Skin-resident memory T cells mediate delayed-onset drug hypersensitivity reactions in human and mice

皮肤驻留记忆 T 细胞介导人类和小鼠迟发性药物超敏反应

基本信息

  • 批准号:
    423175926
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    德国
  • 项目类别:
    Research Fellowships
  • 财政年份:
    2019
  • 资助国家:
    德国
  • 起止时间:
    2018-12-31 至 2021-12-31
  • 项目状态:
    已结题

项目摘要

Delayed-onset drug hypersensitivity reactions (DHRs) are a significant cause of morbidity and mortality as they can manifest as severe cutaneous, blistering disease with potentially internal organ involvement. The most life-threatening presentation is Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis (SJS/TEN). Though there is ample evidence implicating T cells in disease, pathogenesis is largely unknown. Skin-resident memory T cells (TRM) have recently been identified as the predominant T cell population within skin at steady-state. They have also been found to play a protective role against infection and to be directly involved in immune- mediated skin diseases such as psoriasis and contact dermatitis. We therefore propose the hypothesis that skin TRM are causal in delayed-type DHRs. I will use two independent and novel approaches to directly test this hypothesis. The first utilizes multi-spectral immunofluorescence staining and imaging, gene expression profiling and T cell receptor (TCR) sequencing, to interrogate skin TRM cells in formalin-fixed paraffin-embedded (FFPE) skin samples taken from patients with clinically diagnosed and dermatopathologically confirmed cases of SJS/ TEN and healthy human skin controls. The second capitalizes on a recently generated humanized HLA-B*15:02 positive mouse model of SJS/TEN to study skin TRM and other T cell subpopulations in vivo, allowing for deeper mechanistic studies. The data generated through this research should facilitate a better understanding of disease pathogenesis of SJS/TEN and delayed-onset DHRs in general.
迟发型药物超敏反应(DHR)是发病和死亡的重要原因,因为它们可以表现为严重的皮肤起泡疾病,可能累及内脏器官。最危及生命的表现是Stevens-Johnson综合征/中毒性表皮坏死松解症(SJS/TEN)。虽然有充分的证据表明T细胞参与疾病,但发病机制在很大程度上是未知的。皮肤驻留记忆T细胞(TRM)最近已被确定为稳态下皮肤内的主要T细胞群。还发现它们对感染起保护作用,并直接参与免疫介导的皮肤病,如银屑病和接触性皮炎。因此,我们提出的假设,皮肤TRM是因果关系的延迟型DHR。我将使用两种独立而新颖的方法来直接检验这一假设。第一种方法利用多光谱免疫荧光染色和成像、基因表达谱分析和T细胞受体(TCR)测序,以询问福尔马林固定石蜡包埋(FFPE)皮肤样本中的皮肤TRM细胞,这些皮肤样本取自临床诊断和皮肤病理学确诊的SJS/ TEN病例患者和健康人皮肤对照。第二个利用最近产生的人源化HLA-B*15:02阳性小鼠模型SJS/TEN研究皮肤TRM和其他T细胞亚群在体内,允许更深入的机制研究。通过本研究产生的数据应有助于更好地了解SJS/TEN和一般迟发型DHR的疾病发病机制。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Dr. Elisa Schunkert的其他文献

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