Immunopathogenesis of Lupus

描述(申请人提供)：系统性红斑狼疮是一种发病率和死亡率都很高的多系统疾病。目前的治疗与显著的副作用有关。这一应用追求一种新的假设，即细胞毒性T淋巴细胞(CTL)是一种重要的早期机制，通过消除激活的自身反应性B细胞来限制对核抗原的耐受性的破坏，并防止狼疮的发生。这一假设得到了亲本转化F1模型的验证，在该模型中，通过转移亲本品系的CD4+T细胞，在正常的F1小鼠中诱导了狼疮样疾病。由于供者CD8+CTL清除了激活的自身反应性宿主B细胞，因此在转移CD4+和CD8+T亲代细胞的过程中没有观察到狼疮。在之前的资助期间，首席研究人员观察到，穿孔素缺乏的供体细胞会导致宿主B细胞的CTL清除受损，从而导致长期狼疮。这些结果支持一种新的范式，即CTL杀伤缺陷是狼疮发展的最终共同途径，这是由于激活的自身反应性B细胞未完全消除，在CD4驱动的B细胞激活的背景下，允许自身抗体的产生持续并导致狼疮。这一范例在该应用程序中得到了直接测试。首席研究员的长期目标是开发一种治疗诱导内源性CTL的方案，该方案针对并消除激活的自身反应性B细胞作为狼疮患者的治疗。这个应用程序将建立这种方法所需的基本机制，并在Parent-Into-F1模型中测试几种有前景的策略。目的1.无论最初CTL缺陷的性质如何，确定CTL对自身反应性B细胞的清除受损是否是狼疮发生的最终共同途径。次级目标将评估穿孔素或Fas占主导地位。目的2.确定通过阻断下调来促进CTL寿命是否能预防狼疮。Fas、穿孔素、CD80、IL-2和宿主T细胞的作用将通过敲除小鼠或mAb阻断来测试。目的3.确定应用细胞因子促进CTL扩增是否能预防狼疮。这些实验使用了一种以细胞因子的形式给药的创新方法：延长体内生物活性的抗细胞因子抗体复合体。IL-15将作为非复杂细胞因子进行测试。子目标将确定肿瘤坏死因子、干扰素-g和白介素2在CTL效应器成熟过程中发挥关键作用的机制。项目叙事相关性。系统性红斑狼疮是一种自身免疫性疾病，会攻击主要器官系统，导致显著的发病率和死亡率，特别是在育龄妇女中。目前的治疗与显著的副作用有关。这项应用研究了一种利用自己的免疫系统来帮助控制疾病的新方法。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus is a multi-system disease with significant morbidity and mortality. Current treatment is associated with significant side effects. This application pursues the novel hypothesis that cytotoxic T lymphocytes (CTL) are an important early mechanism that limits breaks in tolerance to nuclear antigens and prevents lupus development by eliminating activated autoreactive B cells. This hypothesis is tested using the parent-into-F1 model in which lupus-like disease is induced in normal F1 mice by the transfer of parental strain CD4+ T cells. Lupus is not observed with the transfer of both CD4+ and CD8+ T parental cells due to donor CD8+ CTL elimination of activated autoreactive host B cells. During the previous funding period, the Principal Investigator observed that perforin deficient donor cells result in impaired CTL elimination of host B cells leading to lupus long term. These results support a new paradigm in which defects in CTL killing are a final common pathway in lupus development due to incomplete elimination of activated autoreactive B cells which, in the setting of CD4 driven B cell activation, allows autoantibody production to persist and result in lupus. This paradigm is directly tested in this application. The long-term goal of the Principal Investigator is to develop a protocol for therapeutic induction of endogenous CTL which target and eliminate activated autoreactive B cells as treatment in lupus patients. This application will establish the underlying mechanisms required for this approach and test several promising strategies in the parent-into-F1 model. Aim 1. Determine whether impaired elimination of autoreactive B cells by CTL is a final common pathway for the development of lupus regardless of the nature of the initial CTL defect. Sub-aims will evaluate whether perforin or Fas dominates. Aim 2. Determine whether promoting CTL longevity by blocking downregulation will prevent lupus. The role of Fas, perforin, CD80, IL-2 and host T cells will be tested using knock out mice or mAb blockade. Aim 3. Determine whether promoting CTL expansion by cytokine administration will prevent lupus. These experiments use an innovative method of TNF administration in the form of cytokine:anti-cytokine antibody complexes that prolongs biological activity in vivo. IL-15 will be tested as uncomplexed cytokine. Sub-aims will define the mechanisms by which TNF, IFN-g and IL-2 exert critical roles in the maturation of CTL effectors. Project Narrative Relevance. Systemic lupus erythematosus is an autoimmune disease that attacks major organ systems resulting in significant morbidity and mortality, particularly in women during their child bearing years. Current treatment is associated with significant side effects. This application examines a novel method of harnessing one's own immune system to help control disease.