Role of VISTA in discoid lupus erythematosus

VISTA 在盘状红斑狼疮中的作用

• 批准号: 10425621
• 负责人: Matthew D Vesely
• 金额: $ 17.15万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425621
• 关键词: Address; Affect; Agonist; Antibody Activation; Antigen-Antibody Complex; Architecture; Autoimmune; Binding; Biopsy; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Communication; Cells; Chronic; Cicatrix; Data; Dendritic Cells; Dermatologist; Development; Development Plans; Discoid Lupus Erythematosus; Disease; Doctor of Philosophy; Epidermis; FDA approved; Flow Cytometry; Future; Gene Expression; Gene Expression Profile; Generations; Goals; Hair; Human; Imaging technology; Immune; Immunofluorescence Immunologic; Immunologics; Immunologist; Impairment; In Situ; Inbred MRL lpr Mice; Infiltration; Inflammatory; Interferon Type I; Interferons; Knockout Mice; Knowledge; Label; Lead; Lesion; Lichen Planus; Ligands; Lupus; Maps; Mediator of activation protein; Mentors; Modeling; Molecular; Monitor; Multiplexed Ion Beam Imaging; Mus; Myeloid Cells; Pain; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Persons; Phenotype; Play; Principal Investigator; Production; Proteins; Proteomics; Pruritus; Psoriasis; Quality of life; Receptor Activation; Receptor Signaling; Research; Resolution; Role; Signal Transduction; Skin; Skin Tissue; Suppressor-Effector T-Lymphocytes; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Tumor-infiltrating immune cells; Wild Type Mouse; Work; career development; cell type; cellular imaging; chronic inflammatory skin; clinical development; cytokine; cytotoxic CD8 T cells; digital; immune activation; improved; keratinocyte; lupus cutaneous; medical schools; mentoring community; mouse model; new therapeutic target; novel; novel therapeutics; receptor; skills; skin disorder; targeted treatment; therapeutic target; transcriptome sequencing; transcriptomics; women of color

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.

项目摘要 盘状红斑狼疮（DLE）是一种慢性炎症性皮肤病，严重损害生活质量 其特征在于毁容疤痕、脱发、瘙痒和疼痛。据估计，DLE影响近 225，000美国人，并对有色人种女性造成严重影响。没有FDA批准的治疗方法， 目前的标签外疗法对许多患者通常无效。DLE的新兴靶向疗法是 早期临床发展，但我们缺乏对致病免疫细胞的全谱了解， 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，并且试验开始靶向pDC用于DLE治疗。我们之前的工作表明 免疫抑制受体V域Ig T细胞活化抑制因子（VISTA）抑制DLE的发生 在鼠MRL/lpr狼疮模型中。VISTA是一种独特的免疫抑制受体，因为它在T细胞上表达 和骨髓细胞亚群。我们发现缺乏VISTA的小鼠自发地发展出DLE样疾病， VISTA的刺激减少了MRL/lpr狼疮小鼠中pDC产生I型干扰素。我们也 研究人员发现，与其他自身免疫性疾病相比，来自人类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中的作用或VISTA在DLE中的功能， pDC。本提案的目标是确定pDC是否对VISTA敲除中的DLE发展至关重要 小鼠、表达VISTA的人DLE、VISTA+ pDC在人DLE中的转录谱以及.在目标1中， 我们将鉴定人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，并通过高水平地执行VISTA+细胞的转录谱来确定VISTA+细胞的转录谱。 多重单细胞成像和空间转录组学。在目标2中，我们将确定涉及的关键单元 在条件性VISTA敲除小鼠中DLE发展中的作用以及使用VISTA抑制pDC的机制 激动剂VISTA抗体。主要研究者Matthew Vesely医学博士是一名皮肤科医生， 耶鲁医学院的免疫学家。他的目标是领导一个独立的学术研究实验室， 自身免疫性皮肤病如DLE的免疫发病机制。他将通过以下方式实现这一目标： 在空间蛋白质组学和原位转录组学数据的生成和分析方面的专业知识; 2）成为 VISTA免疫细胞抑制专家; 3）建立DLE导师和合作者社区 和单细胞成像技术; 4）完成课程，以扩大他的计算和统计 背景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发展自己独特的利基，成为专家 在单细胞成像中，并可能为这些疾病开发新的疗法。