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: 9393206
• 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/9393206
• 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; 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; Molecular Profiling; Monitor; Morbidity - disease rate; Nucleic Acids; Onset of illness; Organ; Parents; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Patient Outcomes Assessments; Patients; Peptides; Phenotype; Placebo Control; 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 抗疟疾药物研究是第一项针对不完全性红斑狼疮的预防研究 系统性红斑狼疮，随机分组 240 名具有自身抗体和至少一种临床症状的个体 狼疮的特征是接受羟氯喹 (HCQ) 或安慰剂来评估延迟或预防的能力 制定新的临床标准或过渡到分类 SLE。每季度对个人进行一次评估 狼疮或其他自身免疫性风湿病的新血清学或临床证据的发展，以及 获得标准样品。本申请中提出的辅助研究将利用资源 这项新颖的临床试验添加了分析测试特定所需的新关键样本 狼疮发病机制的假设并确定 HCQ 如何改变失调的潜在机制 人类自身免疫系统。本申请中的研究重点关注三个关键假设 已在现场建立并确认在疾病分类后在狼疮中发现，并将 确定哪些途径对疾病的发生和发病机制至关重要。存在自身抗体 几乎所有 SLE 患者都出现这种情况，并且通常发生在临床症状或疾病分类出现前数年。 使用新型基于芯片的自身抗原和肽阵列，实验将评估 HCQ 对 开发新的自身特异性，并确定多样化的程度和时机以应对 新的临床症状或 SLE 疾病分类的积累。干扰素表达增加 反应性基因在 SLE 中也很常见，并且与疾病活动性和自身抗体增加相关 生产。对军事和家庭收藏的系列样本进行回顾性分析的结果 随后患上狼疮的个体支持干扰素通路在疾病发生前失调 接近分类时出现最大增强。干扰素活性、全血基因特征、可溶性 介质和 TLR/干扰素刺激反应将在我们收集的系列样本中进行评估 该试验并根据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，以及这些反应随着额外干扰素的积累而发生的变化 将评估狼疮的临床特征。最后，自身抗体通过网状作用刺激干扰素产生 并将在新鲜的系列样本上测试低密度中性粒细胞的频率和功能，以确定 它们与狼疮症状发生的时间相关性。最后，血清学标记物组已被 回顾性分析中确定与 SLE 未来发病密切相关的药物将用这些进行测试 新可用的生物标志物集能够预测其他狼疮标准的积累，以及使用 这项研究的新数据可进一步提高识别 SLE 风险最高个体的能力 制定实施预防战略和/或进一步完善的生物学相关预防 试验。