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MONOCLONAL ITP AUTOANTIBODIES--PARADIGM FOR AUTOIMMUNITY

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:
依托单位国家:
美国
项目类别:
财政年份:
1998
资助国家:
美国
项目状态:
已结题
起止时间:
1998-09-30 至 2003-08-31

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中文摘要
翻译
对自身免疫性疾病的研究主要集中在 自身抗体明显导致的疾病 致病过程。因为抗血小板抗体直接导致 这种疾病的表现,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 特发性的或在其他免疫系统紊乱的情况下 如HIV感染、SLE、AIHA和CLL。治疗的直接目标是 修改体液免疫反应是最常用的方法,例如 如类固醇和化疗、静脉注射免疫球蛋白、脾切除术等 实验上,葡萄球菌蛋白A柱。尽管取得了重大进展 在我们对ITP的理解中,基本问题仍然没有得到回答: 是什么导致了自我容忍的崩溃?为什么ITP与 还有其他形式的体液免疫反应受损吗?为什么会有 自然历史中的这种变异性和对治疗的反应 在患者群体中?IVIG和Rh(D)免疫球蛋白是否具有 抗基因特异性机制,以及为什么免疫吸附在葡萄球菌A上 当血浆置换不是有效的时候,柱似乎是有效的?最终,我们可以 开发更具体、更可靠的治疗方法?我们相信 这些临床观察可能是基因突变的结果 限制这些抗原特异性自身抗体。通过确定 猪瘟病毒的抗原特异谱和遗传特性 自身抗体曲目,人们可以问关于分子的问题 致病性的基础。早期的技术不足以 确定这些关系。我们建议利用一种强大的新技术 一种称为Fab/噬菌体展示的技术,用于快速克隆和鉴定 人类血小板自身抗体,并验证这一假设。这些信息 从这些研究中得出的结论将为我们深入了解 免疫曲目组合在自然历史和 ITP的治疗反应性。这方面的知识对于 为未来的实验设计,以研究对 自身免疫反应。对免疫球蛋白有更好的分子理解 《剧目》将构成创作《 抗原特异性调节的新方法,如耐受性 诱导、基于多肽的抑制剂和DNA疫苗诱导 调节性T细胞反应。最终,拟议的方法可能是 应用于了解其他自身免疫性疾病。
英文摘要
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.
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Core B - Cell Engineering and Manufacturing Facility
  • 批准号:
    10713204
  • 项目类别:
  • 资助金额:
    $46.91万
  • 财政年份:
    2017
  • 负责人:
    DONALD Lawrence SIEGEL
  • 依托单位:
Core B: GMP Cell and RNA Manufacturing
  • 批准号:
    9982248
  • 项目类别:
  • 资助金额:
    $17.9万
  • 财政年份:
    2017
  • 负责人:
    DONALD Lawrence SIEGEL
  • 依托单位:
Core B: GMP Cell and RNA Manufacturing
  • 批准号:
    10245069
  • 项目类别:
  • 资助金额:
    $23.58万
  • 财政年份:
    2017
  • 负责人:
    DONALD Lawrence SIEGEL
  • 依托单位:
Phage Display Tools for Automated Blood Typing
  • 批准号:
    6890818
  • 项目类别:
  • 资助金额:
    $10.0万
  • 财政年份:
    2003
  • 负责人:
    DONALD Lawrence SIEGEL
  • 依托单位:
海外基金