The Mechanism of IVIG Action in Pemphigus

IVIG 对天疱疮的作用机制

• 批准号: 6890262
• 负责人: Zhi Liu
• 金额: $ 32.44万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890262
• 关键词: antibody receptor; cell proliferation; clinical research; disease /disorder model; enzyme linked immunosorbent assay; genetically modified animals; human tissue; immunoglobulin G; immunopharmacology; intravenous administration; keratosis; laboratory mouse; laboratory rabbit; pemphigus; pharmacokinetics; protein degradation; receptor binding; recombinant proteins

DESCRIPTION (provided by applicant): High-dose intravenous immunoglobulin (IVIG) has been shown to be effective for the treatment of a variety of immune-mediated inflammatory diseases. Numerous mechanisms have been proposed to explain the mode of action of IVIG. In this application, we propose to investigate the molecular basis for the protective property of IVIG in the autoimmune blistering diseases pemphigus and pemphigoid. Pemphigus and pemphigoid are a group of potentially fatal organ specific autoimmune diseases. Pemphigus is characterized by intraepidermal blisters and epidermal-specific IgG autoantibodies. Pemphigoid is characterized by subepidermal blisters and autoantibodies against hemidesmosomal and extracellular matrix components in the basement membrane zone (BMZ). In this proposal, we will focus on three clinical entities: pemphigus foliaceus (PF), pemphigus vulgaris (PV), and bullous pemphigoid (BP). We will use well-characterized IgG passive transfer and active animal models for these diseases to test a hypothesis that infused WIG prevents IgG antibody-mediated blistering diseases by binding and blocking FcRn, the protection receptor for IgG catabolism, which leads to accelerated clearance of pathogenic IgG. In Aim 1, we will determine whether therapeutic doses of IVlG block blisters in experimental PF, PV, BP, and MMP. In Aim 2, we will determine whether the protective property of IVlG in these disease models depends on FcRn. We will induce skin disease in FcRn-deficient mice with IVIG treatment. In Aim 3, we will determine whether IgG Fc fragments can replace IVIG and FcRn inhibitory peptides are therapeutic. The overall goal of this project is to study the mechanisms of WIG action in autoantibody-mediated diseases and develop novel therapies to replace current immunosuppressive treatments, which confer severe side effects.

描述（由申请人提供）： 高剂量静脉注射免疫球蛋白（IVIG）已被证明可有效治疗多种免疫介导的炎症性疾病。已经提出了多种机制来解释 IVIG 的作用模式。在此应用中，我们打算研究 IVIG 在自身免疫性水疱性疾病天疱疮和类天疱疮中的保护特性的分子基础。天疱疮和类天疱疮是一组可能致命的器官特异性自身免疫性疾病。天疱疮的特征是表皮内水疱和表皮特异性 IgG 自身抗体。类天疱疮的特征是表皮下水疱和针对基底膜区 (BMZ) 中半桥粒和细胞外基质成分的自身抗体。在本提案中，我们将重点关注三种临床实体：落叶型天疱疮（PF）、寻常型天疱疮（PV）和大疱性类天疱疮（BP）。我们将使用针对这些疾病的良好表征的 IgG 被动转移和主动动物模型来检验这样一个假设：注入 WIG 通过结合和阻断 FcRn（IgG 分解代谢的保护受体）来预防 IgG 抗体介导的水疱性疾病，从而加速清除病原体免疫球蛋白G。在目标 1 中，我们将确定治疗剂量的 IVIG 是否可以阻止实验性 PF、PV、BP 和 MMP 中的水泡。在目标 2 中，我们将确定 IVIG 在这些疾病模型中的保护特性是否取决于 FcRn。我们将通过 IVIG 治疗在 FcRn 缺陷小鼠中诱发皮肤病。在目标 3 中，我们将确定 IgG Fc 片段是否可以替代 IVIG 和 FcRn 抑制肽是否具有治疗作用。该项目的总体目标是研究 WIG 在自身抗体介导的疾病中的作用机制，并开发新的疗法来取代目前具有严重副作用的免疫抑制治疗。