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

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.

Keywords: CD86; ROS; alternative methods; dendritic cell activation; drug hypersensitivity; in vitro methods.

Figure 1

Classification of in vitro models able to assess drug-inducing hypersensitivity reactions. In vitro diagnostic tests can be divided in test able to identify the culprit drugs at the resolution of the reaction, and methods that allow to determining the individual risk of HDR before drug administration. On the other hand, some in vitro methods may be used in the pre-clinical phase of drug development for hazard identification of potential to induce hypersensitivity reactions.

Figure 2

The THP-1 activation assay tier approach. Following 24 h of THP-1 chemical/drug treatment, the effect on IL-8 release and CD86 expression are investigated. If positive (statistically significant release of IL-8 at any concentration and/or a SI ≥ 1.5 for CD86), the chemical/drug will be considered as sensitizer. If negative, in order to exclude any activation, IL-8 release and CD86 expression at 48 h (statistically significant release of IL-8 at any concentration and/or a SI ≥ 1.5 for CD86) or CD54 expression at 24 h (SI ≥ 2.0) or alternatively IL-8 mRNA expression (2^−ΔΔCT > 3.0) at 3 h should be assessed. Only if negative results were obtained in all parameters, the chemical/drug will be considered as non-sensitizer.

Figure 3

Role of ROS in chemical allergen-induced DC activation.