials
  • immunotoxic aspects of phytopharmaceuticals
  • immunotoxic aspects of biopharmaceuticals
  • immunotoxic aspects of advanced therapy medicinal products
  • regulatory issues of immunotoxicology

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (7 papers)

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Research

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7 pages, 305 KiB  
Communication
SkinSensPred as a Promising in Silico Tool for Integrated Testing Strategy on Skin Sensitization
by Shan-Shan Wang, Chia-Chi Wang and Chun-Wei Tung
Int. J. Environ. Res. Public Health 2022, 19(19), 12856; https://doi.org/10.3390/ijerph191912856 - 7 Oct 2022
Cited by 1 | Viewed by 2011
Abstract
Skin sensitization is an important regulatory endpoint associated with allergic contact dermatitis. Recently, several adverse outcome pathway (AOP)-based alternative methods were developed to replace animal testing for evaluating skin sensitizers. The AOP-based assays were further integrated as a two-out-of-three method with good predictivity. [...] Read more.
Skin sensitization is an important regulatory endpoint associated with allergic contact dermatitis. Recently, several adverse outcome pathway (AOP)-based alternative methods were developed to replace animal testing for evaluating skin sensitizers. The AOP-based assays were further integrated as a two-out-of-three method with good predictivity. However, the acquisition of experimental data is resource-intensive. In contrast, an integrated testing strategy (ITS) capable of maximizing the usage of laboratory data from AOP-based and in silico methods was developed as defined approaches (DAs) to both hazard and potency assessment. There are currently two in silico models, namely Derek Nexus and OECD QSAR Toolbox, evaluated in the OECD Testing Guideline No. 497. Since more advanced machine learning algorithms have been proposed for skin sensitization prediction, it is therefore desirable to evaluate their performance under the ITS framework. This study evaluated the performance of a new ITS DA (ITS-SkinSensPred) adopting a transfer learning-based SkinSensPred model. Results showed that the ITS-SkinSensPred has similar or slightly better performance compared to the other ITS models. SkinSensPred-based ITS is expected to be a promising method for assessing skin sensitization. Full article
(This article belongs to the Special Issue Current Insights into Immunotoxicology)
18 pages, 3789 KiB  
Article
Proteomic Characterization of the Cellular Effects of AhR Activation by Microbial Tryptophan Catabolites in Endotoxin-Activated Human Macrophages
by Katharina Walter, Henning Grosskopf, Isabel Karkossa, Martin von Bergen and Kristin Schubert
Int. J. Environ. Res. Public Health 2021, 18(19), 10336; https://doi.org/10.3390/ijerph181910336 - 30 Sep 2021
Cited by 9 | Viewed by 2586
Abstract
Sensing microbial tryptophan catabolites by the aryl hydrocarbon receptor (AhR) plays a pivotal role in host-microbiome homeostasis by modulating the host immune response. Nevertheless, the involved cellular processes triggered by the metabolites are mainly unknown. Here, we analyzed proteomic changes in macrophages after [...] Read more.
Sensing microbial tryptophan catabolites by the aryl hydrocarbon receptor (AhR) plays a pivotal role in host-microbiome homeostasis by modulating the host immune response. Nevertheless, the involved cellular processes triggered by the metabolites are mainly unknown. Here, we analyzed proteomic changes in macrophages after treatment with the tryptophan metabolites indole-3-acetic acid (I3AA) or indole-3-aldehyde (IAld), as well as the prototypic exogenous AhR-ligand benzo(a)pyrene (BaP) in the absence and presence of lipopolysaccharide (LPS) to identify affected cellular processes and pathways. The AhR-ligands regulated metabolic and immunologic processes in dependency of LPS co-stimulation. All investigated ligands time-dependently enhanced fatty acid β-oxidation. Differences due to the combination with LPS were observed for all three ligands. Additionally, oxidative phosphorylation was significantly increased by IAld and I3AA in a time and LPS-dependent manner. Immunoregulatory processes were affected in distinct ways. While BaP and I3AA up-regulated IL-8 signaling, IL-6 signaling was decreased by IAld. BaP decreased the inflammasome pathway. Thus, AhR-ligand-dependent regulations were identified, which may modulate the response of macrophages to bacterial infections, but also the commensal microbiota through changes in immune cell signaling and metabolic pathways that may also alter functionality. These findings highlight the relevance of AhR for maintaining microbial homeostasis and, consequently, host health. Full article
(This article belongs to the Special Issue Current Insights into Immunotoxicology)
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13 pages, 2871 KiB  
Article
n-Butyl Benzyl Phthalate Exposure Promotes Lesion Survival in a Murine Endometriosis Model
by Pooja Sharma, Jo-Yu Lynn Lee, Eing-Mei Tsai, Yu Chang and Jau-Ling Suen
Int. J. Environ. Res. Public Health 2021, 18(7), 3640; https://doi.org/10.3390/ijerph18073640 - 31 Mar 2021
Cited by 6 | Viewed by 2868
Abstract
Endometriosis is an inflammatory and estrogen-dependent gynecological disease associated with exposure to environmental endocrine disruptors. n-Butyl benzyl phthalate (BBP), a ubiquitous plasticizer, has weak estrogenic activity, and exposure to BBP is associated with endometriosis. We aimed to elucidate the immunomodulatory effect of BBP [...] Read more.
