Immunopathogenesis of Lupus

狼疮的免疫发病机制

• 批准号: 7380239
• 负责人: Charles S. Via
• 金额: $ 38.48万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7380239
• 关键词: Acute; Adverse effects; Antibodies; Autoantibodies; Autoimmune Diseases; B-Cell Activation; B-Lymphocytes; Biological; CD4 Positive T Lymphocytes; CD80 gene; CD8B1 gene; Cells; Clinical; Clonal Expansion; Collaborations; Complex; Cytotoxic T-Lymphocytes; Defect; Development; Disease; Disease model; Down-Regulation; Engraftment; Exhibits; Funding; Goals; Human; Immune Complex Glomerulonephritis; Immune system; Impairment; Interferon Type II; Interleukin-15; Interleukin-2; Knockout Mice; Ligands; Longevity; Lupus; Lymphocyte Function; Methods; Modeling; Morbidity - disease rate; Mus; Nature; Nuclear Antigens; Onset of illness; Parents; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Prevention; Principal Investigator; Production; Protocols documentation; Receptors, Antigen, B-Cell; Role; Serum; Surrogate Markers; System; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Week; Woman; Work; autoreactive B cell; body system; child bearing; cytokine; cytotoxic; day; disorder control; graft vs host disease; human TNF protein; in vivo; innovation; killings; mortality; novel; novel therapeutics; perforin; prevent; research study; response

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.

描述（申请人提供）：系统性红斑狼疮是一种发病率和死亡率高的多系统疾病。目前的治疗有明显的副作用。该应用程序追求新的假设，即细胞毒性T淋巴细胞（CTL）是一个重要的早期机制，通过消除活化的自身反应性B细胞来限制对核抗原的耐受性中断，并防止狼疮的发展。这一假设通过亲本转入F1模型得到了验证，在该模型中，通过亲本株CD4+ T细胞的转移在正常F1小鼠中诱导狼疮样疾病。由于供体CD8+ CTL消除活化的自身反应性宿主B细胞，因此没有观察到狼疮与CD4+和CD8+ T亲本细胞的转移。在之前的资助期间，首席研究员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，导致狼疮长期存在。这些结果支持了一种新的范式，即由于活化的自身反应性B细胞不完全消除，CTL杀伤缺陷是狼疮发展的最终共同途径，在CD4驱动的B细胞活化的设置下，允许自身抗体持续产生并导致狼疮。此范例在此应用程序中直接进行了测试。首席研究员的长期目标是开发一种治疗性诱导内源性CTL的方案，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方法。此应用程序将建立此方法所需的底层机制，并在parent-into-F1模型中测试几种有前途的策略。目的1。无论初始CTL缺陷的性质如何，确定CTL对自身反应性B细胞的消除受损是否是狼疮发展的最终共同途径。子目标将评估是穿孔还是Fas占主导地位。目标2。确定通过阻断下调促进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单抗阻断来检测。目标3。观察细胞因子促进CTL扩增是否能预防狼疮。这些实验采用了一种以细胞因子形式给药TNF的创新方法：抗细胞因子抗体复合物，延长体内生物活性。IL-15将作为非复杂细胞因子进行检测。子目标将定义TNF， IFN-g和IL-2在CTL效应物成熟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，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。目前的治疗有明显的副作用。本应用研究了一种利用自身免疫系统来帮助控制疾病的新方法。