Regulation of the immune tolerance system determines the susceptibility to HLA-mediated abacavir-induced skin toxicity

Idiosyncratic drug toxicity (IDT) associated with specific human leukocyte antigen (HLA) allotype is a rare and unpredictable life-threatening adverse drug reaction for which prospective mechanistic studies in humans are difficult. Here, we show the importance of immune tolerance for IDT onset and determine whether it is susceptible to a common IDT, HLA-B*57:01-mediated abacavir (ABC)-induced hypersensitivity (AHS), using CD4⁺ T cell-depleted programmed death-1 receptor (PD-1)-deficient HLA-B*57:01 transgenic mice (B*57:01-Tg/PD-1^−/−). Although AHS is not observed in B*57:01-Tg mice, ABC treatment increases the proportion of cytokine- and cytolytic granule-secreting effector memory CD8⁺ T cells in CD4⁺ T cell-depleted B*57:01-Tg/PD-1^−/− mice, thereby inducing skin toxicity with CD8⁺ T cell infiltration, mimicking AHS. Our results demonstrate that individual differences in the immune tolerance system, including PD-1^highCD8⁺ T cells and regulatory CD4⁺ T cells, may affect the susceptibility of humans to HLA-mediated IDT in humans.