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.

通过关注自身免疫性疾病的研究大大促进了 自身抗体显然有助于疾病 致病过程。 因为抗血小板抗体直接导致 疾病的表现，ITP是一个极好的模型 了解自身免疫的发病机理。临床上，ITP是 最常见的自身免疫性血液学障碍。 它可能发生 特发性或在免疫系统的其他疾病的背景下 例如HIV感染，SLE，AIHA和CLL。 直接针对的疗法 修改体液免疫反应最常使用，例如 作为类固醇和化学疗法，IVIG，脾切除术以及更多 在实验上，葡萄球蛋白A色谱柱。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决： 是什么导致自我耐受的崩溃？ 为什么ITP与 那些其他形式的体液免疫反应受损？ 为什么在那里 自然历史上的这种差异和对治疗的反应 在患者组中？ IVIG和RH（D）免疫球蛋白是否具有 抗基因特异性机制，为什么在葡萄球菌上进行免疫吸附 血浆置换不到时，列显得有效？ 最终，可以 开发更具体和可靠的治疗形式？我们相信 这些临床观察可能是遗传的结果 这些抗原特异性自身抗体的限制。通过确定 抗原特异性和遗传特性的光谱 自动抗体曲目，可以提出有关分子的问题 致病性的基础。较早的技术不足 确定这些关系。 我们建议利用一个强大的新 被称为Fab/Phage显示器的技术快速克隆和表征 人血小板自身抗体并检验该假设。信息 从这些研究中得出的将洞悉 免疫曲目组成在自然史上发挥了作用 ITP的治疗反应性。 这些知识对 对未来的实验设计的设计，以调查调节 自身免疫反应。 对IG的更好分子理解 曲目将构成创建的重要第一步 抗原特异性调制（例如耐受性）的新方法 诱导，基于肽的抑制剂和DNA疫苗接种的诱导 调节性T细胞响应。 最终，拟议的方法可能是 应用于对其他自身免疫性疾病的理解。