Evaluation of the Multi-ImmunoTox Assay composed of 3 human cytokine reporter cells by examining immunological effects of drugs

Kimura, Yutaka; Fujimura, Chizu; Ito, Yumiko; Takahashi, Toshiya; Aiba, Setsuya

doi:10.1016/j.tiv.2014.02.013

Cited by 21 publications

(9 citation statements)

References 17 publications

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“…In addition, immune-related end points are also absent from the Tox21 assay coverage. A number of in vitro methods are available to screen human and rodent cells to assess the ability of xenobiotics to modulate the immune system, including cytokine release assays 34 and the Multi-ImmunoTox Assay, 35 but to date, these methods have been focused on evaluating therapeutics rather than environmental chemicals, and are not designed to support risk quantification. 36 A focus on improving the immunotoxicity database for PACs is important, considering the association of some parent PAHs with decreased immune function, 37 the link between immune suppression and cancer, 19 and a lack of immunerelated data on many PACs.…”

Section: ■ Discussionmentioning

confidence: 99%

Harnessing In Silico, In Vitro, and In Vivo Data to Understand the Toxicity Landscape of Polycyclic Aromatic Compounds (PACs)

Hsieh

Sedykh²,

Mutlu

et al. 2020

Chem. Res. Toxicol.

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Polycyclic aromatic compounds (PACs) are compounds with a minimum of two six-atom aromatic fused rings. PACs arise from incomplete combustion or thermal decomposition of organic matter and are ubiquitous in the environment. Within PACs, carcinogenicity is generally regarded to be the most important public health concern. However, toxicity in other systems (reproductive and developmental toxicity, immunotoxicity) has also been reported. Despite the large number of PACs identified in the environment, research attention to understand exposure and health effects of PACs has focused on a relatively limited subset, namely polycyclic aromatic hydrocarbons (PAHs), the PACs with only carbon and hydrogen atoms. To triage the rest of the vast number of PACs for more resource-intensive testing, we developed a data-driven approach to contextualize hazard characterization of PACs, by leveraging the available data from various data streams (in silico toxicity, in vitro activity, structural fingerprints, and in vivo data availability). The PACs were clustered on the basis of their in silico toxicity profiles containing predictions from 8 different categories (carcinogenicity, cardiotoxicity, developmental toxicity, genotoxicity, hepatotoxicity, neurotoxicity, reproductive toxicity, and urinary toxicity). We found that PACs with the same parent structure (e.g., fluorene) could have diverse in silico toxicity profiles. In contrast, PACs with similar substituted groups (e.g., alkylated-PAHs) or heterocyclics (e.g., N-PACs) with varying ring sizes could have similar in silico toxicity profiles, suggesting that these groups are better candidates for toxicity read-across analysis. The clusters/regions associated with certain in silico toxicity, in vitro activity, and structural fingerprints were identified. We found that genotoxicity/carcinogenicity (in silico toxicity) and xenobiotic homeostasis and stress response (in vitro activity), respectively, dominate the toxicity/activity variation seen in the PACs. The “hot spots” with enriched toxicity/activity in conjunction with availability of in vivo carcinogenicity data revealed regions of either data-poor (hydroxylated-PAHs) or data-rich (unsubstituted, parent PAHs) PACs. These regions offer potential targets for prioritization of further in vivo assessment and for chemical read-across efforts. The analysis results are searchable through an interactive web application (), allowing for alternative hypothesis generation.

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Section: ■ Discussionmentioning

confidence: 99%

Harnessing In Silico, In Vitro, and In Vivo Data to Understand the Toxicity Landscape of Polycyclic Aromatic Compounds (PACs)

Hsieh

Sedykh²,

Mutlu

et al. 2020

Chem. Res. Toxicol.

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“…Based on previous reports ( Kimura et al, 2014 ; Saito et al, 2011 ), 2H4 cells (2 × 10 5 cells/50 μl/well) in 96-well black plates (Greiner Bio-One GmbH, Frickenhausen, Germany) were pretreated with different concentrations of individual chemicals for 1 h. The 2H4 cells were then stimulated with 25 nM PMA and 1 μM ionomycin (PMA/Io) for 6 h. Three luciferase activities (SLG luciferase activity (SLG-LA), SLO luciferase activity (SLO-LA), and SLR luciferase activity (SLR-LA)) were simultaneously determined using a microplate-type luminometer with a multi-color detection system (Phelios; Atto Co., Tokyo, Japan) and Tripluc luciferase assay reagent (TOYOBO Co., Ltd., Osaka, Japan) according to the manufacturers’ instructions. Use of the 2H4 cell line enabled measurement of SLG-LA driven by the IL-2 promoter (IL2LA), SLO-LA driven by the INF-γ promoter (IFNLA), and SLR-LA driven by G3PDH (GAPLA) in 2H4 cells.…”

Section: Methodsmentioning

confidence: 99%

“…Our group established the Multi-ImmunoTox assay (MITA) to evaluate the effects of chemicals on the IL-2, IFN-γ, IL-1β, and IL-8 promoters using three stable reporter cell lines ( Kimura et al, 2014 , 2018 ). Of these cell lines, 2H4 derived from Jurkat cells contains stable luciferase green (SLG) regulated by the IL-2 promoter, stable luciferase orange (SLO) regulated by the IFN-γ promoter, and stable luciferase red (SLR) regulated by the G3PDH promoter ( Saito et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

An international validation study of the IL-2 Luc assay for evaluating the potential immunotoxic effects of chemicals on T cells and a proposal for reference data for immunotoxic chemicals

Kimura

Yasuno

Watanabe

et al. 2020

Toxicology in Vitro

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“…The human whole-blood cytokine release assay, which is currently the only cytokine-based assay that has been validated for in vitro immunotoxicology assessments, measures interleukin (IL)-1β and IL-4 release in human blood samples in response to lipopolysaccharide (LPS) or staphylococcal enterotoxin B (SEB) [17]. The Multi-ImmunoTox assay, which uses reporter cell lines derived from Jurkat and THP-1 cells to examine cytokine changes following chemical treatment, has shown promising results in early validation efforts [18]. Additional in vitro tests include the lymphocyte proliferation assay, mixed lymphocyte reaction (MLR) assay, the anti-CD3 T cell proliferation assay, cytotoxic T-lymphocyte (CTL) assay, natural killer (NK) cell activity assay, and the dendritic cell maturation assay [14].…”

Section: In Vitro and High Throughput Approaches To Assess Immunotoximentioning

confidence: 99%

Immunotoxicology: A brief history, current status and strategies for future immunotoxicity assessment

Germolec

Luebke

Rooney

et al. 2017

Current Opinion in Toxicology

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Evaluation of the Multi-ImmunoTox Assay composed of 3 human cytokine reporter cells by examining immunological effects of drugs

Cited by 21 publications

References 17 publications

Harnessing In Silico, In Vitro, and In Vivo Data to Understand the Toxicity Landscape of Polycyclic Aromatic Compounds (PACs)

Harnessing In Silico, In Vitro, and In Vivo Data to Understand the Toxicity Landscape of Polycyclic Aromatic Compounds (PACs)

An international validation study of the IL-2 Luc assay for evaluating the potential immunotoxic effects of chemicals on T cells and a proposal for reference data for immunotoxic chemicals

Immunotoxicology: A brief history, current status and strategies for future immunotoxicity assessment

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