Phillips Elizabeth J
NASHVILLE, TENNESSEE.
Trans Am Clin Climatol Assoc. 2018;129:74-87.
Preventive efforts for serious immunologically mediated adverse drug reactions (IM-ADRs) have been fueled by discovery of strong class I human leukocyte antigen (HLA) associations; however, the low positive predictive value of HLA for IM-ADRs has limited translation. Studies were undertaken to explain why most patients carrying an HLA risk allele do not develop IM-ADR on exposure to the risk drug. Tissue-specific approaches defined the T-cell receptor (TCR) repertoire and phenotype of the pathogenic T cells found in the skin and blister fluid of IM-ADRs. Dominant CD8+ T cell clonotypes representing >50% of total TCRαβ sequences among CD8+ CD137+ T cells were identified in tissue to identify the pathogenic activated T cells. Identification of the specific molecular and cellular signatures of the antigen-driven pathogenic T cells will facilitate more specific mechanisms to determine the small percentage of individuals carrying an HLA risk allele who are likely to develop an IM-ADR before drug exposure.
对严重免疫介导的药物不良反应（IM-ADR）的预防工作因发现与I类人类白细胞抗原（HLA）的强关联而得到推动；然而，HLA对IM-ADR的低阳性预测价值限制了其实际应用。开展了多项研究来解释为什么大多数携带HLA风险等位基因的患者在接触风险药物时不会发生IM-ADR。组织特异性方法确定了在IM-ADR的皮肤和疱液中发现的致病性T细胞的T细胞受体（TCR）库和表型。在组织中鉴定出占CD8+ CD137+ T细胞中总TCRαβ序列>50%的优势CD8+ T细胞克隆型，以识别致病性活化T细胞。鉴定抗原驱动的致病性T细胞的特定分子和细胞特征将有助于采用更具特异性的机制，在药物暴露前确定携带HLA风险等位基因且可能发生IM-ADR的一小部分个体。
