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，如白癜风，易于发生。 使用微创技术进行研究。此外，潜在的治疗剂可以在当地进行测试。的 该项目的长期目标是开发一种用于治疗自身免疫性疾病的新型融合蛋白， 表皮 激活的T细胞，引起自身免疫性破坏，在它们的细胞膜上表达免疫抑制受体。 程序性死亡-1（PD-1）PD-配体1（PD-L1）与PD-1受体结合以产生 发出的信号。这条通路在许多生理系统中很重要，包括维持 慢性病毒感染、肿瘤免疫逃避和正常耐受在预防自身免疫中的作用。 我们已经开发了一种由PD-L1胞外结构域组成的潜在治疗分子， 与抗桥粒芯糖蛋白3（Dsg 3）的非致病性抗体融合。因为Dsg 3是组成型表达的， 在小鼠和人角质形成细胞上，皮内或静脉内注射该融合蛋白靶向 表皮通过将免疫抑制蛋白PD-L1靶向递送至表皮，我们将确定 如果我们能抑制表皮中的T细胞活化，阻止表皮炎症的进展， 防止其初始触发。为了验证这一假设，我们将首先确定融合蛋白是否抑制了一种新的蛋白质。 人同种异体T细胞对体外培养的原代角质形成细胞的应答。然后，我们将测试本地是否 或全身施用该融合蛋白可以阻止小鼠模型中疾病的发作或进展 白癜风的症状最后，我们将确认融合蛋白靶向人类皮肤中的人类角质形成细胞 小鼠异种移植物。 这项研究有可能影响自身免疫性疾病患者的临床护理， 表皮和其他上皮细胞。该项目将为NIH K奖或新的 研究者RO 1应用程序。