Endometriosis is an inflammatory and estrogen-dependent gynecological disease associated with exposure to environmental endocrine disruptors. n-Butyl benzyl phthalate (BBP), a ubiquitous plasticizer, has weak estrogenic activity, and exposure to BBP is associated with endometriosis. We aimed to elucidate the immunomodulatory effect of BBP on endometriosis development. We previously established a surgery-induced endometriosis-like murine model. In the present study, we exposed those mice to BBP 10 days prior to surgery and 4 weeks after surgery at physiologically relevant doses to mimic human exposure. Chronic exposure to BBP did not promote the growth of endometriotic lesions; however, the lesion survival rate in BBP-treated mice did increase significantly compared with control mice. Multiparametric flow cytometry showed that BBP exposure did not affect the homeostasis of infiltrated immune subsets in lesions but did enhance CD44 (adhesion marker) expression on plasmacytoid dendritic cells (pDCs). Blocking CD44 interactions locally inhibited endometriotic lesion growth. Immunofluorescence results further confirmed that CD44 blocking inhibited pDC infiltration and reduced the frequency of CD44+ pDCs in endometriotic tissues. BBP also disrupted the estrus cycle in these mice. This study suggests that chronic exposure to low-dose BBP may promote survival of endometriotic tissue through CD44-expressing pDCs. Full article
(This article belongs to the Special Issue Current Insights into Immunotoxicology)
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24 pages, 1118 KiB  
Article
Investigating Molecular Mechanisms of Immunotoxicity and the Utility of ToxCast for Immunotoxicity Screening of Chemicals Added to Food
by Olga V. Naidenko, David Q. Andrews, Alexis M. Temkin, Tasha Stoiber, Uloma Igara Uche, Sydney Evans and Sean Perrone-Gray
Int. J. Environ. Res. Public Health 2021, 18(7), 3332; https://doi.org/10.3390/ijerph18073332 - 24 Mar 2021
Cited by 18 | Viewed by 31588
Abstract
The development of high-throughput screening methodologies may decrease the need for laboratory animals for toxicity testing. Here, we investigate the potential of assessing immunotoxicity with high-throughput screening data from the U.S. Environmental Protection Agency ToxCast program. As case studies, we analyzed the most [...] Read more.
The development of high-throughput screening methodologies may decrease the need for laboratory animals for toxicity testing. Here, we investigate the potential of assessing immunotoxicity with high-throughput screening data from the U.S. Environmental Protection Agency ToxCast program. As case studies, we analyzed the most common chemicals added to food as well as per- and polyfluoroalkyl substances (PFAS) shown to migrate to food from packaging materials or processing equipment. The antioxidant preservative tert-butylhydroquinone (TBHQ) showed activity both in ToxCast assays and in classical immunological assays, suggesting that it may affect the immune response in people. From the PFAS group, we identified eight substances that can migrate from food contact materials and have ToxCast data. In epidemiological and toxicological studies, PFAS suppress the immune system and decrease the response to vaccination. However, most PFAS show weak or no activity in immune-related ToxCast assays. This lack of concordance between toxicological and high-throughput data for common PFAS indicates the current limitations of in vitro screening for analyzing immunotoxicity. High-throughput in vitro assays show promise for providing mechanistic data relevant for immune risk assessment. In contrast, the lack of immune-specific activity in the existing high-throughput assays cannot validate the safety of a chemical for the immune system. Full article
(This article belongs to the Special Issue Current Insights into Immunotoxicology)
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11 pages, 361 KiB  
Article
Effect of Lambdacyhalothrin on Locomotor Activity, Memory, Selected Biochemical Parameters, Tumor Necrosis Factor α, and Interleukin 1ß in a Mouse Model
by Barbara Nieradko-Iwanicka and Michał Konopelko
Int. J. Environ. Res. Public Health 2020, 17(24), 9240; https://doi.org/10.3390/ijerph17249240 - 10 Dec 2020
Cited by 13 | Viewed by 2755
Abstract
Background: Pyrethroids are synthetic insecticides used for plant protection. They are synthetic analogues of pyrethrins. Lambdacyhalothrin (LCH) is a type II pyrethroid used for wheat, potato, corn farming, and malaria control. There are data that pyrethroids may cause neurotoxicity, nephrotoxicity, hepatotoxicity, and immunotoxicity [...] Read more.
Background: Pyrethroids are synthetic insecticides used for plant protection. They are synthetic analogues of pyrethrins. Lambdacyhalothrin (LCH) is a type II pyrethroid used for wheat, potato, corn farming, and malaria control. There are data that pyrethroids may cause neurotoxicity, nephrotoxicity, hepatotoxicity, and immunotoxicity in non-target organisms. Methods: The experiment was carried on 32 Albino Swiss mice (16 females and 16 males). The animals were divided into four groups. Controls received canola oil; the rest received LCH orally in oil at a dose of 2 mg/kg bw for 7 days. Memory retention was assessed in a passive avoidance task on day 2 and 7, and spatial memory and motor activity in a Y-maze on day 1 and 7. Blood morphology, biochemical tests, tumor necrosis factor α, and interleukin 1ß were measured. Results: Decreased white blood cell count and red blood cell count, increased creatinine, and increased kidney and liver mass were observed in groups exposed to LCH. In LCH-exposed males’ kidneys and livers, interleukin 1ß was significantly elevated, and it was correlated with creatinine concentration. Conclusions: Subacute poisoning with a low dose of LCH does not significantly affect memory nor locomotor activity but increases proinflammatory interleukin 1ß in male livers and kidneys and reduces white and red blood cell counts. Full article
(This article belongs to the Special Issue Current Insights into Immunotoxicology)

