MONOCLONAL ITP AUTOANTIBODIES--PARADIGM FOR AUTOIMMUNITY

单克隆 ITP 自身抗体——自身免疫的范例

• 批准号: 2751779
• 负责人: DONALD Lawrence SIEGEL
• 金额: $ 27.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2751779
• 关键词: autoantibody; autoimmune disorder; clinical research; disease /disorder etiology; genetic library; human subject; human tissue; immunoglobulins; molecular cloning; monoclonal antibody; platelets; thrombocytopenic purpura

The study of autoimmune disease is greatly facilitated by focusing on disorders in which the autoantibodies clearly contribute to the pathogenic process. Because anti-platelet antibodies directly lead to the manifestation of the disease, ITP serves as an excellent model for understanding the pathogenesis of autoimmunity. Clinically, ITP is the most common autoimmune hematologic disorder. It can occur idiopathically or in the context of other disorders of the immune system such as HIV infection, SLE, AIHA and CLL. Therapies aimed directly at modifying the humoral immune response are most frequently utilized, such as steroids and chemotherapy, IVIG, splenectomy and, more experimentally, Staph protein A columns. Despite significant advances in our understanding of ITP, fundamental questions remain unanswered: What causes the breakdown in self-tolerance? Why is ITP associated with those other forms of impaired humoral immune response? Why is there such variability in the natural history and responsiveness to treatment among patient groups? Does IVIG and Rh(D) immune globulin have an antigene-specific mechanism, and why does immunoadsorption on Staph A columns appear effective when plasmapheresis is not? Ultimately, can more specific and reliable forms of therapy be developed? We believe that these clinical observations may be a result of the genetic restriction of these antigen-specific autoantibodies. By determining the spectrum of antigenic specificities and genetic properties of the autoantibody repertoire, one can ask questions regarding the molecular basis for pathogenicity. Earlier technologies were insufficient to determine these relationships. We propose to utilize a powerful new technology known as Fab/phage display to rapidly clone and characterize human platelet autoantibodies and test this hypothesis. The information derived from these studies will provide insight into the role that immune repertoire composition plays in the natural history and therapeutic responsiveness of ITP. This knowledge is critical for the design for future experiments that investigate the regulation of autoimmune responses. A better molecular understanding of the Ig repertoire will comprise the essential first step for the creation of novel approaches for antigen-specific modulation such as tolerance induction, peptide-based inhibitors, and DNA vaccination that induces regulatory T-cell responses. Ultimately, the proposed approach may be applied to the understanding of other autoimmune disorders.

关注自身免疫性疾病的研究将大大促进 自身抗体明显有助于的疾病 致病过程。 因为抗血小板抗体直接导致 疾病的表现，ITP 是一个很好的模型 了解自身免疫的发病机制。临床上，ITP是 最常见的自身免疫性血液病。 它可能会发生 特发性或在其他免疫系统疾病的情况下 例如 HIV 感染、SLE、AIHA 和 CLL。 治疗直接针对 最常用的是改变体液免疫反应，例如 如类固醇和化疗、IVIG、脾切除术等等 实验上，Staph 蛋白 A 柱。尽管取得了重大进展 在我们对 ITP 的理解中，基本问题仍未得到解答： 是什么导致自我宽容崩溃？ 为什么 ITP 与 还有那些其他形式的体液免疫反应受损？ 为什么会有 自然史和治疗反应的这种变异性 在患者群体中？ IVIG 和 Rh(D) 免疫球蛋白有作用吗 抗原基因特异性机制，以及为什么葡萄球菌 A 上的免疫吸附 血浆置换法无效时，色谱柱却显示有效？ 最终可以 是否可以开发出更具体、更可靠的治疗方法？我们相信 这些临床观察结果可能是遗传的结果 这些抗原特异性自身抗体的限制。通过确定 抗原特异性谱和遗传特性 自身抗体库，可以询问有关分子的问题 致病性的依据。早期的技术不足以 确定这些关系。 我们建议利用一个强大的新 称为 Fab/噬菌体展示的技术可快速克隆和表征 人类血小板自身抗体并检验这一假设。信息 从这些研究中得出的结论将有助于深入了解 免疫库成分在自然历史中发挥作用 ITP 的治疗反应。 这些知识对于 为未来研究调控的实验设计 自身免疫反应。 对 Ig 更好的分子理解 剧目将构成创作的重要的第一步 抗原特异性调节（例如耐受性）的新方法 诱导、基于肽的抑制剂和诱导的 DNA 疫苗接种 调节性 T 细胞反应。 最终，所提出的方法可能是 应用于理解其他自身免疫性疾病。