Determine whether an anti-Dsg3 single chain variable fragment antibody (scFv) - P

确定是否存在抗Dsg3单链可变片段抗体（scFv）-P

• 批准号: 7678125
• 负责人: John R Stanley
• 金额: $ 2.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678125
• 关键词: Activated Lymphocyte; Allogenic; Antibodies; Antigens; Apoptosis; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Binding; Cell Culture Techniques; Cell Surface Proteins; Cessation of life; Chimeric Proteins; Chronic; Disease; Disease Progression; Effectiveness; Epidermis; Epithelium; Exposure to; Extracellular Domain; Goals; Human; Immune; Immune response; Immunoglobulin Fragments; Immunosuppressive Agents; In Vitro; Inflammation; Injection of therapeutic agent; Invaded; K-Series Research Career Programs; Lead; Ligands; Lymphocyte Activation; Maintenance; Methods; Mus; Nature; Pathway interactions; Patients; Peripheral; Physiological; Prevention; Proteins; Psoriasis; Regulation; Research; Research Personnel; Screening procedure; Signal Pathway; Signal Transduction; Skin; Surface; System; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Agents; Tissues; United States National Institutes of Health; Virus Diseases; Vitiligo; clinical care; desmoglein III; immunoregulation; in vivo; intravenous injection; keratinocyte; minimally invasive; mouse model; novel; novel strategies; novel therapeutics; prevent; programs; receptor; response; skin xenograft; targeted delivery; tumor

Because of the skin's accessibility, autoimmune diseases of the epidermis, such as vitiligo, are amenable to study using minimally invasive techniques. In addition, potential therapeutic agents can be tested locally. The long-term goal of this project is to develop a novel fusion protein useful for treating autoimmune disorders of the epidermis. Activated T cells, which cause autoimmune destruction, express an immunosuppressive receptor on their surface called Programmed Death-1 (PD-1). PD-Ligand 1 (PD-L1) binds to the PD-1 receptor to generate signals that inactivate T cells. This pathway is important in many physiologic systems, including maintenance of chronic viral infections, tumor immune evasion, and normal tolerance in the prevention of autoimmunity. We have developed a potentially therapeutic molecule consisting of the extracellular domain of PD-L1 that is fused to a non-pathogenic antibody against desmoglein 3 (Dsg3). Because Dsg3 is constitutively expressed on mouse and human keratinocytes, intradermal or intravenous injection of this fusion protein targets the epidermis. By targeting delivery of the immunosuppressive protein PD-L1 to the epidermis, we will determine if we can suppress T cell activation in the epidermis and halt progression of epidermal inflammation or prevent its initial triggering. To test this hypothesis, we will first determine if the fusion protein suppresses a human allogeneic T cell response to cultured primary keratinocytes in vitro. Then, we will test whether local or systemic administration of this fusion protein can arrest onset or progression of disease in a mouse model of vitiligo. Finally, we will confirm that the fusion protein targets human keratinocytes in human skin xenografts on mice. This research has the potential to impact clinical care for patients with autoimmune disorders involving the epidermis and other epithelia. The project will provide preliminary results for an NIH K-award or new investigator RO1 application.

由于皮肤的可及性，表皮的自身免疫性疾病（例如白癜风）可容纳 使用微创技术的研究。另外，可以在本地测试潜在的治疗剂。这 该项目的长期目标是开发一种新型的融合蛋白，可用于治疗自身免疫性疾病 表皮。 激活的T细胞引起自身免疫性破坏，在其上表达免疫抑制受体 表面称为编程死亡-1（PD-1）。 Pd-ligand 1（PD-L1）与PD-1受体结合以产生 信号表明会使T细胞失活。该途径在许多生理系统中都很重要，包括维护 慢性病毒感染，肿瘤免疫逃避和预防自身免疫性的正常耐受性。 我们已经开发了一种潜在的治疗分子，该分子由PD-L1的细胞外域组成 融合了针对Desmoglein 3（DSG3）的非致病性抗体。因为DSG3是组成型表达的 在小鼠和人角质形成细胞上，该融合蛋白的皮内或静脉注射靶向 表皮。通过靶向将免疫抑制蛋白PD-L1递送到表皮上，我们将确定 如果我们可以抑制表皮表皮中的T细胞激活和表皮炎症的停止进展或 防止其初始触发。为了检验该假设，我们将首先确定融合蛋白是否抑制A 人类同种异体T细胞对体外培养的原代角质形成细胞的反应。然后，我们将测试是否本地 或该融合蛋白的全身给药可以在小鼠模型中阻碍疾病的发作或进展 白癜风。最后，我们将确认融合蛋白靶向人皮肤中的人角质形成细胞 小鼠的异种移植物。 这项研究有可能影响涉及自身免疫性疾病的患者的临床护理 表皮和其他上皮。该项目将为NIH K-award或New提供初步结果 研究者RO1应用。