IMMUNOPATHOGENESIS OF LUPUS

狼疮的免疫发病机制

• 批准号: 6497379
• 负责人: Charles S. Via
• 金额: $ 25.99万
• 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 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497379
• 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患者B细胞过度活跃的观点 是T细胞驱动的;然而，对SLE患者T细胞功能的研究 结果有两个强有力但自相矛盾的发现：辅助性T细胞（Th细胞）增加 功能与降低的细胞毒性T细胞（CTL）功能结合。中央 SLE中尚未解决的问题是Th细胞功能增加是否是由于 CMI中的原发性、允许性缺陷，或者基于Th 1和 Th 2细胞相互交叉调节，受损的CMI是次要后果 持续性Th细胞激活 这两种可能性并不相互排斥，有证据支持 后一种可能性。前一种可能性很难解决， 但是可以直接在鼠SLE的诱导模型中测试， 慢性移植物抗宿主病（GVHD）的亲本转化F1模型。基于我们 发表的工作和初步数据在这个模型中，主要研究者 就CTL在SLE中的作用构建了一个新的假说 发展具体地说，我们假设CD 8 + CTL在 消除自身反应性B细胞，当活化的CD 4 + 对自身反应性B细胞特异的Th细胞出现在缺陷性免疫缺陷的情况下。 CTL功能。通过扩展，抑制成熟CTL发育的药剂 效应子将易患SLE，而促进CTL效应子的药物 发展将抑制SLE的发展。 本提案的总体目标是确定对促进可持续发展至关重要的机制， 体内CTL开发和鉴定CTL成熟和/或 功能会导致SLE。 使用SLE GVHD的亲代入F1模型，研究者将检测这些 在以下具体目标的假设。 具体目标1：鉴定CD 8 + T细胞关键的共刺激分子 活化和CTL诱导。 具体目标2：确定IFN-γ、IL-2、TNF-α和IL-12如何调节CTL 这些细胞因子的缺陷如何导致SLE。 目的3：明确穿孔素和Fas/FasL对T细胞的作用 急性GVHD中自身反应性B细胞的清除以及 这些途径的缺陷。 通过定义体内机制，可以促进SLE，我们将确定 潜在的人类SLE的新治疗方法。