IMMUNOPATHOGENESIS OF LUPUS

狼疮的免疫发病机制

• 批准号: 6700214
• 负责人: Charles S. Via
• 金额: $ 8.86万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2004-07-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6700214
• 关键词: B lymphocyte; CD95 molecule; cytotoxic T lymphocyte; developmental immunology; graft versus host disease; helper T lymphocyte; immunopathology; interferon gamma; interleukin 12; interleukin 2; laboratory mouse; leukocyte activation /transformation; systemic lupus erythematosus; tumor necrosis factor alpha

DESCRIPTION: Recent evidence supports the idea that B cell hyperactivity in SLE is T cell driven; however, studies of T cell function in SLE patients have yielded two robust yet paradoxical findings: increased T helper (Th) cell function in conjunction with reduced cytotoxic T cell (CTL) function. A central unresolved question in SLE is whether increased Th cell function results from a primary, permissive defect in CMI or whether, based on the ability of Th1 and Th2 cells to cross regulate each other, impaired CMI is a secondary consequence of persistent Th cell activation. The two possibilities are not mutually exclusive and evidence exists to support the latter possibility. The former possibility has been difficult to address in humans but can be directly tested in an induced model of murine SLE, the parent-into-F1 model of chronic graft-versus-host disease (GVHD). Based on our published work and preliminary data in this model, the principal investigator has constructed a novel hypothesis regarding the role of CTL in SLE development. Specifically, we hypothesize that CD8+ CTL play a critical role in eliminating auto-reactive B cells and that SLE can develop when activated CD4+ Th cells specific for auto-reactive B cells arise in the setting of defective CTL function. By extension, agents that inhibit the development of mature CTL effectors will predispose to SLE whereas agents that promote CTL effector development will inhibit SLE development. The overall goal of this proposal is to identify the mechanisms critical for in vivo CTL development and identify which defects in CTL maturation and/or function will result in SLE. Using the parent-into-F1 model of SLE GVHD, the investigator will test these hypotheses in the following specific aims. Specific Aim 1: Identify the co-stimulatory molecules critical for CD8+ T cell activation and CTL induction. Specific Aim 2: Determine how IFN-g, IL-2, TNF-a, and IL-12 regulate CTL development and how defects in these cytokines result in SLE. Specific Aim 3: Define the contributions of perforin and Fas/FasL to T cell elimination of auto-reactive B cells in acute GVHD and the consequences of defects in these pathways. By defining the in vivo mechanisms that can promote SLE we will identify potentially new therapeutic approaches for human SLE.

描述：最近的证据支持 SLE 中 B 细胞过度活跃的观点 由 T 细胞驱动；然而，对 SLE 患者 T 细胞功能的研究 产生了两个强有力但矛盾的发现：辅助性 T (Th) 细胞增加 与细胞毒性 T 细胞 (CTL) 功能降低相结合。一个中央 SLE 中尚未解决的问题是 Th 细胞功能增加是否是由 CMI 中的原发性、允许性缺陷或是否基于 Th1 和 Th2 细胞相互交叉调节，CMI 受损是次要结果 持续 Th 细胞激活。 这两种可能性并不相互排斥，并且有证据支持 后一种可能性。前一种可能性很难解决 人类，但可以直接在小鼠 SLE 诱导模型中进行测试， 慢性移植物抗宿主病（GVHD）的亲本进入F1模型。基于我们的 首席研究员在该模型中发表的工作和初步数据 构建了关于 CTL 在 SLE 中的作用的新假设 发展。具体来说，我们假设 CD8+ CTL 在 消除自身反应性 B 细胞，当 CD4+ 被激活时，系统性红斑狼疮 (SLE) 就会发生 自身反应性 B 细胞特异性的 Th 细胞出现在有缺陷的环境中 CTL功能。推而广之，抑制成熟 CTL 发育的药物 效应子易患 SLE，而促进 CTL 效应子的药物 的发展会抑制 SLE 的发展。 该提案的总体目标是确定对以下方面至关重要的机制： 体内 CTL 发育并确定 CTL 成熟中的哪些缺陷和/或 功能将导致 SLE。 使用 SLE GVHD 的亲代-F1 模型，研究者将测试这些 提出以下具体目标的假设。 具体目标 1：鉴定对 CD8+ T 细胞至关重要的共刺激分子 激活和CTL诱导。 具体目标 2：确定 IFN-g、IL-2、TNF-a 和 IL-12 如何调节 CTL 发育以及这些细胞因子的缺陷如何导致系统性红斑狼疮。 具体目标 3：定义穿孔素和 Fas/FasL 对 T 细胞的贡献 急性 GVHD 中自身反应性 B 细胞的消除及其后果 这些途径的缺陷。 通过定义可促进 SLE 的体内机制，我们将确定 人类 SLE 的潜在新治疗方法。