Investigating the Mechanisms of Idiosyncratic Drug Reactions: Lessons from Nevirapine-induced Skin Rash in Female Brown Norway Rats.

摘要

Idiosyncratic drug reactions (IDRs) cause significant morbidity and mortality. At present it is impossible to predict who will have such reactions because the mechanisms involved are not understood. This work used nevirapine-induced skin rash in female Brown Norway rats as a model to investigate the mechanisms of IDRs. Specifically, we hypothesized that CD4+ T cells are mediating the rash, and the reactive sulfate metabolite of nevirapine induced the immune response by directly activating antigen presenting cells (APCs).;Independent of which chemical species induced the rash (treatment with nevirapine or 12-OH-nevirapine), CD4+ T cells isolated from the lymph nodes of animals responded vigorously to the parent drug, but not to 12-OH-nevirapine even though oxidation of nevirapine to 12-OH-nevirapine pathway is required to induce the rash. This falsifies the basis for the PI hypothesis, which assumes that what the lymphocytes respond to is what induced the IDR.;In the APC activation study it was found that nevirapine, 12-OH-nevirapine, and 12-OH-nevirapine sulfate all appeared to activate APCs to some degree. For instance, CD40 was upregulated in RAW264.7 cells and bone marrow-derived dendritic cells, while CD86 was upregulated in THP-1 cells. However, the effects were small and not limited to the reactive sulfate.;Several interventions were also used to modulate the rash caused by nevirapine to learn more about possible risk factors; however, no results showed that any of them had a significant effect on the rash. This included depleting B cells and treatment with buthionine sulfoximine, retinoic acid, 1-methyl-tryptophan, lipopolysaccharide, imiquimod, or vitamin D.;This animal model of an IDR allowed us to test mechanistic hypotheses that would be impossible to test by any other method. It provided insights into the mechanism of this IDR, and by extension, into the mechanisms of other IDRs.