VISTA is a negative checkpoint regulator of innate immunity

VISTA 是先天免疫的负向检查点调节剂

基本信息

批准号：
10159197
负责人：
Rodwell Mabaera
金额：
$ 80.45万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-06 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10159197
关键词：
Address Adhesions Anti-Inflammatory Agents Antibodies Apoptosis Arthritis Autoimmune Autoimmune Diseases Binding Biochemistry Biology CTLA4 gene Cells Chemotaxis Chromatin Clinical Conceptions Data Development Disease Disease model Epigenetic Process Event Gene Expression Gene Expression Profile Gene Expression Profiling Genetic Genetic Transcription Glomerulonephritis Heterogeneity Histologic Human Immune Immune Targeting Immunoglobulins Immunology Immunosuppression Inflammation Inflammation Mediators Inflammatory Innate Immune System K/BxN model Kidney Kidney Diseases Kinetics Ligands Lupus Malignant Neoplasms Mediating Mediator of activation protein Methods Modeling Molecular Monoclonal Antibodies Mus Myelogenous Myeloid Cells Natural Immunity Neutrophil Activation PTPRC gene Paralysed Pathology Pathway interactions Penetration Phagocytosis Phase Phenotype Play Positioning Attribute Production Receptor Signaling Regulation Resolution Respiratory Burst Role Septic Shock Signal Pathway Signal Transduction Suppressor-Effector T-Lymphocytes T-Cell Activation Therapeutic Tissues adaptive immunity autoimmune pathogenesis chemokine chemokine receptor chronic autoimmune disease density design experimental study genetic signature human disease in vivo insight intravital imaging intravital microscopy joint inflammation macrophage migration monocyte multiplexed imaging neutrophil novel prevent programmed cell death protein 1 programs receptor receptor expression single-cell RNA sequencing success therapeutic target therapeutically effective transcription factor transcriptome transcriptome sequencing

项目摘要

The overwhelming success of blocking negative checkpoint regulators (NCR; e.g. CTLA-4, PD-1) in cancer has irrefutably validated NCRs as effective therapeutic targets in unleashing adaptive immunity in humans. We now present compelling evidence that V-domain Ig suppressor of T cells (VISTA), in addition to its role in regulating adaptive immunity, is a central negative regulator of innate immunity. Anti-VISTA mabs that trigger through VISTA disrupt neutrophil and macrophage chemotaxis, alter the myeloid transcriptome and program myeloid cells to an anti-inflammatory phenotype. Accordingly, anti-VISTA administration profoundly mitigates pathology in autoimmune disease models mediated by the innate immune system. This proposal will comprehensively address the impact of checkpoint regulation by VISTA on the genetics, epigenetics, biochemistry and immunology of myeloid-mediated inflammation. SA#1. VISTA is expressed on neutrophils at very high densities and we propose that VISTA is a central NCR of neutrophil activities. Data show that anti-VISTA triggering ablates their chemotactic activities to inflammatory chemokines and arrests neutrophil-mediated inflammation in vivo. A comprehensive analysis of VISTA negative regulation of neutrophil activation (chemotaxis, rolling, adhesion, NETs, etc.) will be performed. Unparalleled mechanistic insights into the therapeutic impact of anti-VISTA in the neutrophil-mediated K/BxN arthritis model will be provided by intravital microscopy in treated mice. SA#2. VISTA acts as an NCR in monocytes and the mechanisms by which VISTA re-programs their biology will be characterized. Within the macrophage lineage, we show that VISTA signaling directs macrophages to an anti- inflammatory program. Defined by either macrophage tolerance or enhanced M1àM2 transition, VISTA elicits a well-defined transcriptional and functional program that is anti-inflammatory. We propose that triggering through VISTA can instruct myeloid reprogramming through the induction of a unique, VISTA-specific transcriptional profile that ablates myeloid chemotaxis, mediator production and inflammation. SA#3. Anti-VISTA ameliorates lupus by diminishing myeloid migration into the kidney and re-programming the inflammatory profile of infiltrating myeloid cells. A correlation between the therapeutic impact of anti-VISTA and the treatment-induced changes in myeloid heterogeneity and gene expression at the single cell level within the kidney will be established. Furthermore, a comprehensive understanding of how anti-VISTA alters chemokine-dependent positioning and the histological landscape of myeloid cells in the diseased kidney will be afforded by multiplex imaging of myeloid subsets in anti-VISTA treated NZB/NZW F1 mice. Together, these two approaches will offer unique insights into the negative regulation of innate immunity by VISTA in the pathogenesis of autoimmune kidney disease. In summary, the experiments outlined herein will solidify the emerging role of VISTA as a critical NCR in innate immunity.

阴性阻断检查点调节因子（NCR；例如 CTLA-4、PD-1）在癌症治疗中取得了巨大成功我们现在无可辩驳地证实 NCR 是释放人类适应性免疫的有效治疗靶点。提供令人信服的证据表明，T 细胞的 V 结构域 Ig 抑制因子 (VISTA) 除了在调节适应性免疫是先天免疫的中央负调节因子，通过触发。 VISTA 破坏中性粒细胞和巨噬细胞趋化性，改变骨髓转录组并程序化骨髓因此，抗 VISTA 给药可显着减轻病理学变化。该提案将全面研究先天免疫系统介导的自身免疫疾病模型。解决 VISTA 检查点调节对遗传学、表观遗传学、生物化学和 SA#1 在中性粒细胞上以非常高的密度表达。我们认为 VISTA 是中性粒细胞活动的中心 NCR 数据显示抗 VISTA 触发消融。它们对炎症趋化因子具有趋化活性，并抑制体内中性粒细胞介导的炎症。综合分析VISTA对中性粒细胞激活的负调控（趋化性、滚动性、粘附性、 NETs等）将对抗VISTA的治疗影响进行无与伦比的机制洞察。中性粒细胞介导的 K/BxN 关节炎模型将通过 SA#2 的活体显微镜提供。作为单核细胞中的 NCR，VISTA 重新编程其生物学的机制将是在巨噬细胞谱系中，我们发现 VISTA 信号传导将巨噬细胞导向抗- VISTA 可以通过巨噬细胞耐受性或增强的 M1àM2 转变来定义。我们建议触发一个明确的转录和功能程序，具有抗炎作用。通过 VISTA 可以通过诱导独特的 VISTA 特异性来指导骨髓重编程消除骨髓趋化性、介质产生和炎症的转录谱。通过减少骨髓迁移到肾脏并重新编程炎症谱来改善狼疮抗 VISTA 的治疗效果与治疗诱导之间的相关性。肾脏内单细胞水平的骨髓异质性和基因表达的变化将进一步建立了对抗 VISTA 如何改变趋化因子依赖性的全面了解。多重分析将提供患病肾脏中骨髓细胞的定位和组织学景观这两种方法将共同提供抗 VISTA 治疗的 NZB/NZW F1 小鼠的骨髓亚群成像。 VISTA对先天免疫负调节在自身免疫发病机制中的独特见解总之，本文概述的实验将巩固 VISTA 作为关键药物的新兴作用。先天免疫中的NCR。