Developing non-immunosuppressive immune-based therapeutics for targeted treatment of autoimmune diseases

项目摘要 寻常型天疱疮是一种毁灭性的B细胞介导的自身免疫性疾病。B细胞产生的自身抗体 靶向桥粒蛋白-3(Dsg3)是一种桥粒蛋白，对细胞间黏附至关重要，它负责 以黏膜为主的疾病类型，并在粘膜中引起痛苦的深度侵蚀。抗Dsg3抗体 自身抗体导致角质形成细胞的连接中断，从而导致 水泡和侵蚀。抗Dsg3自身抗体在PV中的直接致病作用已被证实。 单价抗体已被证明足以导致水泡的形成。标准 治疗方法包括在全球范围内抑制免疫系统的免疫抑制药物。这样做的目的是 该项目是开发新的、有针对性的免疫治疗方法，以特定和准确地靶向和 清除识别Dsg3的自身反应性B细胞。已建立的Dsg3特异性自身反应B细胞用于 优化这些方法。我们将使用外周血来确定该方法的有效性和特异性 从疾病不同阶段的PV患者身上获得的单个核细胞(PBMC)，包括治疗- 幼稚和复发，以及体内小鼠的疾病模型。成功完成这项研究将有所帮助 将这些方法转化为临床前阶段，并最终转化为临床环境。生产容易，成本低， 与基于细胞的靶向方法相比，以及与现有的脱靶副作用相比 对PV的治疗使拟议的疗法具有突破性的治疗选择。此外， 开发的技术可直接应用于所有由自身抗体引起的疾病 靶向自身反应细胞，而不会导致全球免疫抑制。

Project Summary Pemphigus vulgaris is a devastating B-cell mediated autoimmune disease. Autoantibodies produced by B cells targeting desmoglein-3 (Dsg3), a desmosomal protein, critical for intercellular adhesion, is responsible for the mucosal-dominant type of the disease and cause painful deep erosions in the mucosa. Anti-Dsg3 autoantibodies result in the disruption of the keratinocytes' connections, and, thereby, cause the formation of blisters and erosions. The direct pathogenic role of anti-Dsg3 autoantibodies in PV has been established. Monovalent antibodies have been shown to be sufficient to result in the formation of blisters. Standard treatments include immunosuppressive drugs that globally suppress the immune system. The goal of this project is to develop novel, targeted, immuno-therapeutic approaches to specifically and precisely target and deplete autoreactive B cells recognizing Dsg3. Established Dsg3 specific autoreactive B cells are used to optimize these methods. We will determine the efficacy and specificity of the approach using peripheral blood mononuclear cells (PBMCs) obtained from PV patients in different phases of the disease, including treatment- naive and relapse, and in vivo mouse models of the disease. Successful completion of this study will help translate the methods into a preclinical and, eventually, a clinical setting. The ease of production, low cost, compared to cell-based targeted approaches, and the lack of off-target side-effects compared to the existing treatments for PV make the proposed therapeutics breakthrough treatment options. Furthermore, the technology developed here can have wider applications to all autoantibody-driven diseases by directly targeting autoreactive cells without causing global immunosuppression.