ANALYSIS OF ANTIBODY AGGREGATION AND ITS EFFECTS

抗体聚集及其影响分析

• 批准号: 3288504
• 负责人: BYRON B GOLDSTEIN
• 金额: $ 11.85万
• 依托单位: UNIVERSITY OF CALIF-LOS ALAMOS NAT LAB
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-04-01 至 1991-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3288504
• 关键词: antibody receptor; antigen antibody reaction; antinuclear autoantibody; basophils; binding proteins; blocking antibody; chemical binding; chemical reaction; crosslink; cyclization; cytoskeleton; haptens; histamine release; hypersensitivity desensitization; immunoglobulin E; laser spectrometry; leukocyte activation /transformation; mathematical model; membrane activity; model design /development; monoclonal antibody; phagocytosis; pinocytosis; receptor mediated endocytosis; systemic lupus erythematosus

This proposal is concerned with the aggregation of antibodies on cell surfaces and in solution, and their biological effects. Aggregation of cell surface immunoglobulin (sIg) generates signals that both activate and deactivate B lymphocytes, basophils and mast cells. Our long range goal is to quantitatively understand such signals, and in so doing understand how antigens in allergic reactions activate and desensitize basophils and mast cells. Our approach is to study simple in vitro model systems, to develop mathematical models to describe these systems, and to test these mathematical models against experiment. The role of the mathematical models is to help rigorously test ideas about the system, aid in analyzing experiments, determine parameter values, and suggest new experiments. To study sIg signal generation the project focuses on rat basophilic leukemia (RBL) cells sensitized with hapten-specific monoclonal immunoglobulin E (IgE). Bivalent haptens of different lengths and flexibilities are used to aggregate sIgE. A specific aim is to characterize the binding properties of these bivalent haptens for a few monoclonal IgEs, by using mathematical models to analyze kinetic binding data and obtain rate constants for binding, crosslinking and ring formation. With these constants one can predict how the distribution of sIgE aggregates changes with time. This will be a useful tool in determining what properties of an IgE aggregate make it an effective initiator of a particular response. The RBL cell responses to be studied are degranulation, cytoskeletal interactions, internalization and desensitization. In many in vivo situations, in addition to antigen and specific sIg, solution antibody is present that can bind the antigen. The sera of many allergic individuals contain "blocking" antibody that competes with their specific IgE for antigen. Our goal is to predict under what conditions solution antibody blocks IgE aggregate formation and prevents histamine release and under what conditions it promotes aggregate formation and enhances release. Another type of aggregation process that has quite different biological consequences, occurs in the autoimmune disease systemic lupus erythematosis (SLE) where anti-DNA antibodies bind to DNA in solution. Our aim is to extend the mathematical models of aggregation to anti-DNA/DNA complex formation and develop theories to be used to analyze a variety of antibody/DNA binding experiments.

该提案与抗体的聚集有关 细胞表面和溶液及其生物学作用。 细胞表面免疫球蛋白（SIG）的聚集产生信号 激活和失活的B淋巴细胞，嗜碱性粒细胞和 肥大细胞。 我们的远程目标是定量理解 这样的信号，因此确实了解过敏反应中的抗原 反应激活并脱敏嗜碱性粒细胞和肥大细胞。 我们的 方法是研究简单的体外模型系统，以开发 数学模型来描述这些系统，并测试这些系统 针对实验的数学模型。 角色 数学模型是为了帮助严格测试有关 系统，帮助分析实验，确定参数 值，并提出新的实验。 为了研究SIG信号的生成，该项目的重点是大鼠 嗜碱性白血病（RBL）细胞与触觉特异性敏感 单克隆免疫球蛋白E（IgE）。 二价触觉不同 长度和灵活性用于汇总sige。 特定的 目的是表征这些二价的结合特性 使用数学模型，用于几个单克隆IGE的触觉 分析动力学结合数据并获得速率常数 结合，交联和环形成。 使用这些常数 可以预测SIGE聚集物的分布如何随着 时间。 这将是确定哪些属性的有用工具 IgE总体使其成为特定的有效启动者 回复。 要研究的RBL细胞反应是脱粒的， 细胞骨架相互作用，内在化和脱敏。 在许多体内情况下，除了抗原和特定的SIG外， 存在可以结合抗原的溶液抗体。 血清 许多过敏的个体都包含“阻断”抗体 与他们的特定IgE抗原竞争。 我们的目标是 预测在哪些条件下溶液抗体阻断IgE 骨料形成并防止组胺释放和下方 它促进骨料形成并增强的哪些条件 发布。 另一类的聚合过程完全不同 生物学后果发生在自身免疫性疾病中 抗DNA抗体的全身性红斑狼疮（SLE） 与溶液中的DNA结合。 我们的目标是扩展数学 抗DNA/DNA复合物形成的聚集模型和 开发用于分析各种抗体/DNA的理论 结合实验。