Immune checkpoint blockade lowers the threshold of naïve T-cell priming to drug-associated antigens in a dose-dependent fashion.

A growing body of clinical and experimental evidence indicates that immune checkpoint blockade enhances patient susceptibility to hypersensitivity reactions to co-administered medications. In this study, we utilized an in vitro T-cell priming assay to demonstrate one of the mechanistic hypotheses on how this occurs; through lowering of the threshold in patients to elicit aberrant T-cell responses. We outline the dependency of de novo T-cell priming responses to drug-associated antigens on dose at initial exposure.

In Vivo Assessment of Drug-Induced Hepatotoxicity Using Embryos.

Failure to predict drug-induced toxicity reactions is a major problem contributing to a high attrition rate and tremendous cost in drug development. Drug screening in embryos is high-throughput relative to screening in rodents, potentially making them ideal for this use. embryos have been used as a toxicity model in the frog embryo teratogenesis assay on (FETAX) for the early stages of drug safety evaluation.

Paracetamol-induced liver injury modelled in Xenopus laevis embryos.

Introduction: Failure to predict drug-induced liver injury (DILI) remains a major contributing factor to lead compound drop-out during drug development. Xenopus embryos are amenable for early stage medium throughput small molecule screens and so have the potential to be used in pre-clinical screens. To begin to assess the usefulness and limitations of Xenopus embryos for safety assessment in the early phases of drug development, paracetamol was used as a model hepatotoxin.

From the Cover: Characterization of Isoniazid-Specific T-Cell Clones in Patients with anti-Tuberculosis Drug-Related Liver and Skin Injury.

Isoniazid, rifampicin, pyrazinamide, and ethambutol are commonly used for the treatment of tuberculosis. Drug exposure is occasionally associated with liver and/or skin injury. The aim of this study was to determine whether drug-specific T-cells are detectable in patients with adverse reactions and if so characterize the nature of the T-cell response.

Characterization of amoxicillin- and clavulanic acid-specific T cells in patients with amoxicillin-clavulanate-induced liver injury.

Unlabelled: Drug-induced liver injury (DILI) frequently has a delayed onset with several human leukocyte antigen (HLA) genotypes affecting susceptibility, indicating a potential role for the adaptive immune system in the disease. The aim of this study was to investigate whether drug-responsive T lymphocytes are detectable in patients who developed DILI with the combination, antimicrobial amoxicillin-clavulanate. Lymphocytes from 6 of 7 patients were found to proliferate and/or secrete interferon-gamma (IFN-γ) when cultured with amoxicillin and/or clavulanic acid.

Negative regulation by PD-L1 during drug-specific priming of IL-22-secreting T cells and the influence of PD-1 on effector T cell function.

Activation of PD-1 on T cells is thought to inhibit Ag-specific T cell priming and regulate T cell differentiation. Thus, we sought to measure the drug-specific activation of naive T cells after perturbation of PD-L1/2/PD-1 binding and investigate whether PD-1 signaling influences the differentiation of T cells. Priming of naive CD4(+) and CD8(+) T cells against drug Ags was found to be more effective when PD-L1 signaling was blocked.