Evaluation of immune-mediated idiosyncratic drug toxicity using chimeric HLA transgenic mice
Evaluation of immune-mediated idiosyncratic drug toxicity using chimeric HLA transgenic mice
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使用嵌合 HLA 转基因小鼠评价免疫介导的特殊药物毒性
DOI：
10.1007/s00204-017-2112-9
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发表时间：
2017
影响因子：
6.1
通讯作者：
Ito Kousei
中科院分区：
文献类型：
--
作者：
Susukida Takeshi;Aoki Shigeki;Kogo Kotaro;Fujimori Sota;Song Binbin;Liu Cong;Sekine Shuichi;Ito Kousei
免疫介导的特异性药物毒性(IDT)是一种罕见的药物不良反应，可能导致死亡。尽管全基因组关联研究表明，免疫介导的IDT的发生与特定的人类白细胞抗原(HLA)异型密切相关，但这些关联尚未被前瞻性地证实。在本研究中，我们以人类白细胞抗原B*57：01和阿巴卡韦(ABC)诱导的免疫介导的IDT为研究对象，构建了携带嵌合的人类白细胞抗原B*57：01(B*57：01-TG)的转基因小鼠，以确定该体内模型是否可用于评价免疫介导的IDT。局部淋巴检测结果显示，ABC(50 mg/kg/d)处理的B*57：01-Tg小鼠CD8+T细胞中BrdU+、IL-2+和干扰素-γ+的百分比显著高于同窝小鼠(LMS)，导致炎症细胞向耳内渗透。在B*57：03-TG小鼠(阴性对照)中未观察到上述免疫反应。此外，1%(v/v)ABC可显著提高B*57：01-Tg小鼠和LMS小鼠脾和淋巴结中CD44HighCD62LlowCD8+记忆T细胞的百分率，但对B*57：03-Tg小鼠和LMS小鼠无明显影响。这些结果表明，B*57：01-TG小鼠有可能复制和评估人类白细胞抗原-B*57：01和ABC诱导的免疫介导的IDT。
Immune-mediated idiosyncratic drug toxicity (IDT) is a rare adverse drug reaction, potentially resulting in death. Although genome-wide association studies suggest that the occurrence of immune-mediated IDT is strongly associated with specific human leukocyte antigen (HLA) allotypes, these associations have not yet been prospectively demonstrated. In this study, we focused on HLA-B*57:01 and abacavir (ABC)-induced immune-mediated IDT, and constructed transgenic mice carrying chimeric HLA-B*57:01 (B*57:01-Tg) to determine if this in vivo model may be useful for evaluating immune-mediated IDT. Local lymph node assay (LLNA) results demonstrated that percentages of BrdU+, IL-2+, and IFN-γ+in CD8+T cells of ABC (50 mg/kg/day)-applied B*57:01-Tg mice were significantly higher than those in littermates (LMs), resulting in the infiltration of inflammatory cells into the ear. These immune responses were not observed in B*57:03-Tg mice (negative control). Furthermore, oral administration of 1% (v/v) ABC significantly increased the percentage of CD44highCD62LlowCD8+memory T cells in lymph nodes and spleen derived from B*57:01-Tg mice, but not in those from B*57:03-Tg mice and LMs. These results suggest that B*57:01-Tg mice potentially enable the reproduction and evaluation of HLA-B*57:01 and ABC-induced immune-mediated IDT.