Role of VISTA in discoid lupus erythematosus

项目总结 盘状红斑狼疮(DLE)是一种严重影响生活质量的慢性炎症性皮肤病 以毁容、结疤、脱发、瘙痒、疼痛为特征。据估计，DLE影响到近 美国有22.5万人，对有色人种女性的影响不成比例。没有FDA批准的治疗方法 目前的非标签疗法对许多患者往往无效。治疗DLE的新靶向疗法问世 早期临床发展，但我们缺乏对致病免疫细胞和 可以作为治疗靶点的细胞因子。有证据表明，浆细胞样树突状细胞(PDC) 是DLE的关键驱动因素，试验开始针对PDCs进行DLE治疗。我们之前的工作证明了 免疫抑制受体V区抑制T细胞活化(VistA)抑制DLE的发生 在小鼠MRL/LPR狼疮模型中。VistA是一种独特的免疫抑制受体，它表达在T细胞上 和髓系细胞亚群。我们发现，缺乏VistA的小鼠会自发患上类DLE疾病，并 VistA的刺激减少了MRL/LPR狼疮小鼠pDC产生的I型干扰素。我们也 发现与其他自身免疫性疾病相比，人类DLE的皮肤活检组织表达高水平的VistA 皮肤病。然而，关于Vista在DLE中的角色或Vista在DLE中的功能，人们还知之甚少 PDCS。该提案的目标是确定pDC是否对Vista淘汰赛中的DLE开发至关重要 小鼠，人DLE表达VistA，VistA pDC在人DLE中的转录谱，以及。在目标1中， 我们将确定人类DLE中哪些免疫细胞亚群表达VistA，它们的细胞连接， Vista受体-配体配对并通过高效表达确定Vista细胞的转录图谱 多路单细胞成像和空间转录。在目标2中，我们将确定所涉及的关键细胞 在条件性VistA基因敲除小鼠DLE发生中的作用及Vista抑制PDC的机制 一种激动剂Vista抗体。首席研究员马修·韦斯利医学博士是一名皮肤科医生， 耶鲁大学医学院的免疫学家。他的目标是领导一个独立的学术研究实验室，研究 自身免疫性皮肤病如DLE的免疫发病机制。他将通过发展来追求这一目标 在空间蛋白质组学和原位转录数据的生成和分析方面的专业知识；2)成为 Vista免疫细胞抑制方面的专家；3)在DLE中建立导师和合作者社区 和单细胞成像技术；4)完成课程，以扩展他的计算和统计 背景资料。这些导师和他的职业发展计划将帮助他获得技能和专业知识 需要在自身免疫性皮肤病的免疫抑制方面开拓自己独特的利基市场，成为专家 在单细胞成像方面，并有可能为这些疾病开发新的治疗方法。

PROJECT SUMMARY Discoid lupus erythematosus (DLE) is a chronic inflammatory skin disease that severely impairs quality of life and is characterized by disfiguring scarring, hair loss, itching, and pain. It is estimated that DLE affects nearly 225,000 US persons and disproportionally affects woman of color. There are no FDA-approved treatments and current off-label therapies are often ineffective for many patients. Emerging targeted therapies for DLE are in early clinical development, but we lack understanding of the full spectrum of pathogenic immune cells and cytokines that could be therapeutically targeted. Evidence suggests that plasmacytoid dendritic cells (pDCs) are a key driver of DLE and trials are starting to target pDCs for DLE therapy. Our previous work demonstrated that immune inhibitory receptor V-domainIg suppressor of T cell activation (VISTA)inhibits DLE development in the murine MRL/lpr lupus model. VISTA is a unique immune inhibitory receptor as it is expressed on T cells and myeloid cell subsets. We showed that mice lacking VISTA spontaneously develop DLE-like disease and that stimulation of VISTA reduces production of type I interferons by pDCs in MRL/lpr lupus mice. We also found that skin biopsies from human DLE express high levels of VISTA when compared to other autoimmune skin diseases. However, not much else is known about the role of VISTA in DLE or the function of VISTA on pDCs. The goal of this proposal is to determine if pDCs are critical for DLE development in VISTA knockout mice, the human DLE express VISTA, the transcriptional profile of VISTA+ pDCs in human DLE and. In Aim 1, we will identify which immune cells subsets within human DLE express VISTA, their cellular connections, VISTA receptor-ligand pairing and determine the transcriptional profile of VISTA+ cells by performing highly multiplexed single cell imaging and spatial transcriptomics. In Aim 2, we will determine the critical cells involved in DLE development in conditional VISTA knockout mice and the mechanism of pDC inhibition by VISTA using an agonist VISTA antibody. The Principal Investigator, Matthew Vesely MD, PhD, is a dermatologist and immunologist at Yale School of Medicine. His goal is to lead an independent academic research lab studying the immunopathogenesis of autoimmune skin diseases such as DLE. He will pursue this goal by 1) developing expertise in the generation and analysis of spatial proteomics and in situ transcriptomic data; 2) becoming an expert in immune cell inhibition by VISTA; 3) establishing a community of mentors and collaborators in DLE and single cell imaging technologies; 4) completing coursework to expand his computational and statistical background. These mentors and his career development plan will help him acquire the skills and expertise needed to develop his own distinct niche in immune inhibition of autoimmune skin diseases, become an expert in single-cell imaging, and potentially develop new therapies for these diseases.