ACTIVATION EVENTS IN TOLERANT AND NORMAL B CELLS

耐受和正常 B 细胞中的激活事件

• 批准号: 3133974
• 负责人: Robert F Ashman
• 金额: $ 18.16万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 1990-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3133974
• 关键词: B lymphocyte; T lymphocyte; antibody formation; antigens; autoimmune disorder; cell morphology; gene expression; growth factor; histocompatibility antigens; immune adherence reaction; immunoglobulin G; immunoglobulin M; immunotherapy; interferons; interleukin 2; laboratory mouse; leukocyte activation /transformation; lymphokines; macrophage; membrane activity; mitogens; monoclonal antibody; monocyte; radiotracer; spleen; tissue /cell culture

Patients with autoimmunity make too much of certain antibodies, especially those directed to "self". Our crude current therapies for these conditions could be greatly improved if we only understood and could manipulate the early events in B lymphocyte activation well enough to turn down specific immune responses to restore self-tolerance. Major accomplishments of cellular immunology in the last decade have been to understand how the antibody response is regulated by a variety of growth and differentiation factors (lymphokines) from T cells and macrophages, and to define several different mechanisms of tolerance. One of those mechanisms is intrinsic tolerance in B cells to attack this problem systematically. We have selected six such events, including significant early, intermediate and late events: 1) membrane depolarization (within 1 hr); 2) increase in cell volume (in less than 1 day); 3) increase in cell surface Ia expression (at about 1 day); 4) accelerated shedding of surface Ig; 5) accelerated replacement of surface IgM and IgG from day 1 to day 4; and 6) progress through the cell cycle to S phase on day 3 to 4. We will show whether these events can be elicited in purified antigen-binding cells from tolerant and nontolerant animals by the following forms of "signal 1": anti-Mu, anti-Gamma, LPS, dextran sulfate, and thymus-independent and dependent antigen. Then we will show how the performance of these early events is affected by the addition of a "second signal" in the form of interleukin 1, B cell growth factors 1 or 2, two T replacing factors from different T cell lines, and interferon. Thus our research has the dual purpose of revealing the impact of lymphokines and intrinsic tolerance on the physiology of the responding B cell.

自身免疫性患者产生过多的某些抗体，特别是 那些指向“自我”的。 我们目前对这些疾病的原始疗法 如果我们能理解并能操纵 B淋巴细胞活化的早期事件足以降低特异性 免疫反应以恢复自身耐受性。 主要成就 在过去的十年里，细胞免疫学一直致力于了解 抗体反应受多种生长和分化的调节 因子（淋巴因子）从T细胞和巨噬细胞，并定义几个 不同的耐受机制。 其中一种机制是内在的 B细胞的耐受性来系统地解决这个问题。 我们有 选择了六个这样的事件，包括重要的早期，中期和 晚期事件：1）膜去极化（1小时内）; 2）细胞凋亡增加 体积（少于1天）; 3）增加细胞表面Ia表达（在 约1天）; 4）加速表面IG脱落; 5）加速 从第1天到第4天的表面IgM和IgG的替换;和6）进展 在第3 - 4天进入S期。 我们将展示 这些事件可以在纯化的抗原结合细胞中引发 耐受性和非耐受性动物通过以下形式的“信号1”： 抗Mu、抗Gamma、LPS、硫酸葡聚糖和胸腺非依赖性， 依赖性抗原 然后我们将展示如何表现这些早期 事件受到以以下形式添加的“第二信号”的影响： 白细胞介素1、B细胞生长因子1或2、两种T替代因子 不同的T细胞系和干扰素。 因此，我们的研究具有双重性， 目的是揭示淋巴因子和内在耐受性对 反应的B细胞的生理机能。