Review

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27 pages, 2193 KiB  
Review
Immunological Mechanisms of Metal Allergies and the Nickel-Specific TCR-pMHC Interface
by Franziska Riedel, Marina Aparicio-Soto, Caterina Curato, Hermann-Josef Thierse, Katherina Siewert and Andreas Luch
Int. J. Environ. Res. Public Health 2021, 18(20), 10867; https://doi.org/10.3390/ijerph182010867 - 15 Oct 2021
Cited by 20 | Viewed by 4970
Abstract
Besides having physiological functions and general toxic effects, many metal ions can cause allergic reactions in humans. We here review the immune events involved in the mediation of metal allergies. We focus on nickel (Ni), cobalt (Co) and palladium (Pd), because these allergens [...] Read more.
Besides having physiological functions and general toxic effects, many metal ions can cause allergic reactions in humans. We here review the immune events involved in the mediation of metal allergies. We focus on nickel (Ni), cobalt (Co) and palladium (Pd), because these allergens are among the most prevalent sensitizers (Ni, Co) and immediate neighbors in the periodic table of the chemical elements. Co-sensitization between Ni and the other two metals is frequent while the knowledge on a possible immunological cross-reactivity using in vivo and in vitro approaches remains limited. At the center of an allergic reaction lies the capability of a metal allergen to form T cell epitopes that are recognized by specific T cell receptors (TCR). Technological advances such as activation-induced marker assays and TCR high-throughput sequencing recently provided new insights into the interaction of Ni2+ with the αβ TCR-peptide-major histocompatibility complex (pMHC) interface. Ni2+ functionally binds to the TCR gene segment TRAV9-2 or a histidine in the complementarity determining region 3 (CDR3), the main antigen binding region. Thus, we overview known, newly identified and hypothesized mechanisms of metal-specific T cell activation and discuss current knowledge on cross-reactivity. Full article
(This article belongs to the Special Issue Current Insights into Immunotoxicology)
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Other

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16 pages, 1257 KiB  
Perspective
In Vitro and In Vivo Models to Assess the Immune-Related Effects of Nanomaterials
by Diana Boraschi, Dongjie Li, Yang Li and Paola Italiani
Int. J. Environ. Res. Public Health 2021, 18(22), 11769; https://doi.org/10.3390/ijerph182211769 - 10 Nov 2021
Cited by 15 | Viewed by 3549
Abstract
The immunological safety of drugs, nanomaterials and contaminants is a central point in the regulatory evaluation and safety monitoring of working and public places and of the environment. In fact, anomalies in immune responses may cause diseases and hamper the physical and functional [...] Read more.
The immunological safety of drugs, nanomaterials and contaminants is a central point in the regulatory evaluation and safety monitoring of working and public places and of the environment. In fact, anomalies in immune responses may cause diseases and hamper the physical and functional integrity of living organisms, from plants to human beings. In the case of nanomaterials, many experimental models are used for assessing their immunosafety, some of which have been adopted by regulatory bodies. All of them, however, suffer from shortcomings and approximations, and may be inaccurate in representing real-life responses, thereby leading to incomplete, incorrect or even misleading predictions. Here, we review the advantages and disadvantages of current nanoimmunosafety models, comparing in vivo vs. in vitro models and examining the use of animal vs. human cells, primary vs. transformed cells, complex multicellular and 3D models, organoids and organs-on-chip, in view of implementing a reliable and personalized nanoimmunosafety testing. The general conclusion is that the choice of testing models is key for obtaining reliable predictive information, and therefore special attention should be devoted to selecting the most relevant and realistic suite of models in order to generate relevant information that can allow for safer-by-design nanotechnological developments. Full article
(This article belongs to the Special Issue Current Insights into Immunotoxicology)
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