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In vitro Models to Evaluate Drug-Induced Hypersensitivity: Potential Test Based on Activation of Dendritic Cells.

Galbiati V, Papale A, Kummer E, Corsini E - Front Pharmacol (2016)

Bottom Line: Enhanced prediction in preclinical safety evaluation is, therefore, crucial.We recently established experimental conditions and markers to correctly identify drug associated with in vivo hypersensitivity reactions using THP-1 cells and IL-8 production, CD86 and CD54 expression.The proposed in vitro method benefits from a rationalistic approach with the idea that allergenic drugs share with chemical allergens common mechanisms of cell activation.

View Article: PubMed Central - PubMed

Affiliation: Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano Milan, Italy.

ABSTRACT
Hypersensitivity drug reactions (HDRs) are the adverse effect of pharmaceuticals that clinically resemble allergy. HDRs account for approximately 1/6 of drug-induced adverse effects, and include immune-mediated ("allergic") and non-immune-mediated ("pseudo allergic") reactions. In recent years, the severe and unpredicted drug adverse events clearly indicate that the immune system can be a critical target of drugs. Enhanced prediction in preclinical safety evaluation is, therefore, crucial. Nowadays, there are no validated in vitro or in vivo methods to screen the sensitizing potential of drugs in the pre-clinical phase. The problem of non-predictability of immunologically-based hypersensitivity reactions is related to the lack of appropriate experimental models rather than to the lack of -understanding of the adverse phenomenon. We recently established experimental conditions and markers to correctly identify drug associated with in vivo hypersensitivity reactions using THP-1 cells and IL-8 production, CD86 and CD54 expression. The proposed in vitro method benefits from a rationalistic approach with the idea that allergenic drugs share with chemical allergens common mechanisms of cell activation. This assay can be easily incorporated into drug development for hazard identification of drugs, which may have the potential to cause in vivo hypersensitivity reactions. The purpose of this review is to assess the state of the art of in vitro models to assess the allergenic potential of drugs based on the activation of dendritic cells.

No MeSH data available.


Related in: MedlinePlus

Role of ROS in chemical allergen-induced DC activation.
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Figure 3: Role of ROS in chemical allergen-induced DC activation.

Mentions: Evidence indicates that oxidative stress is involved in chemical-induced skin allergic and inflammatory diseases (Okayama, 2005; Byamba et al., 2010). Chemical-induced oxidation of the cell surface thiols appears to be one of the triggers of DC maturation, resulting in intracellular redox imbalance that generate stress-related signal (Figure 3). The Keap1/Nrf2-signaling pathway is dedicated to the detection of electrophilic stress in cells leading to the up-regulation of genes involved in protection or neutralization of chemicals reactive species (Natsch and Emter, 2007). It has been shown in human monocyte-derived dendritic cells that chemical sensitizers induced oxidative stress measured by the glutathione GSH/GSSG ratio, as a redox marker (Mizuashi et al., 2005). The reduction of the glutathione GSH/GSSG ratio was accompanied by CD86 up-regulation and p38 MAPK activation, suggesting that the electrophilic properties of chemicals sensitizers may be perceived by DCs as a danger signal leading to DC maturation (Sasaki and Aiba, 2007). Engagement of certain Toll like receptors (TLR1, 2, and 4) leads to mitochondrial translocation of the signal adaptor TRAF6. At the mitochondria, TRAF6 interacts with ECSIT, a protein implicated in the assembly of complex I, leading to its ubiquitylation, which results in increased ROS production. Proteins that are reversibly modulated by ROS are of high interest. In this context, protein kinases and phosphatases, which act co-ordinately in the regulation of signal transduction through the phosphorylation and dephosphorylation of target proteins, have been described to be key elements in ROS-mediated signaling events. In particular, PKC isoforms have been shown to contain a unique structural feature that is susceptible to oxidative modification (Cosentino-Gomes et al., 2012). The high levels of cysteine residues render the regulatory domain susceptible to redox regulation (Gopalakrishna and Jaken, 2000; Giorgi et al., 2010). Currently, evidence supports the direct activation of different PKC isoforms by ROS generation; in particular the β isoform is able to induce ROS generation through mitochondrial damage (Pinton et al., 2007).


In vitro Models to Evaluate Drug-Induced Hypersensitivity: Potential Test Based on Activation of Dendritic Cells.

Galbiati V, Papale A, Kummer E, Corsini E - Front Pharmacol (2016)

Role of ROS in chemical allergen-induced DC activation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940371&req=5

Figure 3: Role of ROS in chemical allergen-induced DC activation.
Mentions: Evidence indicates that oxidative stress is involved in chemical-induced skin allergic and inflammatory diseases (Okayama, 2005; Byamba et al., 2010). Chemical-induced oxidation of the cell surface thiols appears to be one of the triggers of DC maturation, resulting in intracellular redox imbalance that generate stress-related signal (Figure 3). The Keap1/Nrf2-signaling pathway is dedicated to the detection of electrophilic stress in cells leading to the up-regulation of genes involved in protection or neutralization of chemicals reactive species (Natsch and Emter, 2007). It has been shown in human monocyte-derived dendritic cells that chemical sensitizers induced oxidative stress measured by the glutathione GSH/GSSG ratio, as a redox marker (Mizuashi et al., 2005). The reduction of the glutathione GSH/GSSG ratio was accompanied by CD86 up-regulation and p38 MAPK activation, suggesting that the electrophilic properties of chemicals sensitizers may be perceived by DCs as a danger signal leading to DC maturation (Sasaki and Aiba, 2007). Engagement of certain Toll like receptors (TLR1, 2, and 4) leads to mitochondrial translocation of the signal adaptor TRAF6. At the mitochondria, TRAF6 interacts with ECSIT, a protein implicated in the assembly of complex I, leading to its ubiquitylation, which results in increased ROS production. Proteins that are reversibly modulated by ROS are of high interest. In this context, protein kinases and phosphatases, which act co-ordinately in the regulation of signal transduction through the phosphorylation and dephosphorylation of target proteins, have been described to be key elements in ROS-mediated signaling events. In particular, PKC isoforms have been shown to contain a unique structural feature that is susceptible to oxidative modification (Cosentino-Gomes et al., 2012). The high levels of cysteine residues render the regulatory domain susceptible to redox regulation (Gopalakrishna and Jaken, 2000; Giorgi et al., 2010). Currently, evidence supports the direct activation of different PKC isoforms by ROS generation; in particular the β isoform is able to induce ROS generation through mitochondrial damage (Pinton et al., 2007).

Bottom Line: Enhanced prediction in preclinical safety evaluation is, therefore, crucial.We recently established experimental conditions and markers to correctly identify drug associated with in vivo hypersensitivity reactions using THP-1 cells and IL-8 production, CD86 and CD54 expression.The proposed in vitro method benefits from a rationalistic approach with the idea that allergenic drugs share with chemical allergens common mechanisms of cell activation.

View Article: PubMed Central - PubMed

Affiliation: Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano Milan, Italy.

ABSTRACT
Hypersensitivity drug reactions (HDRs) are the adverse effect of pharmaceuticals that clinically resemble allergy. HDRs account for approximately 1/6 of drug-induced adverse effects, and include immune-mediated ("allergic") and non-immune-mediated ("pseudo allergic") reactions. In recent years, the severe and unpredicted drug adverse events clearly indicate that the immune system can be a critical target of drugs. Enhanced prediction in preclinical safety evaluation is, therefore, crucial. Nowadays, there are no validated in vitro or in vivo methods to screen the sensitizing potential of drugs in the pre-clinical phase. The problem of non-predictability of immunologically-based hypersensitivity reactions is related to the lack of appropriate experimental models rather than to the lack of -understanding of the adverse phenomenon. We recently established experimental conditions and markers to correctly identify drug associated with in vivo hypersensitivity reactions using THP-1 cells and IL-8 production, CD86 and CD54 expression. The proposed in vitro method benefits from a rationalistic approach with the idea that allergenic drugs share with chemical allergens common mechanisms of cell activation. This assay can be easily incorporated into drug development for hazard identification of drugs, which may have the potential to cause in vivo hypersensitivity reactions. The purpose of this review is to assess the state of the art of in vitro models to assess the allergenic potential of drugs based on the activation of dendritic cells.

No MeSH data available.


Related in: MedlinePlus