How Reactive Metabolites Induce an Immune Response That Sometimes Leads to an Idiosyncratic Drug Reaction
How Reactive Metabolites Induce an Immune Response That Sometimes Leads to an Idiosyncratic Drug Reaction
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DOI：
10.1021/acs.chemrestox.6b00357
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发表时间：
2017-01-01
影响因子：
4.1
通讯作者：
Uetrecht, Jack
中科院分区：
文献类型：
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作者：
Cho, Tiffany;Uetrecht, Jack
关于特异质药物反应（IDR）的确切机制知之甚少;然而，有大量证据表明，反应性代谢物参与了大多数（但不是全部）IDR。此外，证据还表明，大多数IDR是免疫介导的。这就提出了一个问题，即活性代谢物如何诱导免疫反应，从而导致IDR。占主导地位的假说是半抗原假说和clanger假说。这些是互补的假设：反应性代谢物可以作为半抗原产生新抗原，并且它也可以引起细胞损伤，导致释放激活抗原呈递细胞的与抗原相关的分子模式分子。两者都是免疫反应所必需的。此外，药物可通过炎性小体激活诱导免疫应答。我们已经发现了一些例子，其中激活炎性小体的能力将引起IDR的药物与不引起IDR的类似药物区分开来。还有其他不涉及免疫机制的假设，如线粒体损伤和胆盐输出泵（BSEP）抑制。除了一些可能的例外，这些假设不太可能完全解释IDR。然而，各种类型的线粒体损伤或BSEP抑制可产生危险信号。保护我们免受IDR的主要机制似乎是免疫耐受。与这一假设一致，我们使用检查点抑制来开发第一个特异质药物诱导的肝损伤的动物模型，其具有与人类特异质损伤相同的特征。这是通过用抗CTLA-4抗体和阿莫地喹治疗Pd-1（-/-）小鼠来实现的。Pd-1（-/-）小鼠和抗CTLA-4的组合也揭示了其他药物（如异烟肼）引起延迟型肝损伤的能力。这个模型应该允许严格测试的机制假设，这是不可能的，在过去。
Little is known with certainty about the mechanisms of idiosyncratic drug reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addition, evidence also suggests that most IDRs are immune mediated. That raises the question of how reactive metabolites induce an immune response that can lead to an IDR. The dominant hypotheses are the hapten and clanger hypotheses. These are complementary hypotheses: a reactive metabolite can act as a hapten to produce neoantigens, and it can also cause cell damage leading to the release of danger-associated molecular pattern molecules that activate antigen presenting cells. Both are required for an immune response. In addition, drugs may induce an immune response through inflammasome activation. We have found examples in which the ability to activate inflammasomes differentiated drugs that cause IDRs from similar drugs that do not. There are other hypotheses that do not involve an immune mechanism such as mitochondrial injury and bile salt export pump (BSEP) inhibition. With some possible exceptions, these hypotheses are unlikely to be able to completely explain IDRs. However, soiree types of mitochondrial injury or BSEP inhibition could produce danger signals. The major mechanism that protects us from IDRs appears to be immune tolerance. Consistent with this hypothesis, we used checkpoint inhibition to develop the first animal model of idiosyncratic drug-induced liver injury that has the same characteristics as the idiosyncratic injury hi humans. This was accomplished by treating Pd-1(-/-) mice with anti-CTLA-4 antibodies and amodiaquine. The combination of the Pd-1(-/-) mouse and anti-CTLA-4 also unmasks the ability of other drugs such as isoniazid to cause delayed type liver injury. This model should allow rigorous testing of mechanistic hypotheses that was impossible in the past.