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.

Thrombotic microangiopathy (aHUS/iTTP) reported so far in Covid-19 patients: The virus alone or an omnium gatherum of mechanisms and etiologies?

“…In recovered patients with an exposure to HCQ, rechallenge with the drug could solve the puzzle but this re-exposure would be neither ethical nor clinically prudent since the consequence of a second exposure could be more severe if the drug was the culprit. The role of novel invitro HCQ sensitizing tests need to be determined as well ( Galbiati et al, 2021 ). The virus seems to have directly triggered a primary thrombotic microangiopathy through some novel mechanisms in some of these patients ( Fig.…”

Mebendazole-induced M1 polarisation of THP-1 macrophages may involve DYRK1B inhibition

“…The difference between THP-macrophages and THP-1 monocytes in response to AZ191 and MBZ is presently unexplained. Monocytoid THP-1 cells are often used as surrogate model for dendritic cells (DCs) in evaluation of allergen potential of small molecules [25–27]. MBZ-induced cytokine release in naive THP-1 cells is dominated by IL1β and IL8, a response considered to reflect maturation of immature DCs to active functional antigen-presenting DCs [25, 28].…”

Immune Thrombotic Thrombocytopenic Purpura in a Patient with Suspected COVID-19: Hydroxychloroquine Culprit or Just Happenstance?

“…It needs to be emphasized that quinine-induced thrombotic microangiopathy can occur hours, days, or months after exposure to the drug and HCQ has a very long elimination half-life of 40 days after a single dose. The typical COVID-19-induced TTP-like illness is secondary to diffuse endothelial damage secondary to virus-induced endotheliitis further aggravated by complement overactivity, causing an over-spilling of von Willebrand factor (vWF) from the damaged endothelial network overwhelming the ADAMTS13 protease and producing the relative ADAMTS deficiency typically seen as an ADAMTS13/vWF ratio of <10, but without a critical drop in ADAMTS13 levels and in the absence of a circulating ADAMTS inhibitor [ 9 ]. Nevertheless, some cases of classic iTTP have occurred in association with COVID-19 infection, possibly due to some novel mechanism triggered by the virus or maybe the unmasking of a latent disease with the virus possibly acting as a second hit.…”