VISTA, a novel regulator of immunity and autoimmunity

VISTA，一种新型免疫和自身免疫调节剂

• 批准号: 8463984
• 负责人: RANDOLPH J. NOELLE
• 金额: $ 52.79万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463984
• 关键词: Agonist; Antigen-Presenting Cells; Autoantigens; Autoimmune Diseases; Autoimmunity; Avidin; CD27 Antigens; CD4 Positive T Lymphocytes; CNS autoimmunity; Cells; Chemicals; Chimeric Proteins; Clinical Trials; Development; Disease; Engineering; Evaluation; Experimental Autoimmune Encephalomyelitis; Extracellular Domain; Family; Family member; Frequencies; Graft Rejection; Hematopoietic; Immune; Immune response; Immunity; Immunoglobulins; Immunology; Immunosuppression; In Vitro; Inflammation; Inflammatory; Intervention; Ligands; Malignant Neoplasms; Maps; Mediator of activation protein; Modeling; Molecular; Monoclonal Antibodies; Mus; Myelin; Myelogenous; Myeloid Cells; Myelopoiesis; Names; Neuraxis; Phylogenetic Analysis; Production; Property; Proteins; Regulatory T-Lymphocyte; Self Tolerance; Signal Transduction; Site-Directed Mutagenesis; T cell response; T-Cell Activation; T-Cell Activation Pathway; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Time; Treatment Efficacy; Ursidae Family; Variant; base; cytokine; design; expression cloning; human disease; in vivo; interest; new therapeutic target; novel; overexpression; receptor; receptor binding; sound; therapeutic development; tumor

DESCRIPTION (provided by applicant): We have discovered, characterized and functionally defined a novel, hematopoietically-restricted, structurally- distinct, Ig-superfamily inhibitory ligand whose extracellular domain bears homology to the B7 family ligand PD- L1 and profoundly impacts on immunity. It is named V-region Immunoglobulin-containing Suppressor of T cell Activation (VISTA). VISTA is exclusively within the hematopoietic compartment, most prominently on myeloid antigen-presenting cells, with lower intensity on CD4+ T cells and a subset of Foxp3+ regulatory T cells (Treg). A soluble VISTA-Ig fusion protein, or natural VISTA profoundly inhibits in vitro T activities and induces Foxp3 expression. A blocking anti-VISTA mab interfered with VISTA-induced suppression and intensified experimental allergic encephalomyelitis (EAE). VISTA-/- mice have early indications of spontaneous inflammatory disease. Unlike all other PD-Ligand-related molecules, the hematopoietic restriction of VISTA together with its profound suppressive activities and unique structural features, illustrates that VISTA is a novel, functionally non-redundant, central, negative regulator of immunity. The Specific Aims of this proposal are: 1. Determine how VISTA suppresses the development of pathogenic encephalitogenic T cells. The mechanisms through which VISTA controls the development of pathogenic, myelin-reactive CD4+ T cells will be determined in mice treated with ¿VISTA, in VISTA-/- or in mice that conditionally express VISTAflox/flox. Such approaches will delineate the function of VISTA expressed on CD4+ T cells, Treg, DCs and myeloid cells in EAE. 2. To perform structural studies on VISTA and define the molecular determinants of VISTA function and assist in producing biologically active VISTA-Ig proteins for therapy. Structural studies will identify the chemical and physical determinants and organizational properties that underlie VISTA function. A distinctive primary sequence signature predicts that VISTA possesses unique features, including a novel variation of the Ig-fold and an unexpected mode of self-association. 3) To map the signaling cascades induced by VISTA and identify the VISTA Receptor (R). We have produced multimeric VISTA molecules that identify VISTA R bearing cells. Through expression cloning the VISTA R will be identified. In addition, the early signaling cascades of VISTA R triggering will be delineated. 4. Target the VISTA pathway for immune intervention in autoimmunity. The purpose of this specific aim is to determine if exaggerated signaling via the VISTA pathway will suppress immunity and exert a therapeutic benefit on autoimmune disease.

描述（由适用提供）：我们已经发现，表征和功能定义了一种新型，造血限制的，结构存在的，ig-superfamily抑制性的配体，其细胞外域与B7家族配体PD-L1具有同源性，并对免疫史产生了深远的影响。它被称为V-区域免疫球蛋白的T细胞激活（VISTA）的抑制。 Vista仅在造血区室内，最突出地在髓样抗原呈递细胞上，CD4+ T细胞的强度较低，而Foxp3+调节性T细胞（Treg）的子集。固体Vista-Ig融合蛋白或天然远景深刻抑制体外T活性并影响FOXP3表达。阻塞抗Vista mAb干扰了Vista诱导的抑制作用，并启发了实验性过敏性脑脊髓炎（EAE）。 Vista - / - 小鼠早期表明发育炎症性疾病。与所有其他与PD配体相关的分子不同，对Vista的造血限制及其深刻的抑制作用和独特的结构特征，表明Vista是一种新颖的，功能性的，非冗余的，中央的，负，负的免疫调节剂。该提案的具体目的是：1。确定远景如何抑制致病性脑源性T细胞的发展。 Vista控制致病性，髓磷脂反应CD4+ T细胞的机制将在用vista，Vista - / - 或有条件表达Vistaflox/Flox的小鼠中确定。这种方法将描述EAE中CD4+ T细胞，Treg，DC和髓样细胞上表达的Vista的功能。 2。对远景进行结构研究并定义远景功能的分子确定剂，并有助于生产具有生物活性的Vista-Ig蛋白进行治疗。结构研究将确定远景起源的化学和物理决定者和组织特性。一个独特的主要序列签名预测，即vista潜力独特的特征，包括Ig折叠的新变化和意外的自我关联方式。 3）绘制远景诱导的信号传导级联反应并识别远景受体（R）。我们产生了鉴定远景细胞的多媒体远景分子。通过表达克隆，将确定远景。此外，将描绘出Vista R触发的早期信号传导级联反应。 4。靶向自身免疫性免疫干预的远景途径。该特定目的的目的是确定通过Vista途径夸张的信号传导是否会抑制免疫学并对自身免疫性疾病产生治疗益处。