Immunopathogenesis of Lupus

描述（由申请人提供）：系统性红斑狼疮是一种多系统疾病，发病率和死亡率较高。目前的治疗与严重的副作用有关。该申请追求新的假设，即细胞毒性T淋巴细胞（CTL）是限制对核抗原的耐受性的破坏并通过消除活化的自身反应性B细胞来防止狼疮发展的重要早期机制。使用亲本转化F1模型来检验这一假设，在该模型中，通过转移亲本株CD 4 + T细胞在正常F1小鼠中诱导狼疮样疾病。由于供体CD 8 + CTL消除了活化的自身反应性宿主B细胞，因此在转移CD 4+和CD 8 + T亲本细胞时未观察到狼疮。在之前的资助期间，主要研究者观察到穿孔素缺陷的供体细胞导致宿主B细胞的CTL消除受损，从而导致狼疮长期。这些结果支持了一种新的范例，其中CTL杀伤缺陷是狼疮发展中的最终共同途径，这是由于活化的自身反应性B细胞的不完全消除，在CD 4驱动的B细胞活化的情况下，其允许自身抗体产生持续并导致狼疮。在本应用程序中直接测试了此范例。主要研究者的长期目标是开发一种治疗性诱导内源性CTL的方案，其靶向并消除活化的自身反应性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，并在父母到F1模型中测试几个有前途的策略。目标1.确定CTL对自身反应性B细胞的清除受损是否是狼疮发展的最终共同途径，无论最初CTL缺陷的性质如何。子目标将评估穿孔素或Fas是否占主导地位。目标二。确定通过阻断下调来促进CTL寿命是否可以预防狼疮。Fas、穿孔素、CD 80、IL-2和宿主T细胞的作用将使用敲除小鼠或mAb阻断来测试。目标3。确定通过细胞因子管理促进CTL扩增是否会预防狼疮。这些实验使用了以细胞因子：抗细胞因子抗体复合物的形式施用TNF的创新方法，该复合物在体内抑制生物活性。IL-15将作为未复合的细胞因子进行检测。子目标将定义TNF、IFN-g和IL-2在CTL效应子成熟中发挥关键作用的机制。项目叙述相关性。系统性红斑狼疮是一种自身免疫性疾病，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。目前的治疗与严重的副作用有关。这个应用程序研究了一种利用自身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.