Calorie restriction affects the susceptibility to HLA-mediated idiosyncratic drug toxicity

<p>[Purpose] Idiosyncratic drug toxicity (IDT) associated with specific human leukocyte antigen (HLA) allotype does not occur in all subjects of a given HLA model population, suggesting the difficulties to predict the IDT risk without considering additional factors. We have generated HLA-B*57:01 transgenic mouse (B*57:01-Tg) to identify unclarified onset risk factors in HLA-mediated IDT. Meanwhile, the importance of metabolic regulation including glycolysis for CD8⁺ T cell immunity is now increasingly recognized. Here, we examined whether calorie restriction contributes to the susceptibility to HLA-mediated IDT induced by oral abacavir (ABC) in the B*57:01-Tg mouse model.[Methods] After feeding the CD4⁺ T cell-depleted B*57:01-Tg mice with either a normal diet or 40% calorie restricted (CR) diet for 2 weeks, the mice were further fed for 1 week with ABC-contained diet. CD8⁺ T cells in lymph nodes were isolated and the proportion/function (i.e., IFN-γ secretion) of effector CD8⁺ T cells were analyzed using flow cytometry. Glycolytic rate in CD8⁺ T cells was measured using extracellular flux analyzer.[Results and Discussion] In CR diet-fed B*57:01-Tg mice, ABC treatment failed to show an increase in the percentage of effector memory (CD44^highCD62L^low) CD8⁺ T cells where glycolytic rate was significantly decreased. Alternatively, CR condition resulted in the increase of pre-effector memory CD8⁺ T cell (CD44^lowCD62L^low) proportion instead of effector memory CD8⁺ T cells. IFN-γ secreting CD44^highCD8⁺ T cells was diminished by CR in ABC-treated B*57:01-Tg mice. Our results suggested that CR condition attenuated the ABC-induced CD8⁺ T cell immunity and might reduce the onset risk of HLA-mediated IDT in B*57:01-Tg mice.[Conclusion] Individual differences in the metabolism status might also affect the susceptibility to HLA-mediated IDT in humans.</p>