REGULATION OF AUTOIMMUNITY BY MODULATING ANTIGEN PROCESS

通过调节抗原过程来调节自身免疫

• 批准号: 2793470
• 负责人: KAMAL D MOUDGIL
• 金额: $ 8.95万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 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 1999-10-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2793470
• 关键词: T lymphocyte; active immunization; antigen presentation; antigen presenting cell; autoantigens; autoimmunity; cathepsin D; chemical cleavage; cyanogen bromide; cytokine; flow cytometry; interferon gamma; interleukin 12; interleukin 4; interleukin 6; laboratory rat; lymphocyte proliferation; mutant; protein structure function; rheumatoid arthritis; site directed mutagenesis; stress proteins; tissue /cell culture; tumor necrosis factor alpha

One of the major experimental approaches that has been widely employed for preventing abnormal responses to self antigens is based on deliberate induction of T cell tolerance to a potentially pathogenic self determinant in the neonatal and/or adult period of life of the animal. The rationale for this approach was to inactivate (either physically or functionally) the T cell subset potentially directed against the pathogenic self determinant of a given autoantigen. In this proposal, we describe a novel approach for immunological control of autoimmunity: it involves deliberate induction of determinant-specific T cell response for regulation of autoimmunity by altering antigen processing and presentation. This can be achieved by modulating the function of the antigen presenting cells (APC) as well as by changing the physical form of the immunogen. Our recent studies in adjuvant arthritis (AA) have shown that during the course of AA (in the late phase) in the Lewis rat, there was diversification of the T cell response to the C-terminal determinants of the 65-kD mycobacterial heat shock protein (Bhsp65), and that Bhsp65 C-terminal determinants (BCTD) are involved in natural remission from acute inflammatory arthritis. However, under normal circumstances (in the absence of inflammation or disease) these BCTD are poorly, if at all processed and presented (cryptic determinants) from Bhsp65. Therefore, the beneficial effect of BCTD in the case of AA-susceptible Lewis rats could only be harnessed if the antigen processing of Bhsp65 were altered in such a way that following challenge with this antigen, Lewis rats raised an early and vigorous response to BCTD. We will explore three different approaches to enhance the display of BCTD within Bhsp65-- a) treatment of APC by interferon-g/interleukin-12 (IL-12)/IL-4/IL-6 etc.; b) altering the physical form of Bhsp65 by mild digestion with different cathepsins or cleavage by cyanogen bromide, and c) introduction at defined positions within Bhsp65 of 'dibasic' sites, which are targets of a subset of proteolytic enzymes. Finally, one or more of these approaches will be tested for their ability to prevent and/or treat AA in the Lewis rat. We believe that such a predetermined, experimentally programmed display hierarchy of regulatory determinants would pave the way for novel immunotherapeutic strategies for prevention and treatment of arthritis and other autoimmune diseases.

已广泛采用的主要实验方法之一 预防对自身抗原的异常反应的基础是 有意诱导 T 细胞对潜在致病性的耐受性 新生儿和/或成人时期的自我决定 动物。 这种方法的基本原理是灭活（要么 物理上或功能上）潜在定向的 T 细胞亚群 对抗给定自身抗原的致病性自身决定因素。 在这个 提议，我们描述了一种免疫控制的新方法 自身免疫：它涉及故意诱导特定决定簇 通过改变抗原调节自身免疫的 T 细胞反应 处理和呈现。 这可以通过调制来实现 抗原呈递细胞（APC）的功能以及通过改变 免疫原的物理形式。 我们最近在佐剂方面的研究 关节炎 (AA) 已表明，在 AA 病程中（晚期） Lewis 大鼠中，T 细胞出现多样化 对 65-kD 分枝杆菌热的 C 末端决定因素的反应 休克蛋白 (Bhsp65) 和 Bhsp65 C 末端决定簇 (BCTD) 参与急性炎症性关节炎的自然缓解。 然而，在正常情况下（在没有炎症或没有炎症的情况下） 疾病）这些 BCTD 的处理和呈现很差（如果有的话） （神秘的决定因素）来自 Bhsp65。因此，有益效果 对于 AA 敏感的 Lewis 大鼠，只能利用 BCTD 如果 Bhsp65 的抗原加工方式发生改变 在受到这种抗原的攻击后，Lewis 大鼠早期和 对BCTD的强烈反应。 我们将探索三种不同的方法 增强 Bhsp65 内 BCTD 的展示——a) APC 的处理 干扰素-g/白细胞介素-12(IL-12)/IL-4/IL-6等； b) 改变 Bhsp65 的物理形式，通过不同的组织蛋白酶或 通过溴化氰裂解，以及 c) 在指定位置引入 在“二元”位点的 Bhsp65 内，这些位点是 蛋白水解酶。最后，将采用其中一种或多种方法 测试了它们预防和/或治疗 Lewis 大鼠 AA 的能力。 我们相信这种预先确定的、经过实验编程的显示 监管决定因素的层次结构将为创新铺平道路 预防和治疗关节炎的免疫治疗策略 和其他自身免疫性疾病。