Mechanisms of Lupus Disease Transition and Hydroxychloroquine Immune Modulation

狼疮疾病转变和羟氯喹免疫调节的机制

• 批准号: 9762586
• 负责人: JUDITH A JAMES
• 金额: $ 46.07万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762586
• 关键词: Address; Agonist; Algorithms; American; Ancillary Study; Antigen Presentation; Antimalarials; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Biological; Biological Assay; Biological Markers; Blood; CXCL13 gene; Cause of Death; Cells; Cellular Immunology; Classification; Clinical; Clinical Trials; Collaborations; Collection; Connective Tissue Diseases; Critical Pathways; Data; Development; Diagnosis; Disease; Doctor of Philosophy; Epitopes; Evaluation; Event; Exhibits; Family; Flare; Foundations; Frequencies; Future; Gene Expression Profile; Gene Expression Profiling; Genes; Homeostasis; Human; Hydroxychloroquine; Immune; Immune system; Immunodiffusion; Immunofluorescence Immunologic; Immunologics; Immunophenotyping; Individual; Inflammatory; Innate Immune System; Interferons; Life; Lupus; Lupus Erythematosus; MMP9 gene; Measurement; Mediator of activation protein; Medical center; Military Personnel; Minority; Modeling; Monitor; Morbidity - disease rate; Nucleic Acids; Onset of illness; Organ; Parents; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Patient Outcomes Assessments; Patients; Peptides; Phenotype; Placebos; Plasma; Population; Prevention; Prevention strategy; Prevention trial; Process; Production; Protocols documentation; Publishing; Questionnaires; Randomized; Reporter; Research; Resources; Rheumatism; Risk; Sampling; Serological; Signal Transduction; Stem Cell Factor; Symptoms; System; Systemic Lupus Erythematosus; TIMP1 gene; Testing; Texas; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Treatment-related toxicity; United States; Universities; Whole Blood; Woman; Work; base; clinical investigation; clinical phenotype; cohort; density; disease classification; experimental study; extracellular; genetic signature; high risk; immune activation; immunoregulation; improved; middle age; mortality; neutrophil; new therapeutic target; novel; patient subsets; pre-clinical; prevent; prospective; response; screening; secondary outcome; systemic autoimmune disease; young woman

The Study of anti-Malarials in Incomplete Lupus Erythematosus or SMILE is the first prevention study for systemic lupus erythematosus, randomizing 240 individuals with autoantibodies and at least one clinical feature of lupus to receive either hydroxychloroquine (HCQ) or placebo to assess the ability to delay or prevent the development of new clinical criteria or transition to classified SLE. Individuals are assessed quarterly for development of new serologic or clinical evidence of lupus, or other autoimmune rheumatic diseases, and standard samples are obtained. The ancillary studies proposed in this application will leverage the resources from this novel clinical trial with the addition of new critical samples required for analyses to test specific hypotheses of lupus pathogenesis and to identify potential mechanisms of how HCQ modifies the dysregulated autoimmune system in humans. The studies within this application focus on three critical hypotheses which have been established and confirmed in the field to be found in lupus after disease classification and will establish which of these pathways are critical to disease onset and pathogenesis. Autoantibodies are present in nearly all SLE patients and often occur years before the onset of clinical symptoms or disease classification. Using novel chip-based autoantigen and peptide arrays, experiments will assess the impact of HCQ on development of new autospecificities, and determine the degree and timing of diversification in response to accumulation of new clinical symptoms or SLE disease classification. Increased expression of interferon responsive genes is also common in SLE and associated with increased disease activity and autoantibody production. Results from retrospective analyses of serial samples from military and family collections of individuals who subsequently develop lupus support that interferon pathways are dysregulated before disease onset with greatest enhancement near classification. Interferon activity, whole blood gene signatures, soluble mediators and TLR/interferon stimulated responses will be assessed in the serial samples we will collect from this trial and analyzed in relation to the detailed protocol-driven clinical phenotyping. The influence of HCQ on these interferon responses, as well as the changes in these responses with the accumulation of additional lupus clinical features, will be assessed. Finally, autoantibody stimulated interferon production through netosis and the frequency and function of low density neutrophils will be tested on fresh serial samples to determine their temporal association with lupus symptom accrual. Finally, serologic sets of markers which have been identified to associate strongly with future onset of SLE in retrospective analyses will be tested with these newly available biomarker sets for the ability to predict accumulation of additional lupus criteria, as well as use the new data from this study to further refine the ability to identify individuals at the highest risk of SLE development for implementation of prevention strategies and/or further refined, biologically-relevant prevention trials.

不完全性红斑狼疮或SMILE的抗疟药研究是首个针对 系统性红斑狼疮，随机选择240名自身抗体和至少一种临床 接受羟氯喹（HCQ）或安慰剂以评估延迟或预防狼疮的能力 制定新的临床标准或向SLE分类过渡。每季度对个人进行评估， 出现狼疮或其他自身免疫性风湿性疾病的新血清学或临床证据，以及 获得标准样品。本申请书建议的辅助研究会善用资源， 从这项新的临床试验中增加了分析所需的新的关键样本，以检测特定的 狼疮发病机制的假设，并确定HCQ如何改变失调的潜在机制， 人体自身免疫系统本申请中的研究集中在三个关键假设上， 已经建立并证实在该领域被发现的狼疮疾病分类后， 确定这些途径中哪些对疾病发作和发病机理至关重要。存在自身抗体 几乎在所有SLE患者中，并且经常发生在临床症状或疾病分类开始前数年。 使用新的基于芯片的自身抗原和肽阵列，实验将评估HCQ对免疫应答的影响。 发展新的自身特异性，并确定多样化的程度和时间，以应对 新的临床症状或SLE疾病分类的累积。干扰素表达增加 应答基因在SLE中也很常见，并与疾病活动性和自身抗体增加有关。 生产来自军队和家庭收集的系列样本的回顾性分析结果 随后发生狼疮的个体支持干扰素通路在疾病前失调 在接近分类时出现最大增强。干扰素活性，全血基因签名，可溶性 将在我们将收集的系列样品中评估介质和TLR/干扰素刺激的反应， 这项试验并结合详细的方案驱动的临床表型进行分析。HCQ的影响 这些干扰素反应，以及这些反应的变化与额外的积累， 狼疮临床特征，将进行评估。最后，自身抗体通过内毒素刺激干扰素的产生 低密度中性粒细胞的频率和功能将在新鲜的系列样本上进行测试，以确定 它们与狼疮症状累积的时间关联。最后，血清学标志物集， 在回顾性分析中确定与SLE未来发作密切相关的患者，将使用这些 新的可用的生物标志物集，用于预测额外的狼疮标准的积累的能力，以及使用 这项研究的新数据进一步完善了识别SLE高危个体的能力 制定实施预防战略和/或进一步完善与生物相关的预防措施 审判