IMMUNOPATHOGENESIS OF LUPUS

狼疮的免疫发病机制

• 批准号: 6628074
• 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/6628074
• 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：最近的证据支持系统性红斑狼疮中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 得出了两个强有力但矛盾的发现：辅助性T细胞(Th)增加 其功能与细胞毒性T细胞(CTL)功能降低有关。一个中环 系统性红斑狼疮患者尚未解决的问题是，Th细胞功能的增加是否源于 CMI中的原发、可允许的缺陷，或者基于Th1和Th1的能力 Th2细胞相互交叉调节，CMI受损是次要后果 持续的Th细胞激活。 这两种可能性并不是相互排斥的，有证据支持 后一种可能性。前一种可能性一直很难在 但可以在诱导的小鼠系统性红斑狼疮模型中直接进行测试， 慢性移植物抗宿主病(GVHD)亲代F1模型。基于我们的 已发表的工作和初步数据在这个模型中，主要研究人员 构建了一个关于CTL在SLE中的作用的新假说 发展。具体地说，我们假设CD8+CTL在 消除自身反应性B细胞，当活化的CD4+时可发展为SLE 自身反应性B细胞特异的TH细胞出现在缺陷的环境中 CTL功能。推而广之，抑制成熟CTL发展的药物 效应器易患系统性红斑狼疮，而促进CTL效应器的药物 发展会抑制SLE的发展。 这项提案的总体目标是确定对 体内CTL的发展和识别CTL成熟和/或哪些缺陷 功能会导致系统性红斑狼疮。 使用SLE GVHD的Parent-Into-F1模型，研究人员将测试这些 假设有以下几个具体目标。 特定目标1：确定对CD8+T细胞至关重要的共刺激分子 激活和CTL诱导。 特定目标2：确定干扰素-g、白介素2、肿瘤坏死因子-α和白介素12如何调节CTL 以及这些细胞因子的缺陷如何导致系统性红斑狼疮。 特定目标3：确定穿孔素和Fas/FasL对T细胞的作用 急性移植物抗宿主病患者自身反应性B细胞的消除及其后果 这些通路中的缺陷。 通过定义可以促进SLE的体内机制，我们将发现 人类系统性红斑狼疮潜在的新治疗方法。