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CD39+ regulatory T cells modulate the immune response to carbamazepine in HLA-B*15:02 carriers.
Immunobiology ( IF 2.8 ) Pub Date : 2019-11-15 , DOI: 10.1016/j.imbio.2019.11.003
Meixin Shen 1 , Joey Ming Er Lim 1 , Cheryl Chia 1 , Ee Chee Ren 2
Affiliation  

The HLA-B*15:02 allele is associated with an increased risk of developing carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Many studies, however, have demonstrated that a large majority of HLA-B*15:02 individuals are unlikely to develop the adverse drug reaction while on CBZ. This phenomenon suggests that other factors that modulate the allergic immune response, such as regulatory T cells (Tregs), might contribute to an uncontrolled immune response in SJS/TEN. Peripheral blood mononuclear cells (PBMCs) from 15 healthy HLA-B*15:02 carriers were isolated to investigate the role of Tregs in controlling the immune response towards CBZ. Recognition of CBZ was assessed using enzyme linked immunosorbent spot (ELISPOT) assay for IFN-γ, and the donor T-cell profiles were quantified by flow cytometry to differentiate CBZ responders from non-responders. As CD39 expression on Tregs promotes immune tolerance, we investigated the mechanisms of Treg suppression using inhibitors targeting the CD39/adenosinergic pathway. PBMCs from seven donors (responders) produced high levels of IFN-γ when re-exposed to CBZ, while eight donors (non-responders) did not. Flow cytometric analysis revealed that non-responders produced significantly higher frequencies of CD4+CD25+CD127loCD39+FoxP3+ Tregs compared to responders. CD39 inhibition using POM-1 inhibitor converted five of the eight non-responders into responders (P < 0.05). Higher frequencies of CD4+CD25+CD127loCD39+FoxP3+ Tregs was correlated with lower production of IFN-γ (P < 0.01). Our data suggest that CD4+CD25+CD127loCD39+FoxP3+ Tregs may play a role in promoting CBZ tolerance in HLA-B*15:02 carriers. The CD39/adenosinergic axis can be a potential target to alleviate the uncontrolled immune response during this adverse drug event.

中文翻译:

CD39 +调节性T细胞可调节HLA-B * 15:02载体对卡马西平的免疫反应。

HLA-B * 15:02等位基因与卡马西平(CBZ)引起的史蒂文斯-约翰逊综合征(SJS)和中毒性表皮坏死溶解(TEN)的风险增加有关。但是,许多研究表明,大多数HLA-B * 15:02个体在CBZ上不太可能发生药物不良反应。这种现象表明,其他调节过敏性免疫应答的因素,例如调节性T细胞(Tregs),可能会导致SJS / TEN中不受控制的免疫应答。分离自15种健康HLA-B * 15:02携带者的外周血单个核细胞(PBMC),以研究Treg在控制针对CBZ的免疫反应中的作用。使用酶联免疫吸附斑点(ELISPOT)分析评估IFN-γ对CBZ的识别,并通过流式细胞仪量化供体T细胞谱,以区分CBZ响应者和非响应者。由于Tregs上的CD39表达可促进免疫耐受,因此我们使用靶向CD39 /腺苷能途径的抑制剂研究了Treg抑制的机制。当再暴露于CBZ中时,来自七个供体(响应者)的PBMC产生高水平的IFN-γ,而八个供体(非响应者)则没有。流式细胞仪分析显示,与反应者相比,无反应者产生的CD4 + CD25 + CD127loCD39 + FoxP3 + Treg频率更高。使用POM-1抑制剂的CD39抑制作用将八个非应答者中的五个转化为应答者(P <0.05)。CD4 + CD25 + CD127loCD39 + FoxP3 + Tregs的较高频率与较低的IFN-γ产生相关(P <0.01)。我们的数据表明,CD4 + CD25 + CD127loCD39 + FoxP3 + Treg可能在促进HLA-B * 15:02携带者的CBZ耐受性中起作用。CD39 /腺苷能轴可能是减轻这种不良药物事件期间不受控制的免疫反应的潜在靶标。
更新日期:2020-04-21
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