A transgenic mouse model for HLA-B*57: 01-linked abacavir drug tolerance and reactivity
A transgenic mouse model for HLA-B*57: 01-linked abacavir drug tolerance and reactivity
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DOI：
10.1172/jci99321
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发表时间：
2018-07-02
影响因子：
15.9
通讯作者：
Norcross, Michael A.
中科院分区：
文献类型：
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作者：
Cardone, Marco;Garcia, Karla;Norcross, Michael A.
药物不良反应（adr）是药物开发的主要障碍，其中一些不良反应，包括对HIV逆转录酶抑制剂阿巴卡韦（abacavir， ABC）的超敏反应，与HLA等位基因有关，特别是HLA- b *57:01。然而，并非所有HLA- b *57:01'患者都会发生不良反应，这表明除了HLA遗传风险外，其他因素也可能影响药物反应的结果。为了在体内研究hla相关的adr，我们生成了HLA-B*57:01-Tg小鼠，结果表明，尽管ABC在体外以HLA-B*57:01依赖的方式激活Tg小鼠CD8(+) T细胞，但在体内是耐受的。在免疫功能正常的Tg动物中，ABC诱导具有能量样表型的CD8(+) T细胞，不会导致adr。相比之下，在给予ABC之前，体内CD4(+) T细胞的消耗增强了DC成熟，从而诱导具有效应样和皮肤归巢表型的全身ABC反应性CD8(+) T细胞，并伴随CD8(+) T浸润和药物致敏皮肤炎症。B7共刺激分子阻断可阻止CD8(+) T细胞活化。这些Tg小鼠提供了ABC耐受和产生HLA- b *57:01限制性、ABC反应性CD8(+) T细胞依赖于HLA遗传风险和免疫调节宿主因子的模型。
Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01' patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse CD8(+) T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced CD8(+) T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of CD4(+) T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive CD8(+) T cells with an effector-like and skin-homing phenotype along with CD8(+) T infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented CD8(+) T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive CD8(+) T cells dependent on both HLA genetic risk and immunoregulatory host factors.