薬物による副作用発症の個人差を決定するHLAの重要性

抄録

Individuals vary in their susceptibility to adverse reactions to medications, some of which can be potentially life-threatening. Idiosyncratic drug toxicity (IDT) has been shown to be strongly associated to specific polymorphisms in genes encoding human leukocyte antigens (HLAs) by recent genome-wide association studies. However, the pathogenic mechanisms governing such reactions remain unclarified, at least in part because of a lack of suitable experimental animal models to assess IDT. This review describes our work on the specific allele/drug combination of HLA-B*57:01 and abacavir, an antiretroviral drug targeting the human immunodeficiency virus. As abacavir is known to trigger an HLA-dependent immune response, we engineered a transgenic mouse model—HLA-Tg—by partially substituting the mouse HLA sequence for the corresponding human sequence. Local abacavir exposure was found to trigger a significant immune response in an HLA-dependent manner, and oral administration induced liver injury partially via concurrent activation of the innate immune system. Additionally, we developed a technique for evaluating structural alterations in HLA complexes resulting from drug exposure based on phage display to ensure specificity. Further scrutiny of the mechanism(s) underlying drug-induced immune reactions using the HLA-Tg model, as well as enhanced methods for predicting adverse event incidence, are anticipated to help resolve issues surrounding HLA-associated drug hypersensitivity.