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

由于皮肤的可及性，表皮的自身免疫性疾病，如白癜风，容易发生 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。这个 该项目的长期目标是开发一种新的融合蛋白，用于治疗自身免疫性疾病 表皮。 激活的T细胞会导致自身免疫破坏，其表面表达一种免疫抑制受体 表面称为程序性死亡-1(PD-1)。PD-L1与PD-1受体结合生成 使T细胞失活的信号。这一途径在许多生理系统中都很重要，包括维持 慢性病毒感染、肿瘤免疫逃避和预防自身免疫的正常耐受性。 我们已经开发出一种潜在的治疗分子，它由PD-L1的胞外结构域组成，即 与抗桥粒芯糖蛋白3(Dsg3)的非致病抗体融合。因为Dsg3是结构性表达的 在小鼠和人类角质形成细胞上，皮内或静脉注射该融合蛋白可以靶向 表皮。通过将免疫抑制蛋白PD-L1靶向输送到表皮，我们将确定 如果我们能抑制表皮中T细胞的激活，阻止表皮炎症的进展，或者 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 体外培养的人同种异体T细胞对原代角质形成细胞的反应。然后，我们将测试当地是否 或全身给药这种融合蛋白可以阻止小鼠模型中疾病的发生或发展 白癜风的症状。最后，我们将确认融合蛋白针对人体皮肤中的角质形成细胞。 小鼠的异种移植。 这项研究有可能影响自身免疫性疾病患者的临床护理，包括 表皮和其他上皮细胞。该项目将提供NIH K-奖或新的 调查员RO1应用程序。

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.