Characterization of amoxicillin- and clavulanic acid-specific T cells in patients with amoxicillin-clavulanate-induced liver injury
Characterization of amoxicillin- and clavulanic acid-specific T cells in patients with amoxicillin-clavulanate-induced liver injury
复制标题
DOI：
10.1002/hep.27912
复制
发表时间：
2015-09-01
期刊：
影响因子：
13.5
通讯作者：
Naisbitt, Dean J.
中科院分区：
文献类型：
--
作者：
Kim, Seung-Hyun;Saide, Katy;Naisbitt, Dean J.
药物性肝损伤(DILI)通常起病延迟，几种人类白细胞抗原(HL A)基因影响易感性，提示获得性免疫系统在该病中可能发挥作用。这项研究的目的是调查在联合使用抗菌药阿莫西林-克拉维酸后发生DILI的患者中是否可以检测到药物反应性T淋巴细胞。7例患者中有6例的淋巴细胞在阿莫西林和/或克拉维酸作用下增殖和/或分泌干扰素-γ。阿莫西林(n=105)和克拉维酸(n=16)反应性CD4(+)和CD8(+)T细胞克隆表达CCR、趋化因子(C-C基序)受体4、CCR9和趋化因子(C-X-C基序)受体3。阿莫西林克隆被发现分泌一组不同种类的介质，包括干扰素-22、白细胞介素22和细胞溶解分子。相比之下，克拉维酸克隆的细胞因子分泌受到了更多的限制。CD4(+)和CD8(+)克隆分别是主要的组织相容性复合体II类和I类限制性的，药物抗原在人类白细胞抗原-DR分子的背景下呈递给CD4(+)克隆。一些证据表明，克隆是通过半抗原机制激活的：第一，专业的抗原提呈细胞(APC)需要最佳的激活；第二，脉冲4-16小时的APC激活克隆；第三，抑制处理取消了增殖反应和细胞因子的释放。结论：阿莫西林和克拉维酸特异性T细胞均参与阿莫西林-克拉维酸对某些患者的肝损伤。(《肝病》2015；62：887-899)
Drug-induced liver injury (DILI) frequently has a delayed onset with several human leukocyte antigen (HLA) genotypes affecting susceptibility, indicating a potential role for the adaptive immune system in the disease. The aim of this study was to investigate whether drug-responsive T lymphocytes are detectable in patients who developed DILI with the combination, antimicrobial amoxicillin-clavulanate. Lymphocytes from 6 of 7 patients were found to proliferate and/or secrete interferon-gamma (IFN-) when cultured with amoxicillin and/or clavulanic acid. Amoxicillin (n=105) and clavulanic acid (n=16) responsive CD4(+) and CD8(+) T-cell clones expressing CCR, chemokine (C-C motif) receptor 4, CCR9, and chemokine (C-X-C motif) receptor 3 were generated from patients with and without HLA risk alleles; no cross-reactivity was observed between the two drug antigens. Amoxicillin clones were found to secrete a heterogeneous panel of mediators, including IFN-, interleukin-22 and cytolytic molecules. In contrast, cytokine secretion by the clavulanic acid clones was more restricted. CD4(+) and CD8(+) clones were major histocompatability complex class II and I restricted, respectively, with the drug antigen being presented to CD4(+) clones in the context of HLA-DR molecules. Several pieces of evidence indicate that the clones were activated by a hapten mechanism: First, professional antigen-presenting cells (APCs) were required for optimal activation; second, pulsing APCs for 4-16 hours activated the clones; and third, inhibition of processing abrogated the proliferative response and cytokine release. Conclusion: Both amoxicillin- and clavulanic acid-specific T cells participate in the liver injury that develops in certain patients exposed to amoxicillin-clavulanate. (Hepatology 2015;62:887-899)