Host: The Japanese Society of Toxicology
To aid preclinical prediction of immune reactions associated with cytokine release and caused by LMW pharmaceutical drugs and biologics, Alcyomics developed an in vitro human skin explant assay Skimune® involving activation of dendritic cells and T cells. Activated cells are added to a skin biopsy taken from the same healthy volunteer and incubated for 3 days and then routinely fixed and stained with haematoxylin and eosin and graded from Grade I-IV in order of severity. The activated cells are also assessed for T cell proliferation and the supernatants for IFNƴ analysis. Twelve Low Molecular Weight (LMW) drugs associated with T cell-mediated hypersensitivity reactions in the clinic (including abacavir and amoxicillin,) were compared with 5 drugs with rare or no clinical reports including (acetaminophen and cimetidine). Results for T cell proliferation (r=0.6 p<0.01), IFNγ release (r=0.51 p<0.04) and Skimune® (r=0.77, p<0.001) were statistically significant. The Skimune® method was modified for the testing of biologics and 17 biologics were tested. Biologics known to cause adverse reactions such as Campath and OKT3 as well as a TGN1412 analogue gave a Grade II or III histopathological skin response in 70% to 90% of 10 individual tests. There was a positive correlation between adverse clinical outcome and the response in Skimune® (r=0.815, p<0.0001). The present results demonstrate that Skimune® is a highly sensitive assay for predicting drug-induced adverse immune reactions involving acute cytokine release